1 15 8 https://www.nal.usda.gov/exhibits/speccoll/files/original/3274dbae34e5de29e5c13b745ec55253.pdf 327ada61ba22f79e99d99f056952068b PDF Text Text Item ID Number 01353 Houk, Vernon N. Corporate Author Report/ArtidO TltlO Memorandum: to Ronald W. Hart, Chairman, Science Panel, Agent Orange Workinh Group (AOWG), from Vernon N. Houk, Assistant Surgeon General, with subject Protocol for Women's Vietnam Veterans Health Study, September 10,1987 Journal/Book Title Year 000 ° Month/Day Color D Number of Images 4 DOSCrlptOn NOtBS Memo discusses concerns that Houk has about the study protocol. He wants the concerns addressed before he will be willing to support conduct of the study. Wednesday, July 11, 2001 Page 1854 of 1870 �DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Centers for Disease Control Memorandum Date .September 10, 1987 From Director Center for Environmental Health and Injury Control Subject Protocol for Women's Vietnam Veterans Health Study To Ronald W. Hart, Ph.D., Chairman, Science Panel Agent Orange Working Group We have reviewed the Women's Vietnam Veterans Health Study Protocol submitted by the Hew England Research Institute, Inc. We have serious concerns about this submission which we have listed below. Until these concerns are adequately addressed, I cannot support conduct of the proposed study. Detailed below are comments on the protocol for the Women's Veteran Health Study. A. Cohor^ Selection 1. Unlike the Vietnam Experience Study, there are differences between the exposed group and the comparison groups in variables other than experience in Vietnam. The presence of such differences increases potential confounding and complicates the analyses. Would it be more satisfactory to limit the scope of the study and the selection of a comparison group (e.g., Limit, the study to army cases and controls) to address the most important hypotheses rather than try to do too much? 2. It is not clear how the VA developed its list of 5000 Army Vietnam veterans—how complete is this list? How complete are the lists of Vietnam veterans in the other services? 3. The sampling frame for the non-Vietnam veterans is not clearly described. 4. How valid is their proposed capture-recapture method as a method of documenting the completeness of the cohorts. 5. What duty stations will women veterans for Cohort B come from? Will the Air Force sample of nurses be large enough for separate comparisons? 6. pages 2-3: What does matched on occupation mean and how will this be possible? 7. Consideration might be given to increasing the number of controls (per case) in the overall study, especially in some of the proposed substudies (e.g., reproductive health). �Page 2 - Ronald W. Hart, Ph.D. B. Reproductive Health 1. The expectation is to find major birth defects in 1% of offspring; a more appropriate expectation is 2-3%. It would be wise to compile a list of specific defects which are to be considered "major" before the study begins. 2. Cases are defined as women who have had a baby with a defect or "two or more spontaneous abortions not clearly attributable to an identified cause." They propose excluding those with an 1 "unequivocal karyotypic abnormality", and those with a uterine abnormality. Exclusion of women who themselves have a tcaryotypic abnormality seems reasonable, but it is unlikely that any will be found in the sample. If the reference implies that aborted fetuses that have a karyotypic abnormality will be excluded, this is not reasonable. An abortion associated with a chromosomal anomaly is a health outcome worth considering in the study. In general, more details are needed on why certain diseases/conditions are being excluded. 3. Spontaneous abortions will be difficult to validate since they are frequently not medically documented. 4. It is stated that women with diethylstilbesterol (DBS) exposure would be kept in the sample. We would suggest exclusion since they are excluding spontaneous abortions associated with uterine abnormality, and DES exposed women have a higher rate of abortion, usually from uterine abnormality. 5. We would suggest matching controls on age at the last abnormal pregnancy, rather than the first. Spontaneous abortion is strongly related to age and a woman's pregnancies may be separated by many years. 6. At the time this study will be done, most women Vietnam veterans will be 40 or more years of age. Therefore the evaluation of prolonged amenorrhea should probably be deleted from the study. 7. A definition of fertility/infertility is needed. C. PsycholoRical/KeuropsychoIoRical TestinR 1. The proposal to use the CDC Vietnam Experience Study (VES) neuropsychological battery is inappropriate. That battery was designed to assess primarily neuropsychological deficits which might be expected from exposure to a toxin (e.g. TCDD). The battery also included some assessment of psychological and neuropsychological problems that might be related to stress. �Page 3 - Ronald W. Hart, Ph.D. This latter component is not included (as far as we can tell) in the present protocol. Since TCDD exposure is unlikely to have been a major problem for most nurses in Vietnam, it would probably be better to give greater emphasis to long-term psychological stress faced by these veterans while in Vietnam. This would mean that the proposed battery should include some measures of stress which have been well validated and accepted in psychological research. ' In addition, greater emphasis should be given to depression, anxiety, and alcohol and drug use, which are possible sequelae of stress. Also, consideration should be given to including the Minnesota Multiphasic Personality Inventory (MMPI), and more of the Diagnostic Interview Schedule (DIS) than just the Post Traumatic Stress Disorder (PTSD) section. 2. Another concern in the psychological area is the testing in the home of the participant. The VES battery was designed to be administered in a standard testing environment by trained technicians under close supervision. Quality control and standardization will be difficult in the proposed setting. 3. The rationale for measurement of TCDD levels in the PTSD substudy needs further clarification/justification. 4. With respect to the psychological area in general, we suggest that advice be sought from experts in psychology/psychiatry to evaluate the proposed psychological test battery. In addition, staffing for the study should include a qualified psychologist or psychiatrist. D. Serum. Dioxin (TCDD) Measurement 1. The whole issue of Agent Orange exposure assessment/TCDD testing becomes questionable now that the results of CDC's Validation Study are known. If TCDD testing is to be done, is a whole unit of blood necessary—if willing to accept some cut-off level (e.g. 20 ppt) less blood may be required. Also, if TCDD testing is to be done, consideration should be given to using a sample of Vietnam and non-Vietnam veterans—based on the results of a sample, a decision could be made about testing other participants. 2. Serum TCDD measurements are to be used as the measure of exposure for both the Reproductive Outcomes Study and the Post Traumatic Stress Disorder Study. Apparently about 550 serum analyses will be needed for these two studies combined. The current proposal does not involve flying the participants to a centralized collection center but rather using local Red Cross Centers on contract. These approximately 550 women will be located all over �Page 4 - Ronald U. Hart, Ph.D. the United States and the Red Cross is not even present in every state, so obtaining the samples solely in this manner will not be possible. A very large number (>100) of Red Cross contracts will be involved to obtain blood on persons near a Red Cross Center under the current plan. The use of at least regional Red Cross Centers would be a marked improvement and the quality of sample acquisition would be significantly higher if only a few (even one) Red Cross Center(s) were used. 3. T|he cost of the serum 2,3,7,8-TCDD measurement should be noted to be $1000 apiece. Currently the protocol states that EHLS is the only lab in the U.S. that can perform the measurements, but clearance for such measurements at EHLS has not been obtained. Similarly, has the American Red Cross been approached as to their willingness to participate in this study? E. Operational and Other Issues 1. The protocol anticipates a fair amount of dependence on both interviews and military records. What are the limitations of these data in terms of the questions addressed (e.g., ascertainment of spontaneous abortions by history)?. 2. The authors do not provide information on how they propose to address the issue of name changes in female veterans and the difficulties this might cause in locating these veterans. 3. The operational aspects of the pediatric examination component are not clearly described. Has the Ranch Hand Study been successful in this area? What end points will be looked at and analyzed? 4. The choice of conditions to be validated might be expanded to include same conditions which have been suggested to be associated with TCDD exposure—e.g. skin conditions (chloracne, hyperpigmentation, etc.), liver disorders including prophyria, peripheral neuropathy, immunologic deficits. 5. Quality control of the physical and routine laboratory examinations must be assured. 6. Has adequate effort been made to insure that the medical records and pathology slides will be reviewed in a blinded manner? 7. What efforts are being made to insure quality assurance and quality control of hormone blood testing? Vernon H. Houk, M.D. Assistant Surgeon General � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 069 Folder The folder containing the original item. 1853 Series The series number of the original item. Series III Subseries III Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Houk, Vernon N. Title A name given to the resource Memorandum: to Ronald W. Hart, Chairman, Science Panel, Agent Orange Working Group (AOWG), from Vernon N. Houk, Assistant Surgeon General, with subject Protocol for Women's Vietnam Veterans Health Study, September 10, 1987 Subject The topic of the resource Women Vietnam Veterans Health Study study criticism study protocol dioxin ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/3dc38971d5bafbf104b4eebc59aea4d4.pdf bfe42feb88369199f8ae7bb9357e05e5 PDF Text Text ItBnUDNimbor °1852 Author McKlnlay, Sonja M. Corporate Author New ROpOrt/ArtldB TltlO Women England Research Institute, Inc., Watertown, Mass 's Vietnam Veterans Health Study Protocol Development, Summary Report of Expert Panel Review, Deliverable E Journal/Book HUB Year 000 ° Month/Day Color a Number of hnaoos 25 DBSCriptOn NOtBS Contract No. V101(93)P-1138 Wednesday, July 11, 2001 Page 1853 of 1870 �WOMEN'S VIETNAM VETERANS HEALTH STUDY PROTOCOL DEVELOPMENT CONTRACT NO. V101(93)P-1138 SUMMARY REPORT OF EXPERT PANEL REVIEW DELIVERABLE E SUBMITTED BY NEW ENGLAND RESEARCH INSTITUTE, INC. PRINCIPAL INVESTIGATOR SONJA M. MCKINLAY, Ph.D. NEW ENGLAND RESEARCH INSTITUTE, INC. 42 Pleasant Street Watertown, Massachusetts 02 i 72 (617)923-7747 �TABLE OF CONTENTS INTRODUCTION 1 SECTION 1: LITERATURE REVIEW 2 SECTION 2 : STUDY DESIGN 3 2 .1 COHORT DESIGN AND SUB-STUDIES 3 2.2 VIETNAM EXPERIENCE (VE) EXPOSURE COMPONENTS 8 2. 3 POPULATION DEFINITION AND SAMPLE SIZES 8 2. 4 GENERAL HEALTH OUTCOMES 9 2. 5 REPRODUCTIVE OUTCOMES SECTION 3 : QUESTIONNAIRE 3 .1 3. 2 TABLE 3.3 REPRODUCTIVE FUNCTION/OUTCOME MISCELLANEOUS SUGGESTIONS EXPERT PANEL COMPOSITION EXPERT PANEL AFFIDAVITS 10 11 11 12 14 16 �INTRODUCTION A key task under the current contract was the formation of an Expert Panel of Consultants who would review the following final products: • Literature Review; • Study Design; and • Questionnaire As proposed, NERI expanded this mandated function to include review of preliminary drafts and participation in a one day discussion including prepared written comments on specific assignments. Finally, the Technical Representative (Dr. H. Kang) requested written affidavits indicating acceptance, by panel members, of the final products. The following sections include a summary of input on the Literature Review (Section 1), a summary of input on the Study Design (Section 2) and on the Questionnaire (Section 3). A final section lists the panel members and their areas of expertise, includes copies of the panel assignments for the one day review and affidavits accepting the Study Design and Questionnaire submitted to the VA as final products. �1. LITERATURE REVIEW A draft of the Literature Review was sent to panel members for review and verbal or written comments in January, 1987. Apart from clarification of some ambiguous statements, the primary input was in the form of additional key references which were very recently published or in press. This input was exactly what was desired. Panel members were clearly at the forefront of important areas of research, including phenoxy herbicides, nursing exposures and reproductive toxicology in particular. Interestingly, one important occupational exposure not included in the original review and not raised by the panel was hexachlorophene - a major occupational exposure for nurses in the study period, which also has TCDD as a contaminant in its manufacture. This exposure was identified through two sources: a senior staff member at CDC (personal communication) and the updated report of the NIOSH Occupational Dioxin Registry (Fingerhut et al, 1985). A review of this potentially confounding occupational exposure is included in the final products as an Addendum to the Literature Review. �2. STUDY DESIGN Substantial input was obtained from panel members in the following forms: • written comments submitted for the one day meeting; • verbal comments at the meeting; and • verbal or written comments on a subsequently revised document. For clarity, comments and decisions will be summarized under the following sub-headings: • Basic cohort design and sub-studies; • VE exposure components; • Population definintion and sample size; • General health outcomes; and • Reproductive outcomes. 2.1 COHORT DESIGN AND SUB-STUDIES (a) Cancer Case/Control Study The originally proposed case/control study of cancers was deleted from the study design after the following comments and issues were reviewed and discussed: �1. The inclusion of all cancers was considered insensitive to TCDD exposure. Reference was made to the SEER (NCI) data which included better incidence data with which to estimate expected numbers of relevant cancers (Soft Tissue Sarcoma, Hodgkin's Disease and Non-Hodgkin's Lymphoma). 2. Risk factors (confounders) would differ for each cancer site. 3. The inclusion of cancer cases and controls from Cohort B, which will not have been exposed to TCDD (at least to the same degree) was considered noninformational, given the aim of this substudy to investigate associations between cancer and TCDD exposure. 4. Debilitation and therapy in cancer cases will affect both immune status (one of the intervening variables to be measured) and body fat available for TCDD determinations. As suggested by panel members, the expected number of STS, HD and NHL cancer cases combined was subsequently estimated as 30 for both cohorts combined, using SEER data (NCI, 1987) . These numbers were too small for a case/control study to be feasible. Congenital Abnormality Case/Control Study The case/control study of congenital abnormalities was generally well-received as an important sub-study. The following issues were raised in its design: �1. The study should be restricted to Cohort A (VEexposed subjects). 2. The detection of abnormality in aborted fetuses was considered problematic - not all hospital records would include sufficient details. Rather, panel members recommended including only abnormalities detected in live born offspring. 3. The suggestion was made during discussion to include spontaneous abortions as the other adverse reproductive outcome for this case/control study. This last suggestion was further modified to include only multiple abortions (2+) with no clear cause, as otherwise numbers for this sub-study would have been too large. 4. The suggestion was made to use information on the half-life of TCDD in adipose tissue (if available) to estimate TCDD body burden at conception. (c) Nurses Sub-Study Because nurses are expected to comprise at least 85% of the Cohorts, this sub-study was seen by panel members as perhaps the main study. A lively discussion developed out of which a consensus was obtained that emphasis should be on as homogeneous a group as possible. The decision was therefore made to restrict this substudy to Army nurses from both cohorts. �Further discussion centered on the desirability of a civilian control group in order to unconfound, as much as possible, the basic nursing occupational exposures. This was a major concern given that nurses in Cohort B were also exposed to unique stresses of caring for wounded Vietnam veterans. Subsequent discussions with Dr. Kang on this issue of a third control group produced the alternative proposal from Dr. Kang to include Air Force nurses in Cohort B as a third, relatively unexposed group. This suggestion was also incorporated in the final design. (d) PTSD Sub-Study There was discussion at the one day meeting concerning the possibility of investigating PTSD, its relation to neuro-behavioral functioning and TCDD exposure. The final PTSD sub-study resulted from this discussion. (e) Validation Sub-Studies The following recommendations were made concerning validation of key outcomes: • It was strongly recommended that pathology slides be obtained to validate at least the following cancers - STS, HD, NHL. Early amenorrhea (< 40 years) should be verified with FSH levels. �Records should be obtained (or at least releases to obtain them) for all major diagnoses, "even if all are not verified immediately. Members of the panel also felt that pediatric examination of all congenital abnormalities may not be necessary. Rather record verification with examination of a small sub-sample may be sufficient. The operative note is the most important source for verifying endometrial pathology, rather than the pathology report and should be obtained, if possible. Results of pelvic examination were inadequate validation evidence for endometriosis. Pathology reports should be obtained for all induced abortions. (f) Mortality Study An originally proposed analytic study of deaths in both cohorts was considered not very informative as outlined and somewhat duplicative of the VA Mortality Study in progress. At the same time, it was generally considered essential to include deaths as outcomes in as many analyses as possible, to minimize bias. The final approach proposed involves analysis of primary data sets with and without deceased cohort members included. �2.2 VIETNAM EXPERIENCE (VE) EXPOSURE COMPONENTS There was protracted discussion of VE exposure components and the following points were made (and incorporated in revisions): • Exposure to TCDD and to phenoxy herbicides should be kept distinct, conceptually as there are no satisfactory direct measures of phenoxy herbicide exposure; • Emphasis should be on VE as a whole and exposure to phenoxy herbicides (TCDD); • An attempt should be made to obtain some data on use of insect repellents, even if detailed insecticide exposure is not available; and • The panel members were intrigued with the availability of workload data in the Chief Nurses' Reports and encouraged the extraction and use of such information for the final study. All of these recommendations were incorporated into the final Study Design. 2.3 POPULATION DEFINITION AND SAMPLE SIZES The panel considered that, given the difficulties in obtaining lists with current contact information, use of the VA Mortality Study lists was an acceptable compromise. At the same time the panel members urged that: �1. The sampling design used in compiling the lists be documented; 2. The adequacy (coverage) of the lists (especially for Cohort B) be verified during the Phase II study. Both of these recommendations were incorporated into the final design. With respect to sample size, there was some discussion concerning whether Cohort A constituted a sample or a population. If the emphasis is on generalization to women Vietnam veterans only, then Cohort A is a population and no sampling variation is estimable for this cohort. If the emphasis is on women Vietnam veterans as a sample of women potentially exposed to VE (or its equivalent) then Cohort A is a sample. The consensus was that Cohort A should be considered as a sample and smallest detectable relative risks calculated on this assumption. This consensus is reflected in the final study design. 2.4 GENERAL HEALTH OUTCOMES All the proposed health outcomes were reviewed by the panel and the following recommendations made: • Those cancers likely to be misclassified as organspecific when they are, in fact, STS should be included for record review; and • There should be emphasis on Post Traumatic Shock Disorder (PTSD) and selected other health outcomes. These were incorporated into the final design. �2.5 REPRODUCTIVE OUTCOMES Following panel recommendations this class of outcomes was sub-divided as follows: 1. Reproductive Function; menstrual (ovulatory) function without conception, including measures of infertility, risk factors for anovulatory or irregular cycles, presence of pelvic infection (including sexually transmitted disesases - STD's Tuberculosis of the Pelvis and other Pelvic Inflammatory Disease) and prolonged periods of amenorrhea. 2. Adverse Reproductive Outcome; this includes selected adverse outcomes of conception (major congenital abnormality, multiple spontaneous abortion). The panel also recommended that emphasis be given to adverse reproductive function and conception outcomes in the study. 10 �3. QUESTIONNAIRE The Expert Panel had several suggestions for question content and wording. Most of them were in the areas of reproductive function and outcome (Section 3.1) with some additional miscellaneous suggestions (Section 3.2). 3.1 REPRODUCTIVE FUNCTION/OUTCOME The following specific suggestions were made: (a) Emphasis was placed on obtaining menstrual histories from menarche onwards, to include an assessment of menstrual function (cycle length, regularity etc.) before the exposure period. (b) Certain menstrual symptoms/events are good predictors of ovulatory cycles. In particular, ovulating women are more likely to experience cramps or other pre-menstrual symptoms, while clotting is associated with anovulatory cycles. (c) Benign breast and uterine pathology are more likely in anovulatory women and should be recorded under diagnoses as another measure of probable reduced fertility. (d) Because this is a retrospective longitudinal study, rather than cross-sectional, the definition of infertility used on the National Center for Health Statistics National Survey of Family Growth had to be carefully adapted, using a different set of questions. It was also recommended that subjects be asked directly if they had difficulty conceiving for 11 �a period of at least twelve months of attempting to conceive. (e) Pregnancy complications (toxemia etc.) could be omitted from the pregnancy history. (f) Birth weight and length of gestation should be included as outcome variables. (g) A standard list of occupational exposures for adverse reproductive outcomes should be included. These suggestions were reviewed and revisions made to the questionnaire to accommodate them. 3.2 MISCELLANEOUS SUGGESTIONS An excellent suggestion which was incorporated into the questionnaire was the addition of questions on knowledge of and access to VA services offered to women veterans. The motivation was to help diffuse the focus of the study and was in keeping with this being a Women Veterans Health Study. A further suggestion which was considered carefully was the possibility of sending out to subjects a selfadministered questionnaire (SAQ) on some of the standard histories (pregnancy, contraceptive, military, occcupational, marital) before the telephone interview. This would prepare the subject and give her a framework within which to refresh her memory. After reviewing pre-testing experience, it was decided not to use a SAQ before the telephone interview for the following reasons: 12 �1. subjects were able to remember and complete the histories in a timely fashion; and 2. there was concern that subjects would share this information with other veterans eligible for study, before they were interviewed, increasing the potential for either non-response and/or bias in prepared answers later in the study. 13 �TABLE 3.3 EXPERT PANEL COMPOSITION Affiliation Areas of Expertlee (Reference N . \ ' o)" R. Clapp, MPH Director, Massachusetts Cancer Registry Mass. Dept. Health Boston, MA Agent Orange Exposure Vietnam Veterans (Mass.) Study Occupational/Environmental Exposure Studies T. Colton, ScD School of Public Health Boston University Boston, MA Epidemiologic Methods and Statistical Analysis Agent Orange/Vietnam Veterans Studies Dept. Reproductive Medical Management of Reproductive Health Problems Reproductive Epidemiology A. Haney, MD Medicine Duke University Durham, NC M. Hatch, PhD School of Public Health Columbia University New York, NY D. Mattison, MD Dept. of Ob/Gyn Reproductive Toxicology Div. Reproductive Pharm. and Toxicology University of Arkansas Little Rock, AK D. Ozonoff, MD, MPH School of Public Health Boston University Boston, MA Reproductive Epidemiology Occupational/Environmental Epidemiology Z. Stein, MA, MB, BCh Director, Epidemiology Psydliatric Epidemiology of Brain Disorders Rsch Agent Orange/Exposure Studies NY State Psychiatric inst Dept. Epidemiology Columbia University New York, NY 14 �WOMEN VIETNAM VETERANS HEALTH STUDY PROTOCOL DEVELOPMENT CONTRACT NO. V101(93)P-1138 EXPERT PANEL REVIEW ASSIGNMENT REVIEW Area for Review Reviewer Secondary; Reviewer 1. Phenoxy Herbicide Exposure (definition and measurement) R. Clapp D. Mattison D. Ozonoff. 2. Other VE Exposure (definition and measurement) M. Hatch A. Haney D. Ozonoff 3. General (incl. Mental) Health Outcomes (definition and measurement) Z. stein M. Hatch D. Ozonoff 4. Reproductive Health Outcomes (definition and measurement) A. Haney D. Mattison M. Hatch 5. Reproductive Outcomes D. Mattison A. Haney 6. Design Approach and Sample Size T. Colton D. Ozonoff R. Clapp 7. Population Definition R. Clapp T. Colton Z. Stein (definition and measurement) 15 �EXPERT PANEL 16 A F F I D A V I T S �NEW ENGLAND RESEARCH INSTITUTE, INC. I have reviewed the final study design and questionnaire for the proposed Women's Vietnam Veterans Health Study and my recommendation is as follows (check one option and add any comments): V I approve the design and questionnaire as presented, with no further modi jti cat ions. Any concerns have been clarified by telephone. I do not approve the design and questionnaire as presented. It will require the following revisions to meet with my approval: NAME i 42 Pleasant Street Watertown, Massadiusetts 02172 (617)923-7747 SIGNATURE 0 /L // DAfE �NEW ENGLAND RESEARCH INSTITUTE, INC. I have reviewed the final study design and questionnaire for the proposed Women's Vietnam Veterans Health Study and my recommendation is as follows (check one option and add any comments): I approve the design and questionnaire as presented, with no further modifications. Any concerns have been clarified by telephone. I do not approve the design and questionnaire as presented. It will require the following revisions to meet with my approval: It cru. V -72W NAME 42 Heasant Street Watertown, Massachusetts 02172 (617)923-7747 SMWATURE DAI �NEW ENGLAND RESEARCH INSTITUTE, INC. I have reviewed the final study design and questionnaire for the proposed Women's Vietnam Veterans Health Study and my recommendation is as follows (check one option and add any comments): I approve the design and questionnaire as presented, with no further modifications. Any concerns have been clarified by telephone. I do not approve the design and questionnaire as presented. It wall require the following revisions to meet with my approval: -5WL-V NAME SIGNATURE7T 42 Pleasant Street Watertown, Massachusetts 02172 (617)923-7747 �NEW ENGLAND RESEARCH INSTITUTE, INC. I have reviewed the final study design and questionnaire for the proposed Women's Vietnam Veterans Health Study and my recommendation is as follows (check one option and add any comments): Llit; design and questionnaire as presented, with no further modifications. Any concerns have been clarified by telephone. I do not approve the design and questionnaire as presented. It will require the following revisions to meet with my approval: NAME SIGNATURE 42 Pleasant Street Watertown, Massachusetts 02172 (617)923-7747 DATE �NEW ENGLAND RESEARCH INSTITUTE, INC. I have reviewed the final study design and questionnaire for the proposed Women's Vietnam Veterans Health Study and my recommendation is as follows (check one option and add any comments): f- . v I approve the design and questionnaire as presented, with no further modifications. Any concerns have been clarified by telephone. I do not approve the design and questionnaire as presented. It will require the following revisions to meet with my approval: Dr. Donald Mattison NAME £ t]_ _ S I G N A T U R E D A T E 42 Pleasant Street Watertown, Massachusetts 02172 (617)923-7747 �NEW ENGLAND RESEARCH INSTITUTE, INC I have reviewed the final study design and questionnaire for the proposed Women's Vietnam Veterans Health Study and my recommendation is as follows (check one option and add any comments): ^ I approve the design and questionnaire as presented, with no further modifications. Any concerns have been clarified by telephone. I do not approve the design and questionnaire as presented. It will require the following revisions to meet with my approval: SIGNATURE -' 42 Pleasant Street Watertown, Massachusetts 02172 (617)923-7747 DATE �NEW ENGLAND RESEARCH INSTITUTE, INC. I have reviewed the final study design and questionnaire for the proposed Women's Vietnam Veterans Health Study and my recommendation is as follows (check one option and add any comments): I approve the design and questionnaire as presented, with no further modifications. Any concerns have been clarified by telephone. I do not approve the design and questionnaire as presented. It w.ill require the following revisions to meet with my approval: Zena Stein. M.B.. B.Ch. NAME 42 Pleasant Street Watertown, Massachusetts 02172 (617)923-7747 II T —/ SIGNATURE /****t *1^ � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 069 Folder The folder containing the original item. 1852 Series The series number of the original item. Series III Subseries III Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource McKinlay, Sonja M. Description An account of the resource <strong>Corporate Author: </strong>New England Research Institute, Inc., Watertown, Massachusetts Title A name given to the resource Women's Vietnam Veterans Health Study Protocol Development, Summary Report of Expert Panel Review, Deliverable E Subject The topic of the resource Women Vietnam Veterans Health Study study criticism VA ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/0117810a1dd04d0c2ca086381b0258ad.pdf bf5b5daab295968fbd054a1b10d4f681 PDF Text Text Item ID Number °1851 Author McKinlay, Sonja M. Corporate AllthOT New England Research Institute, Inc., Watertown, Mass RODOrt/ArtldB Tltlfl Women's Vietnam Veterans Health Study Protocol Development, Study Design and Protocol, Appendices, Deliverable D Journal/Book Title Year 000 ° Month/Day Color n Number of Images 253 DOSCrlptOn NOtBS Contract No. V101 (93)P-1138 Wednesday, July 11, 2001 Page 1852 of 1870 �WOMEN VIETNAM VETERANS HEALTH STUDY PROTOCOL DEVELOPMENT CONTRACT NO. V101(93)P-1138 STUDY DESIGN AND PROTOCOL APPENDICES DELIVERABLE D SUBMITTED BY NEW ENGLAND RESEARCH INSTITUTE PRINCIPAL INVESTIGATOR SONJA M. MCKINLAY, PH.D NEW ENGLAND RESEARCH INSTITUTE, INC. 42 Pleasant Street Watertown, Massachusetts 02172 (617)923-7747 �STUDY DESIGN PROTOCOL APPENDICES DELIVERABLE D 1. INFORMED CONSENT AND RELEASE FORMS 2. CONGENITAL ABNORMALITY CLASSIFICATION AND PEDIATRIC EXAMINATION 3. MYOCARDIAL INFARCTION, SUDDEN DEATH AND STROKE CLASSIFICATION 4. NEUROBEHAVIORAL TESTING PROTOCOL 5. SOFT TISSUE SARCOMA CLASSIFICATION 6. PROTOCOL FOR 2, 3, 7, 8 - TCDD BODY BURDEN DETERMINATION �INFORMED AND CONSENT RELEASE FORMS �WOMEN VETERANS HEALTH STUDY date Name Street Address City, State, Zip Dear As part of the "Women Veterans Health Study" sponsored by the Veterans Administration, we are interested in obtaining complete medical records on your hospitalizations which include some more technical information that is needed for the study. As we told you over the telephone, in order to do that we need to obtain a signed authorization form from you first. Could you please help us by signing the enclosed authorization form and returning it to us in the enclosed envelope as soon as possible. You may be assured that the information will be kept confidential and will be used only in completing the review of your record. We will be most grateful for your cooperation. Sincerely yours, Contractor �WOMEN VETERANS HEALTH STUDY Written Release Format and Record Request AUTHORIZATION FOR DISCLOSURE OF MEDICAL INFORMATION Name: Hospital Number: Address: . Date of Birth: I hereby authorize the Hospital/Clinic to release information from my medical records to: CONTRACTOR ADDRESS This authorization covers all medical and/or psychiatric treatment, history of illness or related information. This authorization shall remain in effect as long as necessary (up to one year) to respond to the attached request. I also understand that I may revoke this authorization at any time. This authorization expires one year from date signed. Signature of Patient: Date: Authorization received by: Office: �WOMEN VETERANS HEALTH STUDY 7/1/87 INFORMED CONSENT (PARTICIPANTS) As a participant in the "Women Veterans Health Study" I understand that I am eligible to participate in a follow-up study, on a subsample of individuals funded by the Veterans Administration. This follow-up is being conducted by (Contractor) in collaboration with the Red Cross. It includes collecting information on neuropsychological behavior, and physiological measurements. I understand that as a participant in this study, I will be asked to provide answers to some health-related questions, and participate in neurological testing which will be completed in a home visit, at my convenience, in about 3 hours. I understand that a visit to the nearest Red Cross Center will be scheduled for a blood sample to measure TCDD (dioxin) levels. Risks from the measurement made at the Red Cross Center includes slight discomfort at the insertion of the needle for the blood sample, and a small chance of bruising and infection. This procedure is similar to a donation of blood. The results of my measurements will be provided to me in a summary report about 3 months after the visit. At my request, a copy of this report will be sent to my physician. I also understand that these tests do not replace a physical examination by a physician, and in no way do they imply any form of medical treatment or diagnosis. I understand that all information I give is confidential and will be used for statistical purposes only. Each of these tests and procedures and their risks and discomforts have been explained to me and all of my questions about the study have been answered to my fullest satisfaction. (Respondent) Signature Examining Physician Signature Date �WOMEN VETERANS HEALTH STUDY date Name Street Address City, State, Zip Dear As part of the "Women Veterans Health Study" sponsored by the Veterans Administration, we are interested in obtaining complete medical records on your child's hospitalizations which include some more technical information that is needed for the study. As we told you over the telephone, in order to do that we need to obtain a signed authorization form from you first. Could you please help us by signing the enclosed authorization form and returning it to us in the enclosed envelope as soon as possible. You may be assured that the information will be kept confidential and will be used only in completing the review of your child's record. We will be most grateful for your cooperation. Sincerely yours, Contractor �WOMEN VETERANS HEALTH STUDY 7/1/87 INFORMED CONSENT (CHILDREN) As a participant in the "Women Veterans Health Study" I understand that my child is eligible to participate in a follow-up study, on a subsample of offspring funded by the Veterans Administration. This follow-up is being conducted by (Contractor) in collaboration with the Red Cross. It includes examination of my child by a physician specialist. I understand that as a participant in this study, my child will be given an examination. This will be completed in a home visit, at my and my child's convenience, in no more than 2 hours. The results of my child's exam will be provided to me in a summary report about 3 months after the visit. At my request, a copy of this report will be sent to my child's physician. I also understand that these tests do not replace a physical examination by a physician, and in no way do they imply any form of medical treatment or diagnosis. I understand that all information gathered is confidential and will be used for statistical purposes only. Each of these tests and procedures and their risks and discomforts have been explained to me and all of my questions about the study have been answered to my fullest satisfaction. I give my consent to have my child, (NAME) examined by Dr. (NAME). Parent (Guardian) Signature Date Examining Physician Signature Date �WOMEN VETERANS HEALTH STUDY Written Release Format and Record Request For Child's Medical Records AUTHORIZATION FOR DISCLOSURE OF MEDICAL INFORMATION Name: Hospital Number: Address: , Date of Birth: I hereby authorize the Hospital/Clinic to release information from my child's medical records to: CONTRACTOR ADDRESS This authorization covers all medical and/or psychiatric treatment, history of illness or related information. This authorization shall remain in effect as long as necessary (up to one year) to respond to the attached request. I also understand that I may revoke this authorization at any time, This authorization expires one year from date signed. Signature of Parent: Date: Authorization received by: Office: �CONGEN!TAL A B N O R M A L I TY CLASSI F I C A T I O N AND PEDI ATRI C E X A M I NAT1 ON �VERIFICATION OF CONGENITAL ABNORMALITY Currently the Ranch Hand II Study is relying on records and recoding of these records using modified ICD-9 CM classifications to verify congenital abnormalities detected up to the age of 18 years. Very few hospital records, from up to 18 years ago are unavailable. The following records are solicitied: • Birth Certificate; • Hospital Delivery Record; and • Records for any hospitalizations related to diagnoses of an anomaly. The modified ICD-9 CM classification which follows and the protocol for record abstraction used on Ranch Hand II are proposed for use in this study. �BIRTH DEFECTS BRANCH SIX DIGIT CODE For Reportable Congenital Anomalies Based on B - P - A - Classification of Diseases (1979) and W.H-0. I-C-D.9 CM (197?) Code modifications developed by Birth Defects & Genetic Diseases Branch Center for Environmental Health Centers for Disease Control Atlanta, Georgia 30333 Doc. No. 6digit Version 05/87 �INDEX TO 6-DIGIT CODE ICD-9 Code. Explanation to 6-Digit code Ease. i Anencephalus and similar anomalies 740 1 Spina bifida 741 2-3 Other congenital anomalies of the brain and nervous system 742 3-4 Congenital anomalies of the eye 743 5-6 Congenital anomalies of the ear, face, and neck 744 7-8 Bulbus cordis anomalies and anomalies 745 9-10 Other congenital anomalies of the heart 746 11-12 Other congenital anomalies of 747 13-14 Congenital anomalies of the respiratory system 748 15-16 Cleft palate and cleft lip 749 17 Other congenital anomalies of the 750 18-19 Other congenital anomalies of the digestive system 751 20-22 Congenital anomalies o.f the genital organs 752 23-26 Congenital anomalies of the urinary system 753 27-28 of cardiac septal closure the circulatory system upper alimentary tract �INDEX (cont'd-) ICD-9 Certain corgenital musculo-skeletal deformitj es ....... heac ....... spire ....... hip, legs, feet ....... chest 754 Other congenital anomalies of limbs ....... poljdactyly ....... sync actyly ....... reduction defects ....... other anomalies, upper limbs ....... other anomalies, lower limbs 755 29 29 29 29-30 30 31 31 31 32-33 33 34 Other musct.lo-skeletal anomalies 756 ....... of skull and face bones (craniosynostosis) ....... of the spine and ribs ....... spii.a bifida occulta ....... choi.drodystrophy . ....... oste odystrophies . ....... of the diaphragm ....... of 1 he abdominal wall ....... other specif ied/unspec • • 36 36 37 37 38 38 39 39 39 Congenital anomalies of the integument ....... skin ....... hair, nails, other specified 757 40 40 41 Chromosomal anomalies 758 42-45 Other specified and unspecified congenitj 1 anomalies ....... sple en ...... -adrenal gland • ....... other endocrine ....... situs inversus ....... conjoined twins ....... tubeirous sclerosis ....... other hamartoses ....... multiple congenital anomalies ....... other specified anomalies and syndromes ....... unspecified congenital anomalies 759 45 45 45 45 46 46 46 46 46 47 47 �INDEX (cont'd-) j;CD-9 Lipomas 214 48 Benign n 2Oplasms of the skin 216 49 Hemangionas 228 50 Congenital infections 771-773 50 Other selected codes used in Atlanta surveillance system listed alphabetically 51-52 Other selected codes used in Atlanta surveillance system listed numerically 53-54 �Explanation to Six Digit Code 6th Digit • OOQ .001 .002 .003 .004 .005. .0 06 • 002 •OOa -OOi Code - Master Blank Left Only Right Only Unilateral Unspecified Bilateral Possible or Probable NOS The above sixth digit added by the record abstractor to the B.P-AClassification of Diseases code is used for the following reasons: •001 .002 specify laterality if the location of the defect is known -003. specify if the defect is unilateral, when the specific location is unknown •004 specify that the defect is bilateral (ie- on both sides) •005. 006 ' •002 use in certain circumstances to more specifically define a particular defect- For example, these codes may be created to specify the location of a myelomenlngocele in spina bifida as cervico-thoracic, thoraco-lumbar, or lumbo-sacral (see 741-085, e t c - ) - 00& use this code specification rarely, it is available for defects which are specified as probable or. possible from the hospital recordeg- "probable PDA" = 747-00&, "probable VSD" = 745-49&, or a case of Down syndrome without cytogenetic verificationMedical records of cases with this defect code should be •reviewed periodically in order to update the defect list with the most definitive diagnosis •002. specify that the defect is "not otherwise specified" in any other part of the six-digit code. Notes: An asterisk (*) beside a disease code indicates that the code was created by CDCA pound (#) beside a disease code indicates that the condition or defect is listed on the CDC Exclusion list- Use of the code should be according to the exclusion list criteria- �CONGENITAL ANOMALIES Anencephalus and Similar Anomalies 740-0 Anencephalus 740.000 740.010 740-020 740-030 740.080 740.1 740.100 740-2 Absence of brain Acrania Anencephaly Hemianencephaly> hemicephaly Other Craniorachischisis Iniencephaly 740-200 740.210 740.290 Closed iniencephaly Open iniencephaly Unspecified iniencephaly �741 Spina Bifida Includes: Spina bifida aperta (open lesions) myelocele rachischisis Spina bifida cystica (closed lesions) meningocele meningomyelocele myelomeningocele Excludes: Spina bifida occulta (see 756-100) craniorachischisis (see 740-100) 741-0 Spina Bifida with Hydrocephalus 741-000 Spina bifida aperta. any site, with hydrocephalus 741-010 Spina bifida cystica. any site, with hydrocephalus and Arnold Chiari malformation "Arnold Chiari malformation NOS" Spina bifida cystica. any site, with stenosed aqueduct of Sylvius Spina bifida cystica, cervical, with unspecified hydrocephalus Spina bifida cystica. cervical, with hydrocephalus but without mention of Arnold Chiari malformation or aqueduct stenosis Spina bifida cystica. thoracic, with unspecified hydrocephalus, no mention of Arn.-Chiari Spina bifida cystica. lumbar, with unspecified hydrocephalus, no mention of Arn--Chiari Spina bifida cystica. sacrali with unspecified hydrocephalus, no mention of Arn--Chiari Spina bifida of any site with hydrocephalus of late onset Other Spina bifida, meningocele of specified site with hydrocephalus Spina bifida, meningocele, cervico thoracic, with hydrocephalus Spina bifida, meningocele thoraco-lumbar, with hydrocephalus Spina bifida, meningocele, lumbo-sacral with hydrocephalus ' Spina bifida of any unspecified type with hydrocephalus 741-020 741-030 741-040 741-050 741-060 741.070 741-080 741.085 741.086 741-087 741.090 �741.9 Spina bifida without mention of hydrocephalus 741.900 741.910 741.920 741.930 741.940 741.980 741.985 741.990 Spina Spina Spina Spina Spina Spina bifida (aperta), without hydrocephalus bifida (cystica), cervical, without hydrocephalus bifida (cystica), thoracic, without hydrocephalus bifida (cystica), lumbar, without hydrocephalus bifida (cystica), sacral, without hydrocephalus bifida, oth specified site, without hydrocephalus Includes: cervicothoracic, thoracolumbar, lumbro-sacral Lipomyelomeningocele Spina bifida, site unspecified, without hydrocephalus (myelocoele, myelomeningocoele, meningomyelocoele) 742 Other Congenital Anomalies of Nervous System 742-0 Encephalocele 742.000 742.080 742.085 742.086 742-090 742.1 Occipital encephalocele Other encephalocele of specified site (includes Midline defects) Frontal encephalocele Parietal encephalocele Unspecified encephalocele 742.100 Microcephalus 742-2 Reduction deformities of brain 742.200 742.210 742.220 742.230 742.240 742.250 742.260 742.270 742.280 742.290 742-3 Anomalies of cerebrum Anomalies of corpus callosum Anomalies of hypothalamus Anomalies of cerebellum Agyria and lissencephaly Microgyria, polymicrogyria Holoprosencephaly Arrhinencephaly Other specified reduction defect brain Unspecified reduction defect of brain Congenital hydrocephalus Excludes: hydrocephalus with any condition in 741.9 (741-0) 742'.300 742.310 742.320 742.380 # 742-385 742.390 Anomalies of aqueduct of Sylvius Atresia of foramina of Magendie and Luschka Dandy-Walker syndrome Hydranencephaly Other specified hydrccsphaly Includes: "communicating hydrocephaly" Hydrocephalus secondary to intraventricular hemorrhage (IVH) or CNS bleed Unspecified hydrocephaly, NOS �742.4 Other specified anomalies of brain 742-400 742.410 742-420 742-480 Enlarged brain and/or head Megalencephaly Macrocephaly Porencephaly Includes: porencephalic cysts Multiple cerebral cysts Other specified anomalies of brain Includes: cortical atrophy 742-485 cranial nerve defects Ventricular cysts; 742.486 Excludes: arachnoid cysts (348-000) "small brain" 742-5 Other specified anomalies of spinal cord Excludes: syringomyelia (336-000) 742-500 742-510 742.520 742.530 742-540 742-580 742-8 Amyelia Hypoplasia and dysplasia of spinal cord atelomyelia myelodysplasia Diastematomyelia Other cauda equina anomalies Hydromyelia Hydrorhachis Other specified anomalies of spinal cord and membranes Other specified anomalies of nervous system Excludes: congenital oculofacial paralysis "moebius syndrome" (352-600) 742.800 742-810 742-880 742.9 Jaw-winking syndrome Marcus Gunn syndrome Familial dysautonomia Riley-Day syndrome Other specified anomalies of nervous system Unspecified anomalies of brain, spinal cord and nervous systems 742-900 742-910 742-990 Brain, unspecified anomalies Spinal cord, unspecified anomalies Nervous system, unspecified anomalies �743 Congenital Anomalies of Eye 743-000 743-100 743-2 Anophthalmos agenesis of eye cryptophthalmos Microphthalmos, small eyes aplasia of eye hypoplasia of eye dysplasia of eye rudimentary eye Buphthalmos 743-200 743.210 743-220 743-3 Buphthalmos congenital glaucoma hydrophthalmos Enlarged eye NOS Enlarged cornea keratoglobus congenital megalocornea Congenital cataract and lens anomalies 743-300 743-310 743-320 743-325 743-326 '743.330 743-340 743-380 743-390 743-4 Absence of lens congenital aphakia Spherical lens Spherophakia Cataract, NOS i Cataract anterior polar Cataract, other specified Displaced lens Coloboma of lens Other specified lens anomalies Unspecified lens anomalies Coloboma and other anomalies of anterior segments 743-400 743-410 '743.420 743.430 743-440 743-450 743-480 743-490 Corneal opacity Other corneal anomalies Excludes: megalocornea (743-220) Absence of iris aniridia Coloboma of iris Other anomalies of iris polycoria ectopic pupil Peter's anomaly Blue Sclera Other spec colobomas and ariom- of ant. segments Rieger's anomaly coloboma of optic disc Unspecified colobomas and anomalies of anterior eye segments �74.3-5 Congenital anomalies of posterior segment 743.500 743-510 743-520 743-530 743-535 743-580 743-590 743-6 743-600 743-610 743-620 743-630 743-635 743-636 743-640 # 743-650 743-660 743-670 Specified anomalies of vitreous humour Specified anomalies of retina congenital retinal aneurysm Specified anomalies of optic disc hypoplastic optic nerve Specified anomalies of choroid Coloboma of choroid Other spec anomalies of posterior segment of eye Unspecified anomalies of posterior segment of eye Congenital anomalies of eyelids, lacrimal system and orbit Blepharoptosis congenital ptosis Ectropion Entropion Other anomalies of eyelids fused eyelids absence of eyelashes long eyelashes weakness of eyelid Blepharophimosis small or narrow palpebral fissures Coloboma of the eyelids ' Absence or agenesis of lacrimal apparatus absence of punctum lacrimale Stenosis or stricture of lacrimal duct Other anomalies of lacrimal apparatus) e - g - cyst Anomalies of orbit 743.8 # 743-800 # 743-810 743-9 743-900 Other specified anomalies of eye Includes: exophthalomos epicanthal folds antimongoloid slant upward eyeslant Excludes: congenital nystagmus (379-500) retinitis pigmentosa (362-700) ocular albinism (270-200) wide spaced eyes, hypertelorism (756-020) Epibulbar dermoid cyst Unspecified anomalies of eye Congenital: of eye (any part) Anomaly NOS Deformity NOS �744 Congenital Anomalies of Ear, Face and Neck 744-0 ' Anomalies of ear causing impairment of hearing 744.000 744-010 744-020 744-030 744-090 744-1 Absence or stricture of auditory canal Absence of auricle (Pinna) absence of ear NOS Anomaly of middle ear fusion of ossicles Anomaly of inner ear Includes: congenital anomaly of: membranous labyrinth organ of Corti Unspec anomalies of ear with hearing impairment Includes: congenital deafness, NOS Accessory auricle # 744-100 # 744-110 # 744-120 744-2 Accessory auricle Polyotia Preauricular appendage, tag or lobule (in front of ear canal) Other appendage, tag or lobule include papillomas, ear tags Other specified anomalies of ear 744-200 744-210 744-220 744-230 744-240 # 744-245 # 744-246 744-250 744-280 Macrotia (enlarged pinna) Microtia,(hypoplastic pinna and absence or stricture of external auditory meatus) Bat ear Other misshapen ear pointed ear elfin pixie-like lop ear cauliflower ear cleft in ear malformed ear absent or decreased cartilage Misplaced ears Low Set Ears Posteriorly rotated ears Absence or anomaly of eustachian tube Other spec anomalies of ear (see also 744-230) Darwin's tubercle �744-3 744.300 744-4 Unspecified anomalies of ear Congenital: ear (any part) anomaly, deformity NOS Branchial cleft, cyst or fistula; preauricular sinus 744-400 744.410 744-480 # 744-500 744-8 Branchial cleft, sinus- fistula cyst or pit Preauricular sinus, cyst or pit Other branchial cleft anomalies, include dermal sinus of head Webbing of neck Pterygium colli Other Specified anomalies of face and neck 744-800 744-810 744.820 744.830 744-880 744.9 Macrostomia (large mouth) Microstomia (small mouth) Macrocheilia (large lips) Microcheilia (small lips) Other specified anomalies of face/neck Unspecified anomalies of face and neck 744-900 # 744-910 Congenital anomaly of neck NOS Includes: short neck Congenital anomaly of face NOS Abnormal facies �745 Bulbus Cordis Anomalies and Anomalies of Cardiac Septal Closure 745-0 Common truncus (see 747-200 for pseudotruncus) 745-000 745-010 745-1 Persistent truncus arteriosus absent septum between aorta and pulmonary artery Aortic septal defect Includes: aortopulmonary window Excludes: atriai septal defect (use 745-590) Transposition of great, vessels 745-100 745-110 745-120 745-180 745-190 745.2 Transposition of great vessels, complete (no VSD) Transposition of great vessels, incomplete (w/ VSD) Taussig-Bing syndrome Corrected transposition of great vessels> L-transposition, ventri in version Excludes: dextrocardia (use 746-800) Other spec transposition of great vessels Includes: double outlet right ventricle Unspecified transposition of great vessels Tetralogy of Fallot 745-200 745.210 745-3 Fallot's tetralogy Fallot's pentalogy Fallot's tetralogy plus atrial septal defect (ASD) 745-300 Single ventricle Common ventricle Cor triloculare biatriatum �745-4 Ventricular septal defect 745.AGO 745-410 745.420 745-480 745-490 745-498 745-5 Roger's disease Eisenmenger's syndrome Gerbode defect Other specified ventricular septal defect VSD (ventricular septal defect),NOS Excludes: common atrioventricular canal type (use 745-620) Probable VSD Ostium secundum type atrial septal defect 745-500 745-510 745-520 745-580 745-590 745-6 Nonclosure of foramen ovale NOS Patent foramen ovale Ostium (septum) secundum defect Lutembacher's syndrome Other specified atrial septal defect ASD (atrial septal defect) NOS Auricular septal defect NOS Partial foramen ovale Endocardial cushion defects 745-600 745-610 745-620 745-630 745-680 745-690 Ostium primum defects Single common atrium, cor triloculare biventriculare Common atrioventricular canal with ventricular septal defect (VSD) Common atrioventricular canal Other specified cushion defect Endocardial cushion defect NOS 745.7 745.700 Cor biloculare 745-8 745-800 . Other specified defects of septal closure 745.9 745-900 Unspecified defect of septal closure 10 �746 Other Congenital Anomalies of Heart 746-0 Anomalies of pulmonary valve 746-000 746-010 746-020 746-080 746-090 746-1 Atresia, hypoplasia of pulmonary valve See 746-995 if valve no_L specified; e - g - "pulmonary atresia" Stenosis of pulmonary valve See 746-995 if valve not specified; e.g. "pulmonary stenosis" Excludes: pulmonary infundibular stenosis (use 746-830) Insufficiency of pulmonary valve Other specified anomalies of pulmonary valve Excludes: pulmonary infundibular stenosis (use 746-830) Unspecified anomaly of pulmonary valve Tricuspid atresia and stenosis 746-100 746-105 Tricuspid atresia, stenosis, hypoplasia Tricuspid insufficiency; excludes Ebstein's 746-200 Ebstein's anomaly Ebstein's anomaly 746-2 746-3 Congenital stenosis of aortic valve 746-300 746-4 Congenital stenosis of aortic valve Includes: congenital aortic stenosis subvalvular aortic stenosis Excludes: siLDJ^valvular aortic stenosis (747-220) Congenital insufficiency of aortic valve 746-400 * 746-480 * 746-490 746-5 Congenital insufficiency of aortic valve bicuspid aortic valve congenital aortic insufficiency Other specified anomalies of the aortic valves Includes: aortic valve atresia Excludes: anpx^.valvular aortic stenosis (747-220) Unspecified anomalies of the aortic valves Congenital mitral stenosis 746-500 746-505 Congenital mitral stenosis Absence, atresia or hypoplasia of mitral valve 746-6 746-600 Congenital mitral insufficiency 746-7 746-700 Hypoplastic left heart syndrome Atresia, or marked hypoplasia of the ascending aorta and defective development of left ventricle (with mitral valve atresia) 11 �746-8 Other specified anomalies of the heart 746-800 746-810 746-820 746-830 746.840 746-850 # 746-860 746.870 746.880 746-881 746.882 746-885 746-886 746--8S7 746-9 Dextrocardia without situs inversus (situs solitus) Dextrocardia with no mention of situs inversus• Use 759-300 for dextrocardia with situs inversus. Levocardla Cor triatriatum Pulmonary infundibular (subvalvular) stenosis Trilogy of Fallot Anomalies of pericardium Anomalies of myocardium Congenital cardiomegaly NOS Congenital myopathy Hypertrophic myopathy Congenital heart block Other specified anomalies of heart Includes: Ectopia (ectopic) cordis (Mesocordia) Conduction defects NOS Hypoplastic left ventricle Excludes: Hypoplastic left heart syndrome(746-700) Hypoplastic right heart (ventricle) Uhl's disease Anomalies of coronary artery or sinus Ventricular hypertrophy, (right or left) Other defects of the atria Excludes: congenital Wolfe-Parkinson-White (use 426-705) rhythm anomalies (use 426.-, 427.-) Unspecified anomalies of heart 746-900 746-910 746-920 746-930 # 746-990 746-995 Unspecified anomalies of heart valves Anomalous bands of heart Acyanotic congenital heart disease NOS Cyanotic congenital heart disease NOS Blue baby Unspecified anomaly of heart: Includes: congenital heart disease (CUD) heart murmur "Pulmonic" or "Pulmonary" atresia; stenosis, or hypoplasia NOo (no mention of valve or artery) 12 �747 Other Congenital Anomalies of Circulatory System 747.000 747. OOB. 747.1 .Patent ductus arteriosus Probable PDA (PDA) Coarctation of aorta 747.100 747-110 747.190 747.2 Preductal (proximal) coarctation of aorta Postductal (distal) coarctation of aorta Unspecified coarctation of aorta Other anomalies of aorta 747.200 747.210 747.215 747-220 747.230 747.240 747-250 747-260 747.270 747.280 747.290 747.3 Atresia of aorta absence of aorta pseudotruncus arteriousus Hypoplasia of aorta tubular hypoplasia of aorta Interrupted aortic arch Supra-aortic stenosis (supra-valvular) Excludes: aortic stenosis, congenital (See 746-300) Persistent right aortic arch Aneurysm of sinus of valsalva Vascular ring (aorta) double aortic arch Overriding aorta dextroposition of aorta Congenital aneurysm of aorta congenital dilatation of aorta Other specified anomalies of aorta Unspecified anomalies of aorta Anomalies of pulmonary artery 747.300 747.310 747.320 747.325 747-330 747.340 747-380 747-390 Pulmonary artery atresia. absence or agenesis Use 746-995 if artery or valve is not specified Pulmonary artery atresia with septal defect Pulmonary artery stenosis Use 746-995 if artery or valve is no_t specified Peripheral pulmonary artery stenosis Includes: peripheral pulmonic stenosis Aneurysm of pulmonary artery dilatation of pulmonary artery Pulmonary arteriovenousmalformation or aneurysm Other specified anomaly of pulmonary artery Includes: pulmonarv artery hypoplasia Unspecified anomaly of pulmonary artery 13 �747.4 Anomalies of great veins 747.400 747-410 747.420 747-430 747-440 747.450 747-480 747.490 747.5 Absence or hypoplasia of umbilical artery # 747.500 747.6 Single umbilical artery Other anomalies of peripheral vascular system 747-60.0 747.610 747.620 747.630 747.640 747.650 747.680 747.690 747-8 Stenosis of renal artery Other anomalies of renal artery Arteriovenous malformation (peripheral) Excludes: pulmonary (747.340) cerebral (747-800) retinal (743-510) Congenital phlebectasia congenital varix Other anomalies of peripheral arteries Includes: aberrant subclavian artery Other anomalies of peripheral veins Excludes: Budd-Chiari - occlusion of hepatic vein (use 453-000) Other anomalies of peripheral vascular system Includes: primary pulmonary artery hypertension Unspecified anomalies of peripheral vascular sys Other specified anomalies of circulatory system 747.800 747.810 747-880 747.9 Stenosis of vena cava (inferior or superior) Persistent left superior vena cava (TAPVR) Total anomalous pulmonary venous return Partial anomalous pulmonary venous return Anomalous portal vein termination Portal vein - hepatic artery fistula Other specified anomalies of great veins Unspecified anomalies of great veins 747.900 Arteriovenous (malformation)aneurysm of brain Other anomalies of cerebral vessels Includes: vein of Galen Other specified anomalies of circulatory system Excludes: congenital aneurysm: coronary (746-880) peripheral (747-640) pulmonary (747-330) retinal (747-510) ruptured cerebral arteriovenous aneurysm (630-000) ruptured cerebral aneurysm (430-000) Unspecified anomalies of circulatory system 14 �748 748-0 Congenital Anomalies of Respiratory System 748-000 748-1 Choanal atresia atresia of nares, anterior or posterior congenital stenosis Other anomalies of nose 748-100 748-110 748-120 748-130 748-140 # 748-180 748-185 748-190 748-2 Agenesis or underdevelopment of nose Accessory nose Fissured, notched or cleft nose Sinus wall anomalies Perforated nasal septum Other specified anomalies of nose flat bridge of nose wide nasal bridge small nose and nostril absent nasal septum Tubular nose, single nostril, proboscis Unspecified anomalies of nose Excludes: congenital deviation of the nasal septum (use 754-020) Web of larynx 748-205 748-206 748-209 748-3 Web of larynx-glottic Web of larynx-subglottic Web of larynx-NOS Other anomalies of.larynx, trachea, and bronchus 748-300 748-310 # 748-320 748-330 748-340 748-350 748-360 748-380 748-385 748-390 748-4 Anomalies of larynx and supporting cartilage Congenital subglottic stenosis Tracheomalacia Other anomalies of trachea Stenosis of bronchus Other anomalies of bronchusCongenital laryngeal stridor NOS Other specified anomalies of larynx and bronchus Cleft larynx, laryngo-tracheo-esophageal-cleft Unspecified anomalies of larynx, trachea and bronchus Congenital cystic lung 748-400 748-410 748.420 748-480 Single cyst, lung or lung cyst Multiple cysts, lung Polycystic lung Honeycomb lung Other specified congenital cystic lung 15 �748-5 Agenesis or aplasia of lung 748-500 748-510 748-520 748-580 *748-590 748.6 Agenesis or aplasia of lung Hypoplasia of lung Pulmonary hypoplasia Sequestration of lung Other specified dysplasia of lung Fusion of lobes of lung Unspecified dysplasia of lung Other anomalies of lung 748-600 748-610 748-620 748.625 748-690 748-8 Ectopic tissues in lung Bronchiectasis Accessory lobe of lung Bilobar right lung Other and unspecified anomalies of lung Other specified anomalies of respiratory system 748-800 748-810 748-880 748-'9 Anomaly of pleura Congenital cyst of mediastinum Other specified respiratory system anomalies Includes: congenital lobar emphysema lymphangiectasia of lungs- 748-900 Unspecified anomalies of respiratory system Absence of respiratory organ NOS Anomaly of respiratory system NOS 16 �749 Cleft Palate and Cleft Lip 749.0 Cleft palate alone (If description of condition includes Pierre Robin syndrome, use additional code, 524-080) 749-000 749-010 749-020 749.030 749-040 749-050 749.060 749.070 749-080 749-090 749.1 749.100 749-110 749-.120 749-190 749.2 Cleft Cleft Cleft Cleft Cleft Cleft Cleft Cleft Cleft Cleft hard palate? unilateral hard palate, bilateral hard palate., central hard palate NOS soft palate,alone unilateral soft palate,alone bilateral soft palate,alone central soft palate,alone NOS uvula palate NOS palatoschisis Cleft lip alone Includes: alveolar ridge cleft cleft gum harelip Cleft lip, unilateral Cleft lip, bilateral Cleft lip, central Cleft lip NOS (fused lip) Cleft gum Cleft lip with cleft palate 749.200 749.210 749.220 749-290 Cleft Cleft Cleft Cleft lip, unilateral, with cleft palate (any) lip, bilateral, with cleft palate (any) lip, central, with cleft palate (any) lip NOS, with any cleft palate 17 �750 Other Congenital Anomalies of Upper Alimentary Tract # 750.000 750-1 Other anomalies of tongue 750-100 750-110 750-120 750-130. 750.140 750-180 750-190 750-2 Aglossia Absence of tongue Hypoglossia of tongue (small tongue) Microglossia Macroglossia (large tongue) Dislocation or displacement of tongue (glossoptosis) Cleft tongue (split) Other specified anomalies of tongue Unspecified anomalies of tongue Other specified anomalies of mouth and pharynx 750-200 750-210 750-220 750-230 750-240 750-250 750-260 750-270 750-280 750-3 Tongue tie Ankyloglossia • 750-300 750-310 750-320 750-325 750-330 750-340 750-350 750-380 Pharyngeal pouch Other pharyngeal anomalies Ranula Includes: mucoceles of soft palate, epulis Other anomalies of salivary glands or ducts High arched palate Other anomalies of palate Lip fistulae or pits Other lip anomalies prominent philtrum, long philtrum Other specified anomalies of mouth and pharynx Excludes: receding jaw (see 524-000) large and small mouth (see 744-800) Tracheo-esophageal fistula (T-E), esophageal atresia and stenosis Esophageal atresia without mention of (T-E) fistula Esophageal atresia with mention of (T-E) fistula Tracheo-esophageal (T-E) fistula without mention of esophageal atresia Tracheo-esophageal fistula - "H" type Broncho-esophageal fistula with or without mention of esophageal atresia Stenosis or stricture of esophagus Esophageal web Other tracheo-esophageal anomalies 18 �750.A Other specified anomalies of esophagus 750-400 750.410 750-420 750-430 750-480 750-5 Congenital hypertrophic pyloric stenosis # 750-500 750-510 750-580 750-6 Congenital dilatation of esophagus Giant esophagus Displacement of esophagus Diverticulum of esophagus esophageal pouch Duplication of esophagus Other specified anomalies of esophagus 750-600 750-7 Pylorospasm Congenital hypertrophic pyloric stenosis Other congenital pyloric obstruction Congenital hiatus hernia Cardia displacement through esophageal hiatus Partial thoracic stomach Excludes: congenital diaphragmatic hernia (756-610) Other specified anomalies of stomach 750-700 750.710 750-720 750-730 750-740 750-750 750-780 750-8 Microgastria Megalogastria Cardiospasm achalasia of cardia> congenital Displacement or transposition of stomach Diverticulum of stomach Duplication of stomach Other specified anomalies of stomach 750-800 Other specified anomalies of upper alimentary tract 750-9 Unspecified anomalies of upper alimentary tract 750-900 750-910 750-920 750-990 Unspecified Unspecified Unspecified Unspecified anomalies anomalies anomalies anomalies 19 of of of of mouth and pharynx esophagus stomach upper alimentary tract �751 Other Congenital Anomalies of Digestive System 751-0 Meckel's diverticulum 751-000 # 751-010 75.1.1 Persistent omphalomesenteric duct persistent vitelline duct Meckel's diverticulum Atresia and stenosis of small intestine 751.100 751-110 751-120 751-190 751-195 751-2 Stenosis, atresia Stenosis, atresia Stenosis, atresia Stenosis, atresia Stenosis, atresia with fistula or or or or or absence absence absence absence absence of of of of of duodenum jejunum ileum small intestine small intestine Atresia and stenosis of large intestine, rectum and anal canal 751.200 751-210 751.220 751-230 751-240 751-3 Stenosis, atresia or absence of large intestine Stenosis, atresia or absence of appendix Stenosis, atresia or absence of rectum wJJLh fistula Stenosis, atresia or absence of rectum without mention of fistula Stenosis, atresia or absence of anus with fistula Includes: "imperfofate anus" with fistula Stenosis, atresia or absence of anus without mention of fistulaIncludes: "imperforate anus" without fistula Hirschsprung's disease and other congenital functional disorders of the colon 751-300 751-310 751-320 751-330 751-340 Total intestinal aganglionosis Long-segment Hirschsprung's disease Short-segment Hirschsprung's disease Hirschsprung's disease NOS Congenital megacolon congenital macrocolon, not aganglionic 20 �751-4 Anomalies of intestinal fixation 751-400 751-410 751-420 751-490 751-495 751-5 Malrotation of caecum and/or colon Anomalies of mesentery Congenital adhesions or bands of omentum and peritoneum Other specified and unspecified malrotation Malrotation of small intestine alone Other anomalies of intestine 751-500 751-510 751-520 751-530 751-540 Duplication of anus, appendix, caecum or intestine enterogenous cyst Transposition of appendix, colon or intestine Microcolon Ectopic (displaced) anus Congenital anal fistula 751.550 Persistent cloaca # 751-580 751-590 751-6 . 751-600 751-610 # 751-620 Other specified anomalies of intestine Unspecified anomalies of intestine Anomalies of gallbladder, bile ducts and liver Absence or agenesis of liver, total or partial Cystic or fibrocystic disease of liver Other anomalies of liver hepatomegaly hepatosplenomegaly also use code 759-020 Excludes: . 751-630 751-640 751-650 751-660 751-670 751-680 Budd Chiari (use 453-000) Agenesis or hypoplasia of gallbladder Other anomalies of gallbladder duplication of gallbladder Agenesis or atresia of hepatic or bile ducts Includes: biliary atresia Excludes: congenital or neonatal hepatitis (use 774.480 or 774-490) Choledochal cysts Other anomalies of hepatic or bile ducts Anomalies of biliary'tract, NEC 21 �751-7 Anomalies of pancreas Excludes: diabetes mellitus: congenital (250-000) neonatal (775-100) fibrocystic disease of pancreas (277-000) 751-700 751.710 751-720 751-730 751-740 751-780 751-790 751-8 Absence, agenesis or hypoplasla of pancreas Accessory pancreas Annular pancreas Ectopic pancreas Pancreatic cyst Other specified anomalies of pancreas Unspecified anomalies of pancreas Other specified anomalies of digestive system 751-800 751-810 751-820 751-880 Absence of alimentary tract NOS (complete or partial) Duplication of alimentary tract Ectopic digestive organs NOS Other specified anomalies of digestive system 751.9 # 751-900 Unspecified anomalies of digestive system congenital of digestive system NOS: anomaly NOS deformity NOS obstruction NOS 22 �752 Congenital Anomalies of Genital Organs Excludes: congenital hydrocele (778-600) testicular feminization syndrome (257.800) syndromes associated with anomalies in number and form of chromosomes (758 ) 752-0 Anomalies of ovaries 752-000 752-010 752-020 752-080 752-085 752-090 752-1 Anomalies of fallopian tubes and broad ligaments 752-100 752-110 752-120 752-190 752-2 Absence or agenesis of ovaries Streak ovary Accessory ovary Other specified anom of ovaries Multiple ovarian cysts Unspecified anomalies of ovaries '752-200 Absence of fallopian tube or broad ligament Cyst of mesenteric remnant epoophoron cyst cyst of Gartner's duct Fimbrial cyst parovarian cyst Other .and unspecified anomalies of fallopian tube and broad ligaments Doubling of uterus doubling of uterus (any degree) or associated with doubling of cervix and vagina 23 �752-3 Other anomalies of uterus 752-300 752-310 752-320 752-380 752-390 752-4 Absence or agenesis of uterus Displaced uterus Fistulae involving uterus with digestive or urinary tract uterointestinal fistula uterovesical fistula Other anomalies of uterus bicornuate uterus unicornous uterus Unspecified anomalies of uterus Anomalies of cervix, vagina and external female genitalia 752-AGO 752-410 752-420 752-430 752-440 752-450 # 752-460 752-470 # 752-480 # 752-490 Absence) atresia cr agenesis of cervix Absence or atresia ov vagina-complete or partial Congenital rectovaginal fistula Imperforate hymen Absence or other anomaly of vulva fusion of vulva . hypoplastic labia majora Absence or other anomaly of clitoris Includes: clitoromegaly enlarged clitoris clitoral hypertrophy Embryonal cyst of vagina Other cyst of vaginaj vulva or canal of Nuck Other specified anomalies of cervix, vagina or external female genitalia Includes: vaginal tags hymenal tags Unspecified anomalies of cervix, vagina or external female genitalia 24 �752.5 Undescended testicle Not coded if < 2500 gms Excludes: retractile testicle (V65-50) # 752.500 # # # # 752.501 752.502 752-514 752.520 752.530 752-6 Undescended testicle, unilateral undescended unpalpable Left undescended testicle Right undescended testicle Undescended testicle- bilateral Undescended testicle NOS Ectopic testis, unilateral and bilateral Hypospadias and epispadias 752.600 752-605 752.606 752-607 752-610 752.620 752-621 752.625 752-626 752-627 752-7 Hvpospadias (alone) NOS 1 i glandular,coronal 2°, penile, 3 , perineal, scrotal Epispadias Congenital chordee (with hypospadias),NOS Congenital chordee alone (chordee w/o hypospadias) Cong, chordee with 1 , coronal hypospadias Cong, chordee with 2 , penile hypospadias Cong- chordee with 3 , perineal, scrotal hypospadias Indeterminate sex and pseudohermaphroditism Excludes: pseudohermaphroditism: female, with adrenocortical disorder (see 255.200) male, with gonadal disorder (257.900) with specified chromosomal anomaly (758-000) 752-700 752.710 752-720 752.730 # 752-790 True hermaphroditism ovotestis Pseudohermaphroditism, male Pseudohermaphroditism, female pure gonadal dysgenesis Excludes: gonadal agenesis (758-690) Pseudohermaphrodite NOS ' Indeterminate sex NOS ambiguous genitalia 25 �752-8 Other specified anomalies of male genital organs 752.800 # 752.810 752.820 752-830 752.840 752.850 752-860 752.865 752-870 752-880 Absence of testis monorchidism NOS Aplasia or hypoplasia of testis and scrotum Other anomalies of testis and scrotum polyorchidism bifid scrotum Atresia of vas deferens Other anomalies of vas deferens and prostate Absence or aplasia of penis Other anomalies of penis absent, hooded: or redundant foreskin Small (micro) penis or hypoplastic penis Cysts of embryonic remnants cyst: hydatid of Morgagni Wolffian duct Appendix testis Other specified anomalies of genital organs microgenitalia macrogenitalia 752.9 752.900 Unspecified anomalies of genital organs Congenital: of genital organ, NEC Anomaly NOS cr deformity NOS 26 �753 Congenital Anomalies of Urinary System 753-0 Renal agenesis and dysgenesis 753-000 753-009 753-010 753.1 Bilateral absence, agenesis, dysplasia, or hypoplasia of kidneys Potter's syndrome Renal agenesis NOS Unilateral absence- agenesis, dysplasia or hypoplasia of kidneys Cystic kidney disease 753-100 753-110 753-120 753-130 753-140 753-150 753-160 753-180 753-2 Renal cyst (single) Polycystic kidneys, infantile type Polycystic kidneys, adult type Polycystic kidneys NOS Medullary cystic disease, juvenile type Medullary cystic disease, adult type Medullary sponge kidney Multicystic renal dysplasia Multicystic kidney Other specified cystic disease Includes: cystic kidneys, NOS Obstructive defects of renal pelvis and ureter 753-200 753-210 753-220 753-290 753-3 Congenital hydronephrosis Atresia, stricture, or stenosis of ureter Includes: Ureteropelvic junction obstruction/stenosis UreterovesJ.cal June- obstruction/stenosis Hypoplastic ureter Megaloureter NOS Includes: hydroureter Other and unspecified obstructive defects of renal pelvis and ureter Other specified anomalies of kidney 753-300 753-310 753-320 753-330 753.340 753.350 753-380 Accessory kidney Double or triple kidney and pelvis. Pyelon duplex or triplex .Lobulated, fused cr horseshoe kidney Ectopic kidney Enlarged, hyperplastic or giant kidney Congenital renal calculi Other specified anomalies of kidney 27 �753.A Other specified anomalies of ureter 753-AGO 753-410 753-420 753-480 753-485 753-5 753-500 753-6 Absence of ureter Accessory ureter double ureter Ectopic ureter Other specified anomalies of ureter Includes: ureterocele Variations of vesico-ureteral reflux Exstrophy of urinary bladder ectopia vesicae extroversion of bladder Atresia and stenosis of urethra and bladder neck 753-600 753-610 753-620 753-630 753-690 753-7 Cong, posterior urethral valves or posterior urethral obstruction Other atresia, or stenosis of bladder-neck Obstruction, atresia or stenosis of anterior urethra Obstruction) atresia or stenosis of urinary meatus Includes: meatal stenosis Other and unspecified atresia and stenosis of urethra and bladder neck Anomalies of urachus 753-700 753-710 753-790 753-8 Patent urachus Cyst of urachus Other and unspecified anomaly of urachus Other specified anomalies of bladder and urethra 753-800 753-810 753-820 753-830 753-840 753-850 753-860 753-870 753-880 753-9 Absence of bladder or urethra Ectopic bladder Congenital diverticulum or hernia of bladder Congenital prolapse of bladder (mucosa) Double urethra or urinary meatus Ectopic uretnra or urethral orifice Congenital digestive-urinary tract fistulae •rectovesical fistula Urethral fistula NOS Other specified anomalies of bladder and urethra Unspecified anomalies of urinary system 753-900 753-910 753.920 753-930 753-990 Unspecified Unspecified Unspecified Unspecified Unspecified anomaly anomal" anomaly anomaly anomaly 28 of cf o.f of of kidney ureter bladder urethra urinary system NOS �754 Certain Congenital Musculoskeletal Deformities 734-0 Of skull, face and jaw Excludes: dentofacial anomalies (524-000) Pierre Robin syndrome (524-080) syphilitic saddle nose (090-000) Asymmetry of face Compression (Potter's) facies Congenital deviation of nasal septum bent nose Dolichocephaly Depressions in skull Includes: large fontanelle small fontanelle Plagiocephaly Asymmetric head Scaphocephaly) no mention of craniosynostosis Trigonocephaly) no mention of craniosynostosis Other specified skull deformity, no mention of craniosynostosis Includes: brachycephaly acrocephaly turricephaly oxycephaly Deformity of skull (NOS) 754-000 754-010 754-020 754-030 * 754-040 754-050 754-055 * 754-060 >v 754-070 * 754-080 * 754-090 754.1 754-100 •754-2 Of sternocleidomastoid muscle Includes: * absent or hypoplastic sternocleidomastoid contracture of sternocleidomastoid (muscle) sternomastoid tumor Excludes: congenital sternocleidomastoid torticollis (use 756-860) Certain congenital musculoskeletal deformities of spine 754-200 754-210 754-220 754-3 Congenital postural scoliosis Congenital postural lordosis Congenital postural curvature of spine, NOS Congenital dislocation of hip 754-300 754.310 * 754.320 Congenital dislocation of hip Unstable hip preluxation cf hip subluxation of hie predislocaticn status of hip at birth Clicking hip 29 �754-4 Congenital genu recurvatum and bowing of long bones of leg 754-400 754-410 754-420 754-430 75^.440 754-490 754-5 Bowing, femur Bowing, tibia and/or fibula Bow legs NOS Genu recurvatum Dislocation of kneei congenital Deformity of leg NOS Varus (inward) deformities of feet 754-500 754-510 754-520 754-530 754-590 754-6 Talipes equinovarus Talipes calcaneovarus Metatarsus varus Complex varus deformities Unspecified varus deformities of feet Valgus (outward) deformities of feet 754-600 754-610 754-615 75.4-680 754-690 754-7 Talipes calcaneovalgus Congenital pes planus Pes valgus Other specified valgus deformities of foot Unspecified valgus deformities of foot Other deformities of feet 754-700 754-720 754-730 754-735 754-780 754-8 Pes cavus Claw foot (use 753-350 for claw foot) Short Achilles tendon Clubfoot NOS talipes NOS Congenital deformities of foot NOS Other specified deformities of ankle and/or toes Includes: dorsiflexion of foot widely spaced toes Other specified congenital musculoskeletal deformities 754-800 754-8.10 754-820 754-825 754-830 754-840 754-850 754-880 Pigeon chest (Pectus Carinatum) Funnel chest (Pectus Excavatum) Other anomalies of chest wall Includes: 'deformed chest 1 , barrel chest Shield chest Dislocation of elbow Club hand or fingers Spade-like hand Other specified dsferm- of hands See 755-500 for specified anomalies of fingers, eg- incurving fingers 30 �755 Other Congenital Anomalies of Limbs 755-0 Polydactyly 755-005 # 755-006 755-007 755-010 755-020 755-030 755-090 755-095 755-096 755-1 Accessory fingers, (postaxial polydactyly) (Type A) Skin tag, (postaxial polydactyly) (Type B) Unspecified finger or skin tag (postaxial polydactyly NOS Accessory thumbs, (preaxial polydactyly) Accessory toes (postaxial) Accessory big toe (preaxial) Accessory digits NOS (hand/foot not specified) Accessory digits hand NOS (pre-, postaxial not specified) Accessory digits foot NOS (pre-> postaxial not specified) Syndactyly 755-100 755-110 755-120 # 755-130 755-190 755-191 755-192 755-193 755-194 755-195 755-196 755-199 Fused fingers Webbed fingers Fused toes Webbed toes Unspecified syndactyly Unspecified syndactyly unilateral Unspecified syndactyly bilateral Unspecified (webbed vs and/or fingers NOS Unspecified syndactyly Unspecified syndactyly Unspecified syndactyly Unspecified syndactyly digits not known 31 (see below for specified site) thumb and/or fingers thumb and/or fingers fused) syndactyly thumb toes unilateral toes bilateral toes NOS ( i - e - > webbed vs fused) �755-2 Reduction defects of upper limb If description of condition includes amniotic or constricting bands use additional code( 658-800 755-200 755-210 755-220 755-230 755-240 755-250 755-260 755-270 755-280 '755-290 755-3 Complete absence of upper limb amelia of upper limb Absence of upper arm and forearm with hand present phocomelia of upper limb Absence of forearm only (radius and ulna) Absence of forearm and hand Absence of hand and/or fingers Excludes: hypoplas_ia of upper limb (use 755-585) Lobster claw hand Excludes: shortening of arm (use 755-580) Erfiaxial (longitudinal) reduction defects of upper limb Includes: absence of radius absence of thumb Easiaxial (longitudinal) reduction defects of upper limb Includes: absence of ulna absence of fingers Other specified upper limb reduction defects Unspecified reduction defect of upper limb Includes: congenital amputation of upper limb NOS Reduction defects of lower limb If description of condition includes amniotic or constricting bands use additional code, 658-800 755-300 755-310 755-320 755-330 755-340 755-350 755-360 755-365 755-366 755-380 755-390 Complete absence of lower limb amelia of lower limb Absence of thigh and lower leg with foot present phocomelia of lower limb Absence of lower leg only Absence of lower leg and foot Absence of foot or toes Excludes: hypoplasia of lower limb (use 755-685) Claw foot or Lobster claw foot Excludes: shortening of leg (use 755-680) Longitudinal reduction defect of leg, NOS Absent tibia (preaxial longitudinal defect) Absent fibula (postaxial longitudinal defect) Other Specified reduction, defect of lower limb Includes: absent upper leg or thigh only Unspecified reduction defect of lower limb Includes: congenital amputation of lower limb NOS 32 �755-4 Reduction defects; unspecified limb If description of condition includes amniotic or constricting bands use additional code, 658.800 755-400 755.410 755-420 755-430 755-440 755-480 755-490 755-5 Absence limb NOS amelia NOS Phocomelia NOS Amputation of unspecified limb Longitudinal reduction defect NOS Absent digits NOS Other specified reduction defect of unspecified limb Unspecified reduction defect of unspecified limb Other anomalies of upper limb) including shoulder girdle Includes: complex anomalies involving all or part of upper limb # 755-500 755-520 755-525 755-526 755-530 Anomalies of fingers Includes: Camptodactyly Clinodactyly Macrodactylia Brachydactyly Triphalangeal thumb Incurving fingers Acrocephalosyndactyly (see 756-050) Apert's syndrome (see 756-055) Anomalies of hand Excludes: 'simian crease' (use 757.200) Anomalies of wrist Accessory carpal bones Madelung's deformity Anomalies of forearm, NOS 755-535 755-536 Radio-ulnar dysostosis Radio-ulnar synostosis 755-540 755-550 755-555 755-556 755-560 755-580 Anomalies of elbow and upper arm Anomalies of shoulder Cleidocranial dysostosis Sprengel's deformity Other anomalies of whole arm Other specified anomalies of upper limb Includes: hyperextensibility of upper limb shortening of arm Hypoplasia of upper limb Includes: hypoplasia of fingers, hands, or arms Excludes: 755-510 755-585 aplasia or absent upper limb (see 755-2 755-590 Unspecified anomalies of upper limb 33 ) �755-6 Other anomalies of lower limb, including pelvic girdle Includes: complex anomalies involving all or part of lower limb 755.600 755.605 755-606 755-610 # 755-616 755-620 # 755-630 755-640 755-645 755-646 755-647 755-650 755-660 755-665 755-666 755-667 755-670 755-680 755-685 755-690 Anomalies of toes Includes: overlapping toes hammer toes widespaced 1st and 2nd toes Hallux valgus Hallux varus Anomalies of foot Includes: plantar furrow Excludes: lobster claw foot (use 755-350) Rocker bottom foot Anomalies of ankle Astragaloscaphoid synostosis Anomalies of lower leg Angulation of tibia, tibial torsion (exclude if clubfoot present) Anomalies of knee hyperextended knee Genu valgum Genu varum Absent patella or rudimentary patella Anomalies of upper leg Anteversion of femur Anomalies of hip Includes: coxa vara • coxa valga other abnormalities of hips Hip dysplasia, NOS Unilateral hip dysplasia Bilateral hip dysplasia Anomalies of pelvis fusion of sacroiliac joint Other specified anom- of lower limb hyperextended legs shortening of legs Hypoplasla of lower limb Includes: hypoplasia of toes, feet, legs Excludes: aplasla or absent lower limb (see 755-3 Unspecified anomalies of legs 34 ) �755-8 Other specified anomalies of unspecified limb 755-800 755-810 755-880 755-9 755-900 Arthrogryposis multiplex congenita Temporarily includes-flexion contractures of individual joints Larsen's syndrome Other specified anomalies of unspecified limb Includes: overlapping digits NOS hyperextended joints NOS Excludes: hyperextended knees (use 755-640) Unspecified anomalies of unspecified limb 35 �•756 Other Congenital Musculo-Skeletal Anomalies 756 Other Congenital Musculo-Skeletal Anomalies 756-0 Anomalies of skull and face bones Excludes: skull and face deformities in 754Pierre Robin syndrome (use 524-080) 756-000 756-005 756-006 756-010 756-020 756-030 756-040 756-045 756-046 756-050 756-055 756-056 756-057 756-060 756-065 756-080 756-085 756-090 Craniosynostosis, NOS craniostenosis> NOS closed skull sutures, NOS Sagittal craniosynostosis Metopic craniosynostosis Coronal craniosynostosis Lambdoidal craniosynostosis Other types of craniosynostosis Includes: Basilar craniosynostosis Craniofacial dysostosis Includes: Crouzon's disease Mandibulofacial dysostosis Includes: Franceschett1 syndrome Treacher-Collins syndrome Other craniofacial syndromes Includes: Oculoraandibulofacial syndrome Hallerman-Streif syndrome Acrocephalosyndactyly, NOS Acrocephalosyndactyly types I or II Apert syndrome Acrocephalosyndactyly type III Other. Specified Acrocephalosyndactylies Goldenhar's syndrome oculo-auriculo-vertebral dysplasia Hemifacial macrosomia Other specified skull and face bone anomalies Includes: localized skull defects flat occiput prominent occiput prominent maxilla Excludes: macrocephaly (use 742-400) small chin (use 524-000) Pierre Robin syndrome (use 524-080) Hypertelorism, telecanthus Unspecified skull and face bone anomalies Excludes: dentofacial anomalies (524-000) skull defects associated with brain anomalies such as: Anencephal'j.s 'V'jO-020) Encephalocele 1742-000) Hydrocephalus (743-200) Microcephaius (742-100) 36 �756-1 Anomalies of spine 756-100 756-110 756-120 756-130 756-140 756-145 756-146 756-150 756-155 756-156 756-160 756-165 756-166 756-170 756-179 756-180 756-185 756-190 Spina bifida occulta Klippel-Feil syndrome Wildervanck's syndrome Kyphosis kyphoscoliosis Congenital spondylolisthesis Anomalies of cervical vertebrae Hemivertebrae (cervical) Agenesis (cervical) Anomalies of thoracic vertebrae Hemivertebrae of thoracic vertebrae Agenesis of thoracic vertebrae Anomalies of lumbar vertebrae Hemivertebrae of lumbar vertebrae Agenesis of lumbar vertebrae Sacrococcygeal anomalies Includes: agenesis of sacrum Excludes: pilonidal sinus (see 685-100) Sacral mass, NOS Other specified vertebral anomalies Hemivertebrae NOS Unspecified anomalies of spine 756.2 # 756.200 756-3 Cervical rib supernumerary rib in cervical region Other anomalies of. ribs and sternum 756-300 756-310 756-320 756-330 756-340 756-350 756-360 756-380 756-390 Absence of ribs Misshapen ribs Fused ribs Extra ribs Other anomalies of ribs Absence of sternum Misshapen sternum Other anomalies of sternum bifid sternum, short sternum Anomalies thoracic cage- unspecified Excludes: deformed chest (see 754-820) 37 �756-4 Chondrodystrophy 756-400 756-410 756-420 756-430 756-440 756-445 756-446 756-447 756-450 756-460 756-470 756-480 756-490 756-5 Asphyxiating thoracic dystrophy Jeune's syndrome Thoracic-pelvic-phalangeal dysplasla Excludes: homozygous achondroplasia Chondrodysplasia Oilier's syndrome, enchondromatosis Chondrodysplasia with haemangioraa Kast's syndrome Maffucci's syndrome Achondroplastic dwarfism Other specified chondrodystrophies Excludes: Conradl's (see 756-575) Diastrophic dwarfism Metatrophic dwarfism Thanatophoric dwarfism Metaphyseal dysostosis Spondyloepiphyseal dysplasia Exostosis Excludes: Gardner's syndrome (see 759-63_) Other specified chondrodystrophy Unspecified chondrodystrophy Excludes: lipochondrodystrophy (see 277-59_) Osteodystrophies 756-500 756-505 756-506 756-510 756-520 756-525 756-530 756-540 756-550 756-560 756-570 756-575 756-580 756-590 Osteogenesis imperfecta Osteopsathrosis Fragilitas ossium Polyostotic fibrous dysplasia Albright-McCune-Sternberg syndrome Chondroectodermal dysplasia Ellis-van Creveld syndrome Infantile cortical hyperostosis Caffey's syndrome Osteopetrosis Albers-Schonberg syndrome Marble bones Progressive diaphyseal dysplasia Engelmann's syndrome Camurati-Englemann disease Osteopoikilosis Multiple epiphyseal dysplasia Conradi's syndrome Chondrodysplasia punctata Excludes: warfarin embryopathy Other specified Osteodystrophies Unspecified Osteodystrophies 38 �756-6 Anomalies of diaphragm 756-600 756-610 756-615 756-616 756-617 756-620 756-680 756-690 756-7 Absence of-diaphragm Congenital diaphragmatic hernia Diaphragmatic hernia (Bochdalek) Diaphragmatic hernia (Morgagni) Hemidiaphragm Eventration of diaphragm Other specified anomalies of diaphragm Unspecified anomalies of diaphragm Anomalies of abdominal wall 756-700 .756-710 756.720 # 756.790 756-795 756-8 Exomphalos-omphalocele Gastroschlsis Excludes: umbilical hernia (553-100) Prune belly syndrome Other and unspecified anom of abdominal wall Epigastric hernia Other specified anomalies of muscle, tendon, fascia and connective tissue 756-800 756-810 756-820 756-830 756-840 756-850 756.860 756-880 756-9 Poland's syndrome or anomaly Other absent or hypoplastic muscle Includes: absent pectoralis major Excludes: prune belly syndrome (use 756-720) Absent tendon Nail-patella syndrome Amyotrophia congenita Ehlers-Danlos syndrome Congenital torticollis See also 754-100 Deformities of Sternocleidomastoid muscleOther specified anomalies of muscle, tendont fascia and connective tissue Unspecified anomalies of musculoskeletal system 756-900 756-910 756-920 756-930 756-940 756-990 Unspecified Unspecified Unspecified Unspecified Unspecified Unspecified anomalies anomalies anomalies anomalies anomalies anomalies 39 of of of of of of muscle tendon bones cartilage connective tissue musculoskeletal system �757 Congenital Anomalies of the Integument 757-000 757.1 .Hereditary oedema of legs Hereditary trophoedema Milroy's disease Ichthyosis congenita 757.100 757.110 757.115 757.120 757.190 757.195 757.196 757.197 757.2 Harlequin fetus Collodion baby Bullous type Sjogren-Larsson syndrome Other and unspecified Ichthyosis vulgaris X-linked ichthyosis Ichthysiform erythroderma Dermatoglyphic anomalies # 757.200 757.3 Abnormal palmar creases Includes: simian creases, transverse palmar creases Other specified anomalies of skin Excludes: pigmented mole (216-900) hemangioma (.228-000) 757.300 # 757.310 757.320 757.330 757.340 757.345 757.346 757.350 757.360 757-370 # 757-380 # 757.385 # 757.386 # 757.390 757-395 Specified syndromes, not elsewhere classified) involving skin anomalies Skin tags Includes: anal tags Excludes: preauricular tag' (see 744.110) vaginal tags (see 752-480) Urticaria pigmentosa Epidermolysis bullosa Ectodermal dysplasia Excludes: Ellis-van Creveld syndrome (756-525) X-linked type ectodermal dysplasia Other specified ectodermal dysplasias Incontinentia pigmenti Xeroderma pigmentosum Cutis laxa hyperelastica Nevus> not elsewhere classifiable Includes: port wine stain or nevus flammeus Excludes: hairy naevus (use 216-900) Sturge-Weber syndrome (use 759-610) Birthmark NOS Mongolian blue spot Other specified anomalies of skin Includes: cafs au !?.it spots hypsTpismsnted areas skin c;-stc Absence of skin 40 �757.4 Specified anomalies of hair Excludes: kinky hair syndrome (759-870) 757.400 757.410 757.420 757.430 757.450 757.480 757.5 Congenital alopecia Excludes: ectodermal dysplasia (757.340) Beaded hair Monilethrix Twisted hair Pili torti Taenzer's hair Persistent or excessive lanugo Includes: Hirsutism Other spec anomalies of hair Specified anomalies of nails 757.500 757-510 757-515 757.516 757.520 757.530 757.540 757.580 757-585 757-6 Congenital anonychia Absent nails Enlarged or hypertrophic nails Onychauxis Pachyonychia Congenital koilonychia Congenital leukonychia Club nail Other spec anomalies of nails Hypoplastic (small) fingernails and/or toenails Specified anomalies of breast 757.600 757.610 757.620 757.630 757.640 # 757.650 # 757-680 757.8 Absent breast with absent nipple Hypoplastic breast with hypoplastic nipple Accessory (ectopic) breast with nipple Absent nipple Small nipple (hypoplastic) Accessory (ectopic) nipple> supernumerary Other specified anomalies of breast Widely spaced nipples Other specified anomalies of the integument 757.800 757.9 Includes: scalp defects .For specified anomalies of skin see 757-390 For specified anomalies of hair see 757.480 For specified anomalies of nails see 757.580 Unspecified anomalies of the integument 757-900 757.910 757-920 757-990 Unspecified Unspecified Unspecified Unspecified anomalies anomalies anomalies anomalies 41 of of of of skin hair NOS nail NOS the integument NOS �758 Chromsomal Anomalies 758•0 Down syndrome Clinical Down syndrome karyotype identified as: 758-000 758-010 758-020 758.030 758.040 758-090 758-1 Down syndrome, karyotype trisomy 21 Down syndrome, karyotype trisomy G.NOS Translocation trisomy - duplication of a 21 Translocation trisomy - duplication of a G, NOS mosaic Down Down syndrome NOS Patau's syndrome Clinical Patau's syndrome karyotype identified as: 758-100 758-110 758-120 758-130 758-190 758-2 Patau's syndrome, karyotype trisomy 13 Patau's syndrome, karyotype trisomy D, NOS Translocation trisomy - duplication of a 13 Translocation trisomy - duplication of a D, NOS Patau's syndrome NOS Edwards's syndrome Clinical Edwards's syndrome karyotype identified as: 758-200 758-210 758-220 758-230 758-290 . 758-295 Edwards syndrome, karyotype trisomy 18 Edwards syndrome, karyotype trisomy E, NOS Translocation trisomy - duplication of an 18 Translocation trisomy - duplication of an E, NOS Edwards's syndrome NOS Edwards's phenotype - normal karyotype �758-3 Autosomal deletion syndromes 758-300 758-360 758-380 758-390 Antimongolism syndrome Clinical antimongolism syndrome karyotype - partial or total deletion of: 21 G NOS NOS Cri-du-chat syndrome Clinical Cri-du-chat syndrome karyotype - deletion of: 5 B NOS NOS Wolff-Hirschorn syndrome Clinical Wolff-Hirschorn syndrome karyotype - deletion of: 4 B NOS NOS Deletion of long arm of 13 deletion of long arm of D NOS Deletion of long arm of E deletion of long arm of 17 or 18 Deletion of short arm of E deletion of short arm of 17 or 18 Monosomy G mosaic ism Other loss of autosomal material Unspecified autosomal deletion syndromes. 758-400 Balanced autosomal translocation in normal 758-310 758-320 758-330 758-340 758-350 758-4 individual 758-5 Other conditions due to autosomal anomalies 758-500 758-510 758-520 . 758-530 758-540 758-550 758-580 758-585 758-586 758-590 Trisomy 8 Other trisomy C syndromes Trisomy: 6 10 11 7 9 12 C NOS Other total trisomy syndromes Trisomy 22 Trisomy NOS Partial trisomy syndromes Other translocaticns Excludes: balanced translocation in normal individual (758-400) Additional marker •autcsomes Other specified anomalies of autosomes NOS Polyploidy Triploidy Unspecified anomalies of autosomes 43 �758-6 Gonadal Dysgenesis Excludes: pure gonadal dysgenesis (752.720) Noonan's Syndrome (759-800) 758-600 758-610 758-690 758-7 Turner's phenotype, karyotype 45, X LXO] Turner's .phenotype, variant karyotypes karyotype characterized by: isochromosome mosaic, including XO partial X deletion ring chromosome Turner's phenotype, karyotype normal XX Use 759-800, Noonan's syndrome Turner's syndrome; karyotype unspecified, NOS Bonneville-Ullrich syndrome NOS Klinefelter's syndrome 758-700 758-710 758-790 758-8 Klinefelter's phenotype, karyotype 47, XXY Klinefelter's phenotype, other karyotype with additional X chromosomes XX XXXY XXYY XXXXY Klinefelter's syndrome NOS Other conditions due to sex chromosome anomalies 758-800 758-810 758-820 758-830 758-840 758-850 758-860 758-880 758-890 758-9 Mosaic XO/XY.45X/46XY Excludes: with Turner's phenotype (758-610) Mosaic XO/XX. Excludes: with Turner's phenotype (758-610) Mosaic XY/XXY.46XY/47XXY Excludes: Klinefelter's phenotype (758-710) Mosaic including XXXXY,49XXXXY Excludes: with Klinefelter's phenotype (758-710) XYY, male, 47XYY Mosaic XYY male XXX female,47XXX Additional sex chromosomes NOS Other specified sex chromosome anomaly Unspecified sex chromosome anomaly Conditions due to anomaly of unspecified chromosomes 758-900 758-910 758-920 758-930 Mosaicism NOS Additional chromosome(s) NOS Deletion of chromosome(s1* NOS Duplication of c'h.':circ.??rv*( s) NOS 44 �759 Other and Unspecified Congenital Anomalies 759.0 . Anomalies of spleen 759-000 759.005 759.010 # 759-020 759-030 759-040 759-050 759-080 759-090 759-1 Absence of spleen Asplenia Ivemark's syndrome Hypoplasia of spleen Hyperplasla of spleen Splenomegaly Hepatosplenoniegaly (also use code 751-620) Misshapen spleen Accessory spleen Ectopic spleen Other specified anomalies of spleen Unspecified anomalies of spleen Anomalies of adrenal gland 759-100 759-110 759-120 759-130 759-180 759.190 759-2 Absence of adrenal gland Hypoplasia of adrenal gland Accessory adrenal gland Ectopic adrenal gland Other specified anomaly of adrenal gland Excludes: congenital adrenal hyperplasia (use 255-200) Unspecified anomalies of adrenal gland Anomalies of other endocrine glands 759-200 759-210 759-220 759-230 # 759-240 759.280 759-290 Anomalies of pituitary gland Anomalies of thyroid gland Thyroglossal duct anomalies Thyroglossal cyst Anomalies of parathyroid gland Anomalies of thymus Thymic hypertrophy Other specified anomalies of endocrine gland Unspecified anomaly of endocrine gland �759.3 Situs inversus 759.300 759.310 759.320 759.330 759.340 759.390 759.A Conjoined twins 759.400 759-410 759.420 759.430 759.440 '759.480 759.490 759.5 759.500 759.6 Dicephalus ' Two heads Craniopagus Head joined twins Thoracopagus Thorax-joined twins Xiphopagus Xiphoid- and pelvis-joined twins Pygopagus Buttock-joined twins Other specified conjoined twins Unspecified conjoined twins Tuberous sclerosis Bourneville's disease Epiloia Other hamartoses, not elsewhere classified 759-600 759.610 759.620 759.630 759.680 759-690 759.7 Dextrocardia with complete situs inversus Situs inversus with levocardia Situs inversus thoracis Situs inversus abdominis Kartagener's syndrome (triad) Unspecified situs inversus Excludes: Dextrocardia (746-800) not associated with complete situs inversus # 759.700 Peutz-Jegher's syndrome Encephalocutaneous angiomatosis Kalischer's disease Sturge-Weber syndrome Von Hippel-Lindau syndrome Gardner's syndrome Other specified hamartomas Unspecified hamartomas Multiple congenital anomalies, Anomaly, multiple NOS Deformity, multiple MOS 46 �759.8 Other specified anomalies and syndromes 759-800 759-820 759-840 759-860 759-870 759-890 759-9 Cong malformation syndromes affecting facial appearance Cyclops Noonan's Syndrome Oral-facial-digital syndrome, type I Oro-facial-digital syndrome, type II (Mohr's syndrome) Waardenburg's syndrome Whistling face syndrome Cong malf- syndromes associated with short stature Amsterdam dwarf (Cornelia de Lange syndrome) Cockayne syndrome Laurence-Moon-Biedl syndrome Russell-Silver syndrome Seckel syndrome Smith-Lemli-Opitz syndrome Congenital malformation syndromes involving limbs Carpenter's syndrome Holt-Oram syndrome Klippel-Trenaunay-Weber syndromes Rubenstein-Taybi syndrome Sirenomelia Thrombocyopenia Absent Radius (TAR) syndrome Cong malformation syndromes with other skeletal changes Marfan's syndrome Cong malformation syndromes with metabolic disturbances Alport's syndrome Beckwith's (Wiedemann-Beckwith) syndrome Leprechaunism Meconium ileus Menke's syndrome (kinky hair syndrome) Prader-Willi syndrome Zellweger's Syndrome Other specified anomalies Includes: Hemihypertrophy Meckel-Gruber syndrome Congenital anomaly, unspecified # 759-900 759-910 759-990 Anomalies of umbilicus low-lying umbilicus umbilical cord atrophy Embryopathia NEC Congenital anomaly N03 �214 Lipomas 214-0 214-000 214-100 214-200 214.300 214.400 214.800 214.810 214-900 Skin and subcutaneous tissue of face Other skin and subcutaneous tissue Intrathoracic organs Intra-abdominal organs Spermatic cord Other specified sites Lumbar or sacral lipoma paraspinal lipoma Lipoma, unspecified site 48 �216 Benign Neoplasm of Skin 216-0 Benign neoplasm of skin Includes: blue nevus pigmented nevus papilloma dermatofibroma syringoadenoma * dermoid cyst hydrocystoma syringoma Excludes: skin of genital organs (221.0_-222.9_) 216-000 216-100 216-200 216-300 216-400 216-500 216-600 216-700 216-800 # 216-900 Skin of lip Excludes: vermillion border of lip (210-0) Eyelid, including canthus Excludes: cartilage of eyelid (215-0) Ear and external auditory canal Includes: auricle ear external meatus auricular canal external canal pinna Excludes: cartilage of ear (215-0) Skin of other and unspecified parts of face Includes: cheek, external nose, external eyebrow temple Scalp and skin of neck Skin of trunk, except scrotum Includes: Axillary fold Perianal skin Skin of: chest wall abdominal wall groin buttock anus perineum back umbilicus breast Excludes: anal canal (211-4) anus NOS (211-4) skin of scrotum (222-4) Includes: skin of upper limb, shoulder Includes: skin of lower limb, hip Other specified sites of skin Excludes: epibulbar dermoid cyst (use 743-810) Skin, site unspecified Includes: hairy nevus sebacscus cvst 49 �228-0 # Hemangioma Include: if greater than 4 inches diameter, if multiple hemangiomas, or if cavernous hemangioma # 228-000 # 228-010 228-020 228-030 228-040 228-090 228-100 Of unspecified site Skin & subcutaneous — unless otherwise specified Intracranial Retinal Intraabdominal Of other sites Cystic hygroma Lymphangioma, any site 771-0 Congenital infections (in utero infections only) 090.000 Congenital syphilis 771.000 771-090 Congenital rubella Unspecified TORCH infection 771.1 771-100 Cytomegalovirus (C.M-V.) 771.2 771-210 Toxoplasmosis 771-220 771-280 Herpes simplex Includes: encephalitis meningoencephalitis Other specified congenital infection 774.480 774-490 Neonatal hepatitis, other specified Neonatal hepatitis, NOS 774-4 50 �Other Specified Codes Used in Metro Atlanta Congenital Defects Program List ordered alphabetically 524-000 255-200 270-200 277-620 658-800 270-600 778-000 # 770-710 453-000 427-900 348-000 330-100 363-200 277-000 277-010 279-110 253-820 # 767-600 425-300 553-200 Abnormalities of jaw size Micrognathia Macrognathia Adrenogenital syndrome Albinism Alpha-1 antitrypsin deficiency Amniotic bands (Constricting bands, amniotic cyst) Arginosuccinic aciduria Ascites, congenital Bronchopulmonary dysplasia Budd-Chiari, occlusion of hepatic vein Cardiac arrhythmias, NEC Cerebral cysts Cerebral lipidoses (Includes: Tay Sachs disease, Gangliosidosls) Chorioretinitis Cystic Fibrosis No mention of meconium ileus Cystic Fibrosis With mention of meconium ileus DiGeorge syndrome Diencephalic syndrome Erb's palsy Endocardial fibroelastosis Epigastric hernia # 368-000 Esotropia # 378,000 # 351-000 Exotropia Facial palsy 331-890 760-710 760-718 760-750 282.200 271-000 # 527-600 282-000 286-000 774.480 202.300 # 769-000 # 778-600 270.700 251-200 252-100 275-330 253-280 243-990 345-600 Familial degenerative CNS disease Fetal alcohol syndrome Probable Fetal alcohol syndrome ( includes: 'fades ') Fetal hydantoin (dilantin) syndrome G-6PD deficiency Glycogen storage diseases Gum cysts, Includes: mucocele Hemolytic disease of the newborn Hemophilia (all types) Hepatitis - Other specified neonatal Histiocytosis, malignant Hyaline membrane disease Hydrocoele, congenital Hyperglycinemia Hypoglycemia, idiopathic Hypoparathyroidism, congenital Hypophosphatemic rickets Hypopituitarism, conssnitiiJ. Hypothyroidlsm, congenital Infantile spasms, congenital 51 �# 550-000 # 550-900 # 550-100 # 560-000 208-000 457-800 270-300 777-000 # 777-600 # 777-100 352-600 # 520-600 239-200 159-800 191-000 171-800 155-000 162-800 186-000 194-000 774-490 774-480 237-700 524-080 270-100 # 685-100 277-630 284-000 362-600 190-500 282-600 238-000 238-010 238-020 238-030 238-040 238.080 257.800 # 608-200 # 553-100 286-400 335-000 189-000 426-705 Inguinal hernia with mention of gangrene Inguinal hernia no obstruction with no mention of gangrene Inguinal hernia with obstruction, (incarcerated) with no mention of gangrene Intussusception Leukemia, congenital NOS Lymphatics - Other specified disorders of Maple syrup urine disease Meconium ileus Meconium peritonitis Meconium plug Moebius syndrome Natal teeth Neck cyst Neoplasms of the abdomen, oth- specNeoplasms of the CNS Includes: medulloblastoma gliomas Neoplasms of connective tissue Includes: Ewing's sarcoma fibrosarcoma Neoplasms of the liver Includes: hepatoblastoma hemangio-epithelioma Neoplasms of the lung Neoplasms of the testes Neuroblastoma Neonatal hepatitis, NOS Neonatal hepatitis, other specified Neurofibromatosis Pierre Robin syndrome Phenylketonuria Pilonidal sinus (sacrodermal), sacral sinus Pseudocholinesterase enzyme deficiency Red cell aplasia Retinal degeneration, peripheral Retinoblastoma Sickle cell anemia Teratoma. NOS Teratoma, head and face Teratoma, neck Teratoma, abdomen Teratoma, sacral, coccyxgeal Teratoma, other specified Testicular feminist ion syndrome Torsion of the testes jr spermatic cord Umbilical hernia von Willebrands disease Werdnig Hoffman disease Wilm's tumor (Nephroblastoma) Wolfe-Parkinson-White syndrome, congenital 52 �Other Specified Codes Used in Atlanta Surveillance System List ordered by six digit code number 155-000 159.800 162.800 171-800 186.000 189-000 190-500 191.000 194-000 202.300 208-000 238-000 238-010 •238.020 238-030 238-040 238-080 237-700 239.200 243-990 251-200 252-100 253-280 253-820 255.200 257.800 270-100 270-200 270-300 270-600 270-700 271-000 275-330 277-000 277-010 277-620 277-630 279-110 282-000 282-100 Neoplasms of the liver Includes: hepatoblastoma hemangio-epithelioma Neoplasms of the Abdomen, Oth- Spec. Neoplasms of the Lung: Oth. SpecNeoplasms of Connective tissue Includes: Swing's sarcoma fibrosarcoma Neoplasms of the testes Wilm's tumor (nephroblastoma) Retinoblastoma Neoplasms of the CNS Includes: gliomas medulloblastoma 'Neuroblastoma Histiocytosis, malignant Leukemia, congenital NOS Teratoma, NOS Teratoma, head and face Teratoma, neck Teratoma, abdomen Teratomaj sacral, coccyxgeal Teratoma, other specifiedNeurofibromatosis Neck cyst Hypothyroidism, congenital Hypoglycemia, idiopathic Hypoparathyroidism, congenital Hypopituitarism, congenital Diencephalic syndrome Adrenogenital syndrome (adrenal hyperplasia) Testicular feminization syndrome Phenylketonuria Albinism Maple syrup urine disease Arginosuccinic aciduria Hyperglycinemia Glycogen storage diseases Hypophosphatemic rickets Cystic Fibrosis No mention of msconiura ileus Cystic Fibrosis With mention of ™.°cc"-iium ileus Alpha-1 antitrypsir. deficiency Pseudocholinesterase enzyme deficiency DiGeorge syndrome Hereditary spherocytosis Hereditary elliptocytosis 53 �282-600 282.3UJ0 284-000 286.000 286-400 330-100 331.890 335.000 345-600 348-000 # 351-000 352-600 362-600 363-200 # 368-000 # 378-000 425-300 ' 426-705 427-900 453-000 457-800 # 520-600 # 527-600 524-000 524-080 # 550-000 # 550-100 # 550-900 # 553-100 553-200 # 560-000 # 608-200 658-800 # 685-100 760-710 760-718. 760-750 # 767-600 # 769-000 # 770-710 # 777-100 777-000 # 777-600 778-000 # 778-600 Sickle cell anemia G-6PD deficiency Red cell aplasia Hemophilia (all types) von Willebrands disease Cerebral lipidoses Includes: Tay Sachs disease Gangliosidosis Familial degenerative CNS disease Werdnig Hoffman disease Infantile spasms, congenital Cerebral cysts Facial palsy Moebius syndrome Retinal degeneration, peripheral Chorioretinitis Esotropia Exotropia Endocardial fibroelastosis Congenital Wolfe-Parkinson-White syndrome Cardiac arrhythmias, NEC Budd-Chiari, occlusion of hepatic vein Other Specified Disorders of Lymphatics Natal teeth Gum cysts, Includes: mucocele Abnormalities of jaw size Micrognathia Macrognathia Pierre Robin syndrome Inguinal hernia with mention of gangrene Inguinal hernia with obstruction) (incarcerated) with no mention of gangrene Inguinal hernia no obstruction with no mention of gangrene Umbilical hernia Epigastric hernia Intussusception Torsion of testes or spermatic cord Amniotic bands (Constricting bands, amniotic cyst) Pilonidal sinus (sacrodermal), sacral sinus Fetal alcohol syndrome Prpbable fetal alcohol syndrome ( includes: 'fades ') Fetal hydantoin (dilantin) syndrome Erb's palsy Hyaline membrane disease Bronchopulmonary dysplasia Meconium plug Meconium ileus Meconium peritonitis Ascites, congenital Hydrocoele, congenital HHS:PHS:CDC:CEH:DBDDD:BDGDB:JXM:05/20/87 Doc- 6digit, Version 05/87 54 �PEDIATRIC EXAMINATION In addition to record abstraction, a pediatric examination is proposed, following that developed for the .original Boston Fetal Alcohol Syndrome (FAS) Study and recently revised for a new FAS study, based on the prior experience. This protocol is included here. The Project Director of the Planning Contract (Dr. McKinlay) collaborated in the development and reliability testing of this protocol. �Maternal Health Habits Study BABY EXAM Subject ID // Instrument Type _1 Card // 0 0 :05-:06 1 :07-:08 Pregnancy // in Study Examiner :09-:10 (1) DF (2) SP (3) JD (4) BV (5) (6) (7) Exam // :1I :12 Date of Birth mo day year :13-:18 mo day year :19-:24 Exam Date Outcome of this pregnancy (1) Liveborn (2) Stillborn (3) Post partum death I. :25 INFANT PHYSICAL EXAM Was multiple contact necessary to complete exam? (1) Yes (2) No :26 II. NEUROLOGICAL EXAM 1. Age in hours when neurological exam was done (Round up over 1/2 hour) 2. Minutes since last feed :27-:29 (888 not fed (npo) 999 missing data) :30-:32 3. Adaptive Capacity - Perform only in predominant state 3 or Jess See code in Amiel, Tisson & Vitele a) Respond to sound 0 1 2 9 b) Habit uation to sound 0 1 2 9 c) Response to light 0 1 2 9 :33 :35 �Maternal Health Habits Study 2 1 2 9 1:36 Consolability 0 Specify from state 5 or state 6 1 2 9 :37 :38 f) Scarf sign 0 1 2 9 :39 g) Recoil of elbows 0 1 2 9 >40 h) Popliteal angle 0 1 2 9 sty 1 i) Recoil of lower limbs 0 1 2 9 :*2 j) Active contraction of neck flexors 0 1 2 9 tty-3 k) Active contraction of neck extensors 0 1 2 9 •(ill J) Palmar grasp 0 1 2 9 *fy-5 m) Response to traction 0 1 2 9 1*6 n) Supporting reaction 0 1 2 9 :47 o) Automatic walking 0 1 2 9 148 P) Moro reflex 0 1 2 9 149 q) Sucking 0 1 2 9 :50 r) Alertness 0 1 2 9 :51 d) Habituation to light e) 0 Crying (0) Absent (1) Weak (2) Normal (3) Excessive - (9) Not done :52 Motor Activity (0) (1) (2) (3) (4) (9) Absent Diminished Normal Mildly excessive Grossly excessive Not done :53 �Maternal Health Habits Study 3 Tremulousness (0) (1) (2) (3) CO (5) (6) (7) (8) (9) Not done No tremors or tremulousness noted Tremors only during sleep Tremors only after the Moro or startles Tremulousness seen 1 or 2 times in states 5 or 6 Tremulousness seen 3 or more times in states 5 or 6 Tremulousness seen 1 or 2 times in state 4 Tremulousness seen 3 or more times in state 4 Tremulousness seen in several states Tremulousness seen consistently in all states 1:54 Tremor Frequency (1) (2) (3) (9) < 6 times per seconds > 6 times per second Not applicable, no tremor Not recorded :55 Tremor Amplitude (1) (2) (3) (9) k. < 3 cm > 3 cm Not applicable, no tremor Not recorded :56 Predominant states (2) during neurological exam Most predominant state Next most predominant state III. :57 :58 ANTHROPOMETRIC Specify age in hours 1. :59-:61 Length . cm. _•__ :62 cm 2. Head 3. Right palperbral fissure 4. Intercanthal distance 5. R ear length ______ cm. :72-:73 6. L ear length :74-:75 . - -:64 :65-:67 . . cm. cm. cm. :68-;69 :70-:71 �Maternal Health Habits Study 7. R subscapular skinfold . mm. l:76-:78 ID// Type j_ £ Card // _0_ _2_ Pregnancy // 2:01-04 :05-:06 :07-:08 :09-:10 8. L subscapular skinfold . 9. R arm circumference . cm. :14-:16 10. L arm circumference . cm. :17-:19 11. Right triceps . 12. Left triceps 13. Penile length . . mm. :11-:13 mm. :20-:22 mm. :23-:25 cm. IV. GENERAL AND DYSMORPHIC EXAM 1. :26-:27 Sex (1) Male (2) Female (3) Ambiguous 2. :28 Anomalies Code as follows: (0) Absent (1) Present Unilateral (2) Present Bilateral (3) Present Multiple (3 or more) (9) Exam could not be done Head-Major a) Hydrocephaly 0 1 2 3 9 :29 b) Anencephaly 0 1 2 3 9 :30 c) Encephalocele 0 1 2 3 9 :31 d) Craniostenosis 0 1 2 3 9 :32 e) Other 0 1 2 3 9 :33 Head-Minor a) Metopic fontanel or 0 suture open to glabella �Maternal Health Habits Study 5 Defect 0 c) Absen t whorl 0 d) 2 or r lore hair whorls 0 e) Fronti i! Hair upsweep 0 f) Other 0 1 1 1 2 3 9 2:35 2 3 9 :36 2 3 9 :37 1 1 2 3 9 :38 2 3 9 :39 Ears-Major a) non patent canal 0 Ears-Minor a) Preauricular skin tag 0 1 2 3 9 :41 b) Preauricular sinus or pit 0 1 2 3 9 :42 c) Malformed ears 0 1 2 3 9 :43 d) Poster iorally rotated ears (more than 15 ) 0 1 2 3 9 :4* a) Lid Coloboma 0 1 2 3 9 :45 b) Iris Coloboma 0 1 2 3 9 :46 c) Brushfield spots 0 1 2 3 9 :<f7 d) Epicanthal folds 0 1 2 3 9 :48 e) Synophrys 0 1 2 3 9 :49 f) Upslanting palpebral fissures 0 1 2 3 9 :50 g) Downs lanting palpebral fissures 0 1 2 3 9: :51 h) Ptosis 0 1 2 3 9 :52 i) Other: Specify 0 1 2 3 9 :53 Eyes �Maternal Health Habits Study 6 Nose-Major a) 2:54 Choanal atresia Nose-Minor a) Smooth or indistinct philtrum b) Flat nasal bridge 0 1 2 3 9 :56 c) Anteverted naves 0 1 2 3 9 :57 :55 Oropharynx a) Cleft lip 0 1 2 3 9 :58 b) Cleft palate 0 2 3 9 :59 c) Thin upper lip 0 1 1 2 3 9 :60 d) Short mandible 0 2 3 9 -.61 e) Broad alveolar ridge 0 2 3 9 :62 f) Other: Specify 0 1 1 1 2 3 9 :63 a) Cyst 0 2 3 9 :64 b) Goiter 0 2 3 9 :65 c) Branchial sinus 0 2 3 9 :66 d) Webbed 0 1 1 1 1 2 3 9 :67 e) Other: 0 1 2 3 9 :68 1 1 1 1 2 3 9 :69 2 3 9 :70 2 3 9 :71 2 3 9 :72 Neck Chest a) Pectus excavatum 0 b) Accessory nipples 0 c) Areolar skin tag 0 d) Other: 0 �Maternal Health Habits Study 7 Abdomen a) Gastroschisis 0 1 2 3 9 2:73 b) Omphalocele 0 1 2 3 9 :74 c) Diaphragmatic hernia 0 1 2 3 9 :75 d) Single umbilical artery 0 1 2 3 9 :76 e) Liver more than 3 cm (below RCM) 0 1 2 3 9 :77 f) Kidney more than 3 cm wide to palpation 0 1 2 3 9 :78 g) Abdominal mass 0 1 2 3 9 :79 h) Other: 0 1 2 3 9 :80 3:01-04 ;05-:06 :07-:08 :09-:10 ID// Type 1 0 Card // 0 3 Pregnancy // Extremities a) Phocomelia 0 1 2 3 9 :11 b) Polydactyly hands 0 1 2 3 9 :12 c) Polydactyly feet 0 1 2 3 9 :13 d) Clinodactyly (more than 8 5th finger) 0 1 2 3 9 :14 e) Camptodactyly 0 1 2 3 9 :15 f) Hypoplastic fingernail 0 1 2 3 9 :16 g) Simian or bridged simian crease 0 1 2 3 9 :17 h) 0 More than 1/4 inch between 1st <5c 2nd toe 1 2 3 9 :18 i) Syndactyly more than 0 1 2 3 9 :19 1 tp 2nd & 3rd toes �Maternal Health Habits Study 8 3:20 j) Calcaneouvalgus 0 2 3 9 k) Clubbed foot talipes equinovarus 0 2 3 9 1) Dislocated hip: Con0 firmed by x-ray assessment in first 14 days m) Inability to supinate forearm 0 1 2 3 9 :23 n) Other joint limitations-Specify: 0 1 2 3 9 :24 o) Other: 0 1 2 3 9 :25 a) Meningo myelocele 0 1 2 3 9 :26 b) Vertebral anomalies 0 1 2 3 9 :27 c) Scoliosis 0 2 3 9 :28 d) Sacral hypoplasia 0 2 3 9 :29 e) Pilonoidal sinus 0 2 3 9 :30 f) Deep prescarcral dimple 0 1 1 1 1 2 3 9 :31 g) Other: 0 1 2 3 9 :32 a) Hemangiomas (other than stork bites) 0 1 2 3 9 :33 b) Pigmented Nevi 0 1 2 3 9 :34 c) Mongolian spots other than buttocks 0 1 2 3 9 :35 d) Cafe au lait spots 0 2 3 9 :36 e) Other: 0 1 1 2 3 9 :37 :22 Back Skin �Maternal Health Habits Study 9 Genitalia a) 3:38 Inguinal hernia Female 1 hypertrophy 1 2 3 9 1 skin tag 0 1 2 3 9 hypoplasia d) 0 0 1 2 3 9 0 I 2 3 9 Other: :39 Male a) Hypospadias If yes, specify: 1st degree 2nd degree 3rd degree b) Chordee e 0 1 2 3 9 c) Cryptc rchidism 0 1 2 3 9 d) Other: 0 1 2 3 9 V. NEONATAL RECORD REVIEW 1. Ordinal Position of this birth (0) Singleton (1) (2) (3) Of) 2. Twin A Twin B Triplet C Other weeks Gestational Age by Dubowitz: (1) Study Pediatrician (2) Other Pediatrician (3) Not done (gestational age by LMP) :52 3. Birth weight :53-:56 4. Apgar 1 :57-:58 5. Apgar 5 :59-:60 zrams �Maternal Health Habits Study 10 6. Number Days in Special Care (code 1 for up to 24 hours) 7. Number Days Post-partum hospitalization 8. Information from record review only :64-:66 (1) Yes (2) No 9. 3:61-:63 :67 If yes, specify reason (1) Baby transferred due to illness (2) Baby discharged before examined (3) NA - Baby examined :68 10. Condition at discharge from nursery (1) Alive-discharged to home or foster home (2) Dead (3) Transferred to another hospital or another ward at BCH 11. If dead, age at death 12. days (code 001 for up to 24 hours) :70-:72 (code 000 for alive) Medications: (00) (01) (02) (03) (04) (05) (06) (07) (08) (09) (10) None (except Vit K and eye prophylaxis) Chlorpromazine Barbiturates Dilantin Theophyllin/Caffeine Antibiotics Diuretics Digitalis preparation Other Missing data Multiple meds (from list aboveXcircle all relevant above) 13. Maximum Bilirubin in chart 14. :69 Age in hours. Maximum bili recorded ID// Type 1 0 Card // _0_ _4_ Pregnancy // . :73-:74 :75-:77 (hours) :78-:80 4:01-:04 :05-:06 :07-:08 :09-:10 �Maternal Health Habits Study 11 VI. GENERAL Noted Not Noted 1. Intubate for visualization (1) (2) 4:11 2. Intubate for meconium (1) (2) :12 3. Intubate for resuscitation (1) (2) :13 4. Bagged at birth (1) (2) :14 5. Feeding problem requiring gavage (1) (2) :15 VII. RESPIRATORY 1. RDS (1) (2) :16 2. Meconium aspiration syndrome (1) (2) :17 3. Congenital pneumonia (1) (2) :18 4. Apnea (1) (2) :19 5. Other respiratory distress (1) (2) :20 6. Transient tachypnea (1) (2) :21 7. PFC (1) (2) :22 8. BPD (1) (2) :23 9. Pneumothorax (1) (2) :24 VIII. METABOLIC DISORDERS 1. Hypoglycemia <M (1) (2) :25 2. Hypocalcemia <7.5 (1) (2) :26 3. Hypothyroidism (1) (2) :27 4. Jitteriness or hyperactivity without specific causes (1) (2) :28 �Maternal Health Habits Study 12 IX. CARDIAC 1. Major cardiac anomalies which require immediate catheterization within 14 day of birth Specify (1) (2) 2. Congestive Heart Failure (1) (2) 3. Cardiac anomalies not requiring immediate catheterization within 14 days of birth Specify (1) (2) 4. Persistent cyanosis (cardiac) (1) (2) :32 5. Murmur (0 (2) :33 X. HEMATOLOGIC PROBLEMS 1. Phototherapy (1) (2) :34 2. Exchange transfusion for bill (1) (2) :35 3. Reduction transfusion (1) (2) :36 4. Hemmorrhagic diathesis (1) (2) :37 5. Anemia noted within 72 hours (0 (2) :38 6. Polycythemia noted within 72 hours (1) (2) :39 XL SEPSIS 1. v/o sepsis workup (1) (2) :40 2. sepsis diagnosed (1) (2) :41 XII. CNS 1. CNS depression > 24 hours (1) (2) :42 2. CNS depression < 24 hours (1) (2) :43 3. Withdrawal syndrome (1) (2) :44 4. Seizures (1) (2) :45 5. Non-chromosomal syndrome Specify. (I) (2) :46 :30 �Maternal Health Habits Study 13 6. Chromosomal syndrome Specify (1) (2) 4:47 XIII. GI 1. Necrotizing enterocolitis suspected (1) (2) :48 2. Necrotizing enterocolitis confirmed (0 (2) :49 Other GI problems Specify XIV. RENAL (1) (2) :50 1. ATN (1) (2) :51 2. Hydronephrosis (1) (2) :52 3. Other (specify) (1) (2) :53 3. XV. CONGENITAL INFECTIONS 1. Syphylis (0 (2) :54 2. Herpes (1) (2) :55 3. CMV (1) (2) :56 4. Toxo (1) (2) :57 5. Other (specify) (1) (2) :58 XVI. NEONATAL SURGERY 1. Circumcision (1) (2) :59 2. Other (specify) (1) (2) :60 Specify if palpebral fissure 1) Open spontaneously 2) Pried open 9) Not done :61 Raw Score of Dubowitz :62 Neurologic :63-64 Physical -.65-66 �STUDY DESIGN PROTOCOL APPENDICES DELIVERABLE D 1. INFORMED CONSENT AND RELEASE FORMS 2. CONGENITAL ABNORMALITY CLASSIFICATION AND PEDIATR1C EXAMINATION 3. MYOCARDIAL INFARCTION, SUDDEN DEATH AND STROKE CLASSIFICATION 4. NEUROBEHAVIORAL TESTING PROTOCOL 5. SOFT TISSUE SARCOMA CLASSIFICATION 6. PROTOCOL FOR 2, 3, 7, 8 - TCDD BODY BURDEN DETERMINATION �z ol I H z U |- 4f\' 'I' ' M - .. m Of — » E ^L. OL 5 y> U- a z < t/) to O Z ! ' ' z' —J. . LU< <! -| Q. Q Q o: *^ o o 2 :D t/i <JI _J u �Acknowledgements The authors are indebted to the many colleagues in their parent institutions, and to their colleagues in the Community Cardiovascular Surveillance Program for the synthesis represented in this paper and the accompanying three papers. �While it is well recognized that coronary heart disease mortality has declined in the United States during the past two decades, the reasons remain obscure. A major factor in our inability to fully understand the process has been a lack of information on disease morbidity rates, through which better understanding of mortality trends might occur. Three major research projects are currently in place in the United States that should provide insights into the cause of coronary heart disease mortality changes. These three programs testing community based cardiovascular disease prevention strategies are the Stanford Five-City Program, the Minnesota Heart Health Program, and the Pawtucket Heart Health Program. All are conducting ongoing surveillance for in-hospital myocardial infarcts and coronary heart disease mortality in a combined total of 13 communities totaling over 850,000 people. Two other major initiatives include similar surveillance activities. The Atherosclerosis Risk In Communities Study of the National Heart, Lung and Blood Institute has evolved from the Community Cardiovascular Surveillance Pilot Study and includes surveillance in four communities across the United States. Although the populations under morbidity and mortality surveillance are smaller in the Atherosclerosis Risk in Communities Study than in the three community studies, a larger number of known or potential risk factor variables will be studied and related to disease outcomes. The multi-national monitoring program for cardiovascular disease outcomes sponsored by the World Health Organization (MCNICA) is a cooperative study using similar protocols across many countries seeking to understand differential morbidity and mortality rates on a nation-to-nation basis. Each of these, and other similar research initiatives requires accurate, easily applied, and cost-efficient methods for surveillance of cardiovascular disease endpoints. Developmental work has been ongoing in the design of such methods in the United States and elsewhere and has resulted in steadily 1 �improving criteria and algorithms for coronary heart disease surveillance. Criteria and algorithms which originated in the Minnesota Heart Survey and have been utilized in the early stages of the three community projects have been published (1). Similar methods currently are being applied by MONICA, were utilized by the Community Cardiovascular Surveillance Pilot and will be employed in the recently funded Atherosclerosis Risk in Communities Study. In order to facilitate collaboration among the three community projects at Stanford, Minneapolis and Pawtucket, the National Heart, Lung and Blood Institute provided additional, separate funding in July, 1981 to form a Coordinating Committee for Coimnunity Demonstrations Studies (CCCDS). The major goal of this coordinating effort has been, wherever possible, to develop common outcome measurements for risk factors and for morbid and mortal events. Comparability of these outcome estimates, in turn, may enhance the interpretability and impact of conclusions from these conrttunity-based cardiovascular disease prevention research programs. The Evaluation Subcommittee of the Coordinating Committee of Community Demonstration Studies, consisting of the authors of the present paper, has carried out substantial developmental and pilot work on the surveillance approach for detecting cases of hospitalized acute myocardial infarction. The present trilogy of papers reports this pilot work, focusing upon applications of different diagnostic algorithms. The goal has been to produce a robust algorithm of high sensitivity and specificity, applicable in all three projects, for in-hospital nonfatal myocardial infarction (including in-hospital fatalities after diagnosis). Attributes of importance include robustness in the face of potential shifts in diagnostic categorization as may occur, for example, in the recently instituted Diagnosis Related Group hospital reimbursement policies. The approach should also be applicable across a wide range of medical �record content and be stable in the face of evolving diagnostic testing procedures. In the present series of papers, the algorithm originally developed by Gillum and colleagues (1) has been used as the Reference Algorithm (presented diagrammatically in Figure 1). Conceptually, this Reference Algorithm does not give differential weight to the hospital discharge diagnoses (as indicated by ICD-9 code) of cases screened. The diagnostic codes used most widely are ICD-9 410-414, although other codes can also be screened. Three diagnostic components are abstracted from the medical record of screened cases. Cardiac enzymes including creatine kinase (CK), lactic dehydrogenase, and aspartate amino transferase are directly copied from the record along with laboratory-specific information on the upper limits of normal in order to categorize enzyme levels. Any electrocardiograms are copied and subsequently coded according to the Minnesota code. The third component abstracted from the medical record is presence or absence, and (if present) duration and character of ches^pain. Substantial abstractor judgement is required to determine the length, location, and quality of the pain. Moreover, many medical records unfortunately contain no or very incomplete information on this item. As shown in Figure 1, the first priority for diagnosis is placed on the electrocardiogram (ECG) in the Reference Algorithm. An evolving diagnostic BCG suffices to conclude that an acute myocardial infarction occurred. A diagnostic electrocardiogram with abnormal enzymes also results in a diagnosis of definite myocardial infarction. In the absence of a diagnostic electrocardiogram, only the combination of prolonged pain and abnormal enzymes results in a conclusion of definite myocardial infarction. �The time and abstractor judgement required to abstract medical records for the Reference Algorithm, combined with the frequently inadequate medical record documentation of pain, led the Coordinating Conmittee Evaluation Subcommittee to investigate other potential algorithms with enhanced repeatability and equivalent validity. The algorithm presented in Figure 2 was developed to meet these goals. Several features represent conceptual changes fron the Reference Algorithm. The first is the departure from the usual anterospective clinical process in which the character of pain and the electrocardiogram are critical diagnostic components. In the new CCCDS Algorithm, the role of pain and of the electrocardiogram have been subjugated to that of creatine kinase. Duration and quality of chest pain is not considered. Further, cases which have already been judged clinically to represent acute coronary heart disease events (ICD-9 CM codes 410 & 411) are treated differently from cases which have not (codes 412-414 and any additional screening codes). For example, the absence of a mention of chest pain in the record has been equated with presence of pain for cases with diagnostic codes 410 and 411 rather than with the absence of pain, as in the Reference Algorithm. In essence, the resulting algorithm treats abnormal creatine kinase as diagnostic of acute myocardial infarction if it occurs in the presence of a hospital discharge diagnosis coded as ICD 9 CM 410 or 411. In the presence of equivocal enzymes, an evolving or diagnostic electrocardiogram also yields a definite myocardial infarction diagnosis in cases coded 410 or 411. Cases with codes other than 410-411 can reach a definite infarct diagnosis only if enzymes are abnormal and the electrocardiogram is evolving or diagnostic and pain is present. If enzymes are normal or equivocal for these cases, the only diagnoses possible under the CCCDS Algorithm are possible myocardial infarction or non-event. �The accompanying papers address a number of issues comparing the Reference and the CCCDS Algorithms. The CCCDS Algorithm, by minimizing abstractor judgement and decisions by medical review panels, is designed to be compatible with direct data entry and with computerized application of the criteria for diagnostic categorization. The cost and reproducibility of the abstracting process are considered in the paper by McKinlay and colleagues. Differential sensitivity and specificity of variations on the CCCDS Algorithm are discussed in detail by Mascioli and colleagues. The paper by Fortmann directly compares diagnoses derived from application of the Reference Algorithm, as used in the Stanford Study, to those using the CCCDS Algorithm. The results presented by these papers indicate that the CCCDS Algorithm represents a potentially important advance in heart disease surveillance methodology. �LEGENDS Figure 1: Reference Alogrithm for myocardial infarction surveillance derived from work of Gillum and colleagues. Abnormal enzymes = at least twice normal. Equivocal enzymes = above normal, but not twice normal. D = definite and P = possible myocardial infarction. N = no event. Figure 2: Revised CCCDS Algorithm for myocardial infarction surveillance. For criteria and abbreviations, see Figure 1. �REFERENCE 1. Gillum, R.F., Fortmann, S.P., Prineas, R.J., and Kottke, T.E. International Diagnostic Criteria for Acute Myocardial Infarction and Acute Stroke. Am. Heart J. 108:150-158, 1984. �<10-4M, 766.3. at/if codti optional (Evolving ECC7J Reference Algorithm C 01ogn i ECC? 'Prolonged Po n?J jntym C Dirymt Coltgpfy") I " C tnrynn Cotigofyj _ I " ( Eniymi Category) I /. CCCDS Algorithm ( C^ryfnt Cettflory J ' �PROGRESS IN CARDIOLOGY International diagnostic criteria for acute myocardial infarction and acute stroke Richard F. Gillum, M.D., Stephen P. Fortmann, M.D.,* Ronald J. Prineas, M.B., Ph.D., and Thomas E. Kottke, M.D., Minneapolis, Minn. Almost every investigator studying the occurrence, causes, treatment, or prevention of myocardial infarction or stroke will at some time require an explicit set of diagnostic criteria to classify potential cases on the basis of retrospectively collected data.1 These data may come from hospital records, clinic records, autopsy or coroner's reports,, next-of-kin interviews, and death certificates. Direct patient interview or examination often will be impractical or impossible, and baseline ECGs and neurologic examinations unavailable. The desire to study the determinants of the recent sharp downward trends in ischemic heart disease and stroke death rates as well as the need to evaluate morbid outcomes in community trials or cardiovascular disease prevention have led to the widespread application of community surveillance of hospitalizations for cardiovascular morbidity. This methodology, its problems, and applications have been reviewed recently.2 In the past, each study developed its own diagnostic criteria, making interstudy comparisons difficult. The current interest in explaining national mortality trends by examining morbidity and case fatality rates in many centers around the world calls for a concerted effort toward interstudy standardization of methods. This would enable the application of a single set of criteria to data collected in all centers, even though centers may wish to use other criteria for specific purposes. Diagnostic criteria developed for use in longitudinal From the Division of Epidemiology, School of Public Health, University of Minnesota and the Department of Medicine, School of Medicine, Stanford University*. Supported by National Institutes of Health Research Grants HL-23727 and HL-21906, National Institutes of Health Research Career Development Award 1K04 HL-00329 (Dr. Gillum), National Research Service Award 5T32 HL-07036, Preventive Cardiology Academic Award K07 HL-00662 (Dr. Kottke), and Research Training Grant 5T32 HL-07034 (Dr. Fortmann). Received for publication Oct. 17. 1983; accepted Nov. 16, 1983. Reprint requests: Ronald J. Primeas, M.B., Ph.D., Division of Epidemiology, 611 Beacon St. SE, Minneapolis, MN 55455. 150 prospective studies or in clinical trials probably will not be suitable when information for the diagnostic classification of potential cases must be abstracted from hospital records. The baseline data readily available in prospective cohort studies or clinical trials frequently are missing, equivocal, or uninterpretable in clinical records. Therefore, criteria must be formulated with particular regard to these limitations and must allow for cardiovascular events to be classified as definite or possible according to the degree of specificity of the criteria which have been met. The combined class of definite and possible cases should be highly sensitive to the event under study at the cost of lowered specificity, whereas the group of definite cases should be sufficiently specific to be used in etiologic research, where it is preferable to erroneously exclude some true cases than to include noncases. Excluding true cases reduces sample size and perhaps generalizability of findings, while including noncases dilutes by misclassification any associations that may be present within the study sample. The need for explicit, high-quality diagnostic criteria has become more generally recognized since an earlier report in 1964.3 At that time many published studies stated no criteria, and many of those stated were highly subjective in nature. In response to the need for a uniform set of procedures and criteria for interstudy comparisons of morbidity rates, we undertook to refine a set of diagnostic criteria previously used for community surveillance of myocardial infarction and stroke.4"7 All or parts of the set of criteria developed are currently being used with major or minor modifications by the Minnesota Heart Survey (MHS),8'9 the Minnesota Heart Health Program, the Stanford Five City Project, the Pawtucket Heart Health Program, and three large community intervention demonstration programs. These criteria were major inputs to the criteria independently developed by the Multicenter Community Cardiovascular Surveillance Program (CCSP) �Volume 108 Number 1 International criteria AMI'/stroke diagnosis Table I. Characteristics of criteria used in community surveillance population studies of myocardial infarction Characteristics Total number of studies in each group Written criteria published Source of criteria Self-designed WHO No explicit criteria Explicit criteria given for ECG Enzymes Clinical judgment use Unknown 1+ 2+ 3+ 4+ Evaluation published of Validity Repeatability n 24 18 14 6 4 11 9 of the National Heart, Lung and Blood Institute and the World Health Organization (WHO)-coordinated Project on Multinational Monitoring of Trends and Determinants in Cardiovascular Diseases (MONICA). Extensive testing of the validity, repeatability, and sensitivity of these criteria is currently being conducted.9 Computer algorithms have been written and tested for^ application in the MHS. This report seeks to review previously used criteria and to make the currently recommended criteria and the instructions for their use available to all investigators planning studies of acute myocardial infarction, ischemic heart disease death, and stroke so that their results may be more directly comparable to those of other current studies. PREVIOUS CRITERIA A previous report analyzed criteria used in 57 studies of myocardial infarction published prior to 1964.3 A review of the criteria used in all subsequent published studies of myocardial infarction and stroke is beyond the scope of this article. However, a selective review was performed of several types of studies. The criteria of the Framingham Heart Study,10 a community-based cohort study, were reviewed. This study developed its own criteria for myocardial infarction, which included fairly explicit criteria for interpreting the ECG and serum glutamic oxaloacetic transaminase (SGOT) levels obtained from review of hospital records from the suspected acute event. However, the degree of explicitness of criteria 151 Table II. Characteristics of criteria used in community surveillance population studies of stroke Characteristics Total number of studies Written criteria published Source of criteria Self-designed WHO NINDB 1958 No explicit criteria Other Explicit criteria given Neurologic symptoms and signs CT scan Other laboratory findings Clinical judgment use 1+ 2+ 3+ 4+ Unknown Evaluation published of Validity Repeatability n 16 9 5 2 2 6 1 3 1 5 1 0 4 4 7 0 0 was sufficiently low to require considerable use of subjective clinical judgment by the diagnostic review panel. Reports on the validity or repeatability of diagnoses derived from the process have not been published. Stroke criteria were also selfdesigned but tended to be less explicit, with heavy reliance on the clinical judgment of the review panel. The criteria of the only published nationwide cross-sectional survey, the Health Examination Survey, 1960-62,13 were reviewed. Detailed written criteria for myocardial infarction, derived from New York Heart Association criteria, were published. They included explicit criteria for chest pain history and ECG, and required relatively little use of clinical judgment in their application. A repeatability study of diagnostic assignment was published. Characteristics of diagnostic criteria used by 24 published community surveillance studies of myocardial infarction and stroke are shown in Tables I and II. Other features of these studies have been previously summarized.2 Hospital records were used by all as the primary data source.often supplemented by autopsy records and office records. The criteria of the WHO were used by several European studies including the WHO myocardial infarction and stroke registers.14 WHO criteria as revised in 1971 included explitic ECG criteria but required great use of clinical judgment for diagnosis of myo- �July, 1984 152 Gillum et al. cardial infarction. WHO stroke criteria were not explicit, relying almost entirely on clinical judgment. One study of repeatability was done in North Karelia, Finland.15 The prospective Health Insurance Plan of New York study16 and the retrospective Kaiser-Permanente study17 have both published self-designed criteria for myocardial infarction, which are explicit for ECG and enzymes. A series of major clinical trials of the secondary or primary prevention of ischemic heart disease death, myocardial infarction, and/or stroke have each developed diagnostic criteria for their end points. However, only a few have published their criteria. The Coronary Drug Project designed criteria for recurrent myocardial infarction, which were explicit for ECGs but not for enzymes or clinical symptoms.18 There was heavy reliance on clinical judgment in assigning the diagnosis. Stroke criteria were reasonably explicit regarding neurologic symptoms and signs but still relied heavily on clinical judgment. The Aspirin Myocardial Infarction Study also developed criteria for recurrent infarction, which included explicit ECG and enzyme criteria.19 Stroke criteria were less explicit. Little clinical judgment was required to diagnose myocardial infarction but much more to diagnose stroke. Studies varied considerably in the content and application of criteria. Those adopting WHO criteria usually modified them before use. In the few studies publishing explicit ECG criteria, the only common ground was that a new pathologic Q wave was diagnostic of definite myocardial infarction. Other studies accepted various combinations of Q waves, ST and T wave changes, and clinical symptoms as also diagnostic of definite infarction. Although the Minnesota code1 was sometimes used in criteria to describe ECG changes, it was seldom formally applied except in United States multicenter clinical trials.18'19 Likewise, the few studies publishing explicit enzyme criteria showed great variation in the requirements for the diagnosis of definite infarction. The one area of agreement was that enzyme elevations alone were not sufficient. DEVELOPMENT AND EVALUATION OF CRITERIA The following are specific goals pursued in the development of a refined set of criteria: (1) Create a set of validated cardiovascular disease event criteria, which maximize reliability by minimizing the need for "clinical judgment." (2) Minimize the need for manual calculations and manual algorithm application. (3) Minimize the use of implicit assumptions, criteria, or values. (4) Maximize the use of data usually found on a hospital chart, while avoiding a level of stringency that precludes applications to American Heart Journal records that were collected without research in mind. The criteria should also maintain validity by allowing "clinical judgment" to override the algorithm when it is apparent that the algorithm cannot deal with a specific case. The criteria should be based on symptoms, physical signs, tests, and other data validated or accepted as valid by the practicing medical community. This implies the following course of events: (1) Make a first draft of criteria based on "best judgment" and a literature review. (2) Make a first draft of chart abstracting forms based on the criteria. (3) Test whether data required for application of criteria are available, whether the forms can deal with the situations arising in hospital records, and whether the forms present the data to accurately reflect the sense of the record. (4) Continue to correct and update the criteria and forms in a feedback loop until steps 2 and 3 above are satisfactorily met. (5) Test reliability at the following levels: (a) Are multiple abstractors able to abstract the chart reaching the same conclusion in a sufficient proportion of cases? (b) Can the criteria be correctly applied to the abstracts in a satisfactory proportion of the cases? (c) If computer programs are used: Do they accurately reflect the logic of the criteria? Can they be applied with minimal data editing? Are they free of logic flaws or other "bugs"? Do they identify situations in which the algorithm is likely to reach an inappropriate conclusion? (d) After errors are eliminated, does reliability of diagnosis meet a priori defined criteria? (6) Test validity by the following methods: (a) Present the conclusions of criteria to a panel of experts, (b) Apply criteria to a set of cases with unusually complete data and compare conclusions reached with the "full" and the "reduced" data set. (For example, to test the robustness of the criteria when enzymes alone are present on a record, apply the criteria to the complete data set and then to the data set with all the information except enzyme values deleted.) The criteria are valid to the extent that the conclusions from the "reduced" data set correspond to the conclusions from the complete data set. (c) Apply the criteria to a set of autopsied cases including and excluding autopsy information. (Good agreement with and without autopsy data would support the validity of the criteria in nonautopsied cases). The initial set of criteria proposed here was built upon those of the Framingham Cardiovascular Disease Survey,4'7 which were designed in the early 1970s drawing heavily upon the criteria used in the Framingham Heart Study.10 The criteria of all the recent major cardiovascular clinical trials in the United States were reviewed with the assistance of �Volume 108 International criteria AMI/stroke diagnosis Number 1 153 Quarterly Review of Sample of al Death Certificates at MN Dept of Hearth (Data Clerk) EXCLUDE: - • Persons Aoed < 30 or > 75 • Nonresidents EXCLUDE: . Non-CHD or Non-CVD PosaMMes OUT-OF-HOSPITAL DEATHS IN-HOSPITAL DEATHS CLOSCST RELATIVE HEALTH CARE PROVIDERS LAST WITNESS PHOTOCOPY POST-MORTEM REPORT (SURVEY CLERK) • QUESTIONNAIRE TO PHYSICIAN • OBTAM RECORDS OP RECENT HOBPrTALBATIONS « 1 YH.) • ABSTRACT HOSPITAL RECORDS RECORDS INCOMPLETE • • • • IN-HOSPfTAL SURVIVORS • ABSTRACT HOSPITAL RECORDS • PHOTOCOPY ECO'I • PHOTOCOPY POST-MORTEM REPORT(ABSTRACTOR) NTERVEWS WITH MORTALITY FOLLOW-UP REQUEST MORE INFORMATION • PHOTOCOPY ECO'I NATIONAL DEATH INDEX MINNESOTA DEATH INDEX DIAGNOSIS RECORDED IN DATA CENTER COMPUTER FILES DEFINITE CASES UNCERTAIN CASES MORBIDITY AND MORTALITY FILE PHYSICIAN PANEL Fig. 1. Case finding and diagnosis validation of hospitalized cases of acute myocardial infarction and acute stroke and coronary heart disease death out of hospital. investigators intimately involved in their development and subsequent use in these trials. In addition, criteria used in community surveillance studies in the United States and those of the WHO myocardial infarction and stroke registers14 were reviewed. A dialogue was maintained with a WHO working group, who were updating the WHO myocardial infarction register system. Drafts of the criteria were circulated to experts in the epidemiology and clinical diagnosis of myocardial infarction and stroke. At several points in the process the criteria were pilot tested on case records from the Framingham Cardiovascular Disease Survey files, as well as on cases from hospitals cooperating in current research efforts. This led to further revisions. Finally, in a rigorous test of their logic, the criteria were reduced to algorithms suitable for translation into a computer program for assigning diagnoses. Many further revisions resulted from this process, as flaws in the logic became evident. The aim was to make the criteria so explicit that the exercise of clinical judgment would be necessary in only a small fraction of �July, 1984 154 Gillum et al. difficult cases. The criteria have now been applied to over 5,000 cases by the Minnesota Heart Survey, Stanford Five City Project, and other programs. The criteria are included in test form as Appendix 1. They are presented in tabular form in Appendix 2 (available upon request from authors). Some illustrative cases are included as Appendix 3 (available on request from authors). It is vital that the data to which the criteria are applied be collected in a standardized way. The following is a description of the proposed casefinding process and the data set to be collected. The case-finding process used by the Minnesota Heart Survey is diagrammed in Fig. 1. The investigators must carefully define the population at risk by specifying its age limits and its geographic limits as determined by place of usual residence. It is not feasible to routinely validate all hospitalized cases of illness in a community. A list of 1CD-9-CM discharge diagnosis codes is proposed here to ascertain nearly all cases in which a myocardial infarction or stroke might have occurred (Appendix 2). If there is reason to believe that other discharge codes may at times be used in a local situation for myocardial infarction or stroke cases these should be added to the list. After a large number of cases have been abstracted, all codes proved to yield few cases of myocardial infarction or stroke may be omitted from the list. However, to assure nearly complete ascertainment of cases, the list in Appendix 2 (available on request from the authors) is suggested as a starting point for pilot testing. All cases bearing codes of this list, either as a primary or secondary diagnosis, are to be reviewed initially. Appendix 4 (available on request from the authors) contains data collection forms designed for use with these criteria. Defined is the minimum data set needed to apply the criteria in a reasonably comparable manner. Other data may be collected according to the needs and purpose of each study. However, if each study collects the minimum data set, it will be possible to apply the criteria and make direct interstudy comparisons of morbidity rates. This in no way prevents any study from using one or more different sets of criteria, which may use more or less data than the minimum data set suggested. Appendix 5 (available on request from the authors) presents preliminary results of analyses of data availability, and to the validity and repeatability of diagnoses assigned by these criteria. CONCLUSIONS The use of the outlined surveillance procedures and the current criteria with necessary modifications will facilitate interstudy and longitudinal com- American Heart Journal parisons of cases and morbidity rates and will reduce bias arising from differing methods of case ascertainment, validation, and diagnostic criteria. The availability of such comparable data will be a major advance in the epidemiologic study of geographic and longitudinal variation in cardiovascular morbidity and mortality. We thank the following persons for assistance in revising the diagnostic criteria: Drs. Sonja McKinlay, David Jacobs, Richard Carleton. William Zukel, Jack Shisnant, Milton Ettinger, Howard Burchell, Lila Elveback, Paul Gunderson, Philip Wolf, Manning Feinleib, Paul Leaverton. Richard Havlik, John Kipp, Joseph Stokes III. Hugh Tunstall Pedoe, the members of the Committee on Criteria and Methods and of the Executive Committee, the Council on Epidemiology of the American Heart Association, and Ms. K. C. Jenkins and the nurse abstractors of the Minnesota Heart Survey. REFERENCES 1. Rose G, Blackburn H, Gillum R, Prineas R: Cardiovascular Survey Methods. Geneva, 1982, World Health Organization. 2. Gillum R: Community surveillance for cardiovascular diseases: Methods, problems, applications—a review. J Chron Dis 31:87, 1978. 3. Weinstein BJ, Epstein FH, and the Working Subcommittee on Criteria and Methods, Committee on Epidemiological Studies, American Heart Association: Comparability of criteria and methods in the epidemiology of cardiovascular disease. Report of a survey. Circulation 30:643, 1964. 4. Margolis JR, Gillium R, Feinleib M, Brasch RC, Fabsitz RR: Community surveillance for coronary heart disease: The Framingham Cardiovascular Disease Survey. Methods and preliminary results. Am J Epidemiol 100:425, 1974. 5. Margolis JR, Gillum RF, Feinleib M, Brasch RC, Fabsitz RR: Community surveillance for coronary heart disease: The Framingham Cardiovascular Disease Survey. Comparisons with the Framingham Heart Study and previous short-term studies. Am J Cardiol 37:61, 1976. 6. Gillum RF, Margolis JR, Feinleib M, Fabsitz RR, Brasch RC: Community surveillance for cardiovascular disease: The Framingham Cardiovascular Disease Survey. Some methodologic problems in the community study of cardiovascular disease. J Chron Dis 29:289, 1976. 7. Gillum RF, Fabsitz RR, Feinleib M, Wolf PA, Margolis JR, Brasch RC: Community surveillance for cerebrovascular disease: The Framingham Cardiovascular Disease Survey. Public Health Rep 93:438, 1978. 8. Gillum RF, Blackburn H, Feinleib M: Current strategies for explaining the decline in ischemic heart disease mortality. J Chron Dis 35:467, 1982. 9. Gillum RF, Prineas RJ, Luepker RV, Taylor HL, Jacobs DR, Kottke TE, Blackburn H: The decline in ischemic heart disease mortality. Minn Med 65:235, 1982. 10. Kannel WB, Gordon T: The Framingham Study: An epidemiological investigation of cardiovascular disease. Section 8. Two-year incidence by exam interval by age and sex at Exam 1. Washington, DC, 1968, United States Government Printing Office. 11. The Pooling Project Research Group: Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: Final report of the Pooling Project. J Chron Dis 31:201, 1978. 12. Epstein FH, Ostrander LD Jr, Johnson BC, Payne MW, Haynes NS, Keller JB, Francis T Jr: EpidemiologicaJ studies of cardiovascular disease in a total community—Tecumseh, Michigan. Ann Intern Med 62:1170, 1965. 13. National Center for Health Statistics: Coronary heart disease in adults. United States, 1960-62. Vital and Health Statistics �Volume 108 Number 1 14. 15. 16. 17. 18. 19. International criteria AMI/stroke diagnosis Series 11, No. 10, Washington, DC, 1965, United States Government Printing Oftice. Myocardial Infarction Community Registers. Results of WHO International Collaborative Study. Regional Office for Europe. World Health Organization, Copenhagen, 1976. Salonen JT, Puska P, Mustaniemi H: Changes in morbidity and mortality during a comprehensive community programme to control cardiovascular diseases during 1972-77 in North Karelia. Br Med J 2:1178, 1979. Shapiro S, Weinblatt E, Frank CW, Sager RV: Incidence of coronary heart disease in a population insured for medical care (HIP). Am J Public Health 59(Suppl):l, 1979. Friedman GD, Klatsky AL, Siegelahib AB. McCarthy N: Kaiser-Permanente epidemiologic study of myocardial infarction. Am J Epidemiol 99:101. 197-1. Coronary Drug Project Research Group: The Coronary Drug Project. Design, methods, and baseline results. American Heart Association Monograph No. 38. New York, 1973, American Heart Association, Aspirin Myocardial Infarction Study Research Group: Aspirin myocardial infarction study: Design, methods and baseline results. National Institutes of Health Publication No. 80-2106. Washington, D.C., 1980, United States Government Printing Office. APPENDIX 1 C R I T E R I A FOR EVENTS The events will be classified as definite, possible, and no event. I. Fatal coronary events A. Definite fatal myocardial infarction (MI) (Dx code 01) la. Definite MI within 4 weeks of death by criteria (see below for criteria for definite MI) -ORIb. Acute MI diagnosed by autopsy -AND2. No known nonatherosclerotic or noncardiac-atherosclerotic process that was probably lethal according to death certificate, autopsy report, hospital records, or physician records. B. Definite sudden death due to coronary heart disease (CHD) (Dx code 02) 1. Death witnessed as occurring within 1 hour after the onset of severe cardiac symptoms (prolonged cardiac pain—see below, shortness of breath, fainting) or within 1 hour after the subject was last seen without symptoms -AND2. No documentation of definite acute MI within 4 weeks prior to death by criteria (see below for criteria for definite MI) -AND3. No known nonatherosclerotic or noncardiac-atherosclerotic process that was probably lethal according to death certificate, autopsy report, hospital records, or physician report. C. Definite fatal CHD (DX code 03) 1. Death certificate with consistent underlying or immediate cause(s) (ICD-9 codes 410-414) -AND- 155 2. No documentation by criteria of definite acute MI within 4 weeks prior to death -AND3. Criteria for sudden death not met -AND4. No known nonatherosclerotic or noncardiac-atherosclerotic process or event that was probably lethal according to death certificate, autopsy report, hospital records, or physician records -AND5a. Previous history of MI according to relative, physician, or hospital records, or definite or possible MI by criteria (see below) -OR5b. Autopsy reporting severe atherosclerotic-coronary artery disease or old MI without acute MI (>50^o proximal narrowing of two major vessels or >75% proximal narrowing of one more vessel if anatomic details given) -OR5c. Rapid death: Death occurring greater than 1 and less than or equal to 24 hours after the onset of severe cardiac symptoms or after subject was last seen without symptoms. D. Possible fatal CHD (Dx code 08) 1. No documentation by criteria of definite acute MI within 4 weeks prior to death -AND2. No documentation by criteria of definite sudden death -AND3. No documentation by criteria of definite fatal CHD -AND4. Death certificate with consistent underlying or immediate cause (ICD-9 codes 410-414) -AND5. No known nonatherosclerotic or noncardiac-atherosclerotic process that was probably lethal according to death certificate, autopsy report, hospital records, or physician records. II. Nonfatal Ml A. Definite (Dx code 04) 1. Evolving diagnostic EGG -AND/OR2. Diagnostic EGG and abnormal enzymes -AND/OR3. Prolonged cardiac pain and abnormal enzymes. B. Possible—one or more of the following categories using the stated definitions below (Dx code 10): 1. Equivocal enzymes and equivocal EGG (with or without pain). 2. Equivocal enzymes and diagnostic EGG (no pain). 3. Abnormal enzymes and other EGG (no pain). 4. Abnormal enzymes and equivocal EGG (no pain). 5. Abnormal enzymes alone (no pain, ECG absent or uncodable). �July, 1984 American Heart Journal 156 G'ilium et al. 6. Prolonged cardiac pain and equivocal enzymes (ECG absent or uncodable). 7. Prolonged cardiac pain and equivocal ECG (enzymes incomplete). 8. Prolonged cardiac pain and diagnostic ECG (equivocal or incomplete enzymes). 9. Prolonged cardiac pain alone (ECG and enzymes incomplete). 10. Prolonged cardiac pain, "other" ECG, equivocal enzymes. 11. Prolonged cardiac pain, "other" ECG, incomplete enzymes. Definitions Prolonged cardiac pain: When it is characterized by pain with the following characteristics. (a) Occurring anywhere in the anterior chest, left arm, or jaw, which may also involve the back, shoulder, right arm, or abdomen on one or both sides. (b) Duration of more than 20 minutes. ECG (a) Evolving diagnostic ECG—an evolving pattern on serial ECGs of a diagnostic ECG. (An evolving pattern of changes [appearance or disappearance within lead groups: anterior (VrV6); lateral (1, aV,, V6); inferior (II, HI, aVF)] establishes the infarct as acute. Two or more ECG recordings during the hospitalization are needed for this classification.) (1) No Q code in one ECG record followed by a record with a diagnostic Q code (Minn, code 1-1-1 through 1-2-5 plus 1-2-7) -OR(2) An equivocal Q code (Minn, code 1-2-8 or any 1-3 code) and no major ST segment depression in one ECG record followed by a record with a diagnostic Q code PLUS a major ST segment depression (Minn, code 4-1, or 4-2) -OR(3) An equivocal Q code and no ST segment elevation in one ECG record followed by a record with a diagnostic Q code PLUS an ST segment elevation (Minn, code 9-2) -OR(4) An equivocal Q code and no major T wave inversion in one ECG record followed by a record with a diagnostic Q code PLUS a major T wave inversion (Minn, code 5-1 or 5-2) -OR(5) No Q code and neither Minn, code 4-1 nor 4-2 followed by a record with an equivocal Q code plus a 4-1 or a 4-2 -OR(6) No Q code and no Minn, code 9-2 followed by a record with an equivocal Q-code plus a 9-2 -OR- (7) No Q code and neither Minn, code 5-1 nor 5-2 followed by a record with an equivocal Q code plus a 5-1 or a 5-2. (b) Diagnostic ECG. (1) Minn, code 1-1-1 through 1-2-5 and 1-2-7 for diagnostic Q and QS patterns -OR(2) Minn, code 9-2 for ST segment elevation PLUS any T wave depression item coded 5-1 or 5-2 (none of the above T wave depression items can be used in the presence of ventricular conduction defects). (c) Equivocal ECG. (1) Q and QS pattern Minn, code 1-2-8 through 1-3-6 -OR(2) ST junction (J) and segment depression Minn, code 4-1 through 4-3 -OR(3) T wave items Minn. Code 5-1 through 5-3 -OR(4) ST segment elevation item Minn, code 9-2. (d) Other ECG: all other findings, including normal. (e) Uncodable ECG. (1) Missing lead. (2) Baseline drift greater than 1 in 20, if it obscures ST-T wave. (3) Muscle tremor artifact giving more than 2 mm peak-to-peak oscillation. (4) Other technical errors making Q-wave measurement impossible, such as extreme lack of centering or marked clipping. (5) Major abnormal QRS conduction patterns, e.g., complete bundle branch blocks, artifically paced rhythms, etc. (f) Absent ECG: No ECG available for coding. The ECG series will be assigned the highest category for which criteria are met, i.e., evolving diagnostic > diagnostic > equivocal > other. Cardiac enzymes Enzymes will be considered for the category of "abnormal" only if the upper limit of normal for the laboratory making the determination is recorded for the enzymes(s) used to make the diagnosis and: a. CPK-MB and total CPK have been measured within 72 hours of admission or onset of acute event, whichever is later -ORb. Total CPK has been measured and one of LDH or SGOT has been measured within 72 hours of admission or onset of acute event, whichever is later. Enzymes are "abnormal" if: 1. CPK-MB has been measured and is "present" (if hospital uses criteria of "present" and "absent") or at least twice the upper limits of normal (if hospital uses quantitative criteria) and total CPK is at least twice the upper limits of normal -OR- �Volume 108 Number 1 2. Total CPK has been measured and is at least twice the upper limits of normal and either LDH or SCOT has been measured and is at least twice the upper limits of normal. Enzymes will be considered for the category of "equivocal" only if the upper limit of normal for the laboratory making the determination is recorded for the enzyme(s) used to make the diagnosis. Enzymes are "equivocal" if: 1. CPK-MB and total CPK have been measured within 72 hours of admission or onset of acute event and CPK-MB is above the upper limits of normal for laboratories giving quantitative values or "present" for laboratories giving qualitative values but in either case total CPK is less than twice the upper limits of normal -OR2. At least one of CPK, LDH, or SCOT has been measured within 72 hours of admission or onset of acute event and is above the upper limits of normal, and the criteria for "abnormal" enzymes are not met -OR3. Enzymes (CPK-MB, CPK, SCOT, or LDH) are "abnormal," as defined above, but there is a nonischemic cause present (defibrillation, surgery, liver disease, injections, etc.). Enzymes are "normal" if: They meet criteria for consideration as "abnormal" or "equivocal" but criteria for these categories are not met. Enzymes are "incomplete" if: They do not meet criteria for consideration as "abnormal" or "equivocal." III. Primary cardiac arrest with successful resuscitation A. Definite (Dx code 07) 1. Ischemic arrest (a) Sudden cardiovascular (absent pulse) and pulmonary (absent spontaneous respiration) collapse with successful resuscitation -AND(b) Ventricular fibrillation or asystole reported on resuscitation ECG -AND(c) ECGs, enzymes, and history necessary for diagnosis of "definite" or "possible" MI collected. "Definite" and "possible" MI by criteria have been excluded -AND(d) No known nonatherosclerotic or noncardiacatherosclerotic acute or chronic process or event that would have been probably lethal -AND(e) History of previous MI -AND(f) Subsequent documentation of significant CHD (but not acute MI) during same hospitalization (coronary angiography showing >50% proximal narrowing of two or more International criteria AMI/stroke diagnosis 157 major vessels, or >75% proximal of one or more major vessels, old MI on ECG—Minn, codes 1-1, 1-2). 2. Primary arrhythmia (without ischemia) (a) Sudden cardiovascular (absent pulse) and pulmonary (absent spontaneous respiration) collapse with resuscitation -AND(b) Ventricular fibrillation or asystole reported on resuscitation ECG -AND(c) ECGs, enzymes, and history necessary for diagnosis of "definite" or "possible" MI collected. "Definite" and "possible" MI by criteria have been excluded -AND(d) No known nonatherosclerotic or noncardiacatherosclerotic acute or chronic process or event that would have been probably lethal -AND(e) No history of previous MI -AND(f) Subsequent documentation of no significant CHD during same hospitalization (absence of both >50Sc proximal narrowing of two or more or >75% proximal narrowing of one or more major vessels on coronary angiography). 3. Nonspecific (insufficient information to classify as ischemic or primary arrhythmia) (a) Sudden cardiovascular (absent pulse) and pulmonary (absent spontaneous respiration) collapse with resuscitation -AND(b) Ventricular fibrillation or asystole reported on resuscitation ECG -AND(c) ECGs, enzymes, and history necessary for diagnosis of "definite" or "possible" MI collected. "Definite" and "possible" MI by criteria have been excluded -AND(d) No known nonatherosclerotic or noncardiacatherosclerotic acute or chronic process or event that would have been probably lethal. B. Possible (Dx code 12) 1. Apparent sudden cardiovascular and pulmonary collapse with resuscitation as with "definite primary cardiac arrest." -AND2. Lack of documentation for ventricular fibrillation or asystole during resuscitation -AND3. Definite MI by criteria has not been diagnosed for this event -AND4. No known nonatherosclerotic or noncardiac-atherosclerotic acute or chronic process or event that would have been probably lethal. �July, 1984 158 Gillum et al. IV. Fatal stroke A. Definite (Dx code 05) la. Cerebral infarction or hemorrhage diagnosed at autopsy -ANDIb. Other disease process or event such as brain tumor, subdural hematoma, subarachnoid hemorrhage, metabolic disorder, or peripheral lesion that could cause localizing neurologic deficit or coma—according to death certificate, autopsy, hospital records, or physician records -OR2a. History of rapid onset (approximately <48 hours from onset to time of admission or maximum acute neurologic deficit) of localizing neurologic deficit and/or change in state of consciousness -AND2b. Documentation of localizing neurologic deficit by unequivocal physician or laboratory finding within 6 weeks of death with >24 hours duration of objective physician findings -AND2c. See list under Ib above. B. Possible (Dx code 09) 1. Death certificate with consistent underlying or immediate cause (ICD-9, codes 431-437) -AND2. No evidence at autopsy examination of the brain, if performed, of any disease process other than cerebral infarction or hemorrhage that could cause localizing neurologic signs (see Ib above). V. Nonfatal stroke A. Definite (Dx code 06) 1. History of rapid onset (approximately <48 hours from onset to time of admission or maximum acute neurologic deficit) of localizing neurologic deficit and/or change in state of consciousness -AND2. Documentation of localizing neurologic deficit by unequivocal physician or laboratory finding within 6 weeks of onset with >24 hours duration of objective physician findings -AND3. No other disease process or event such as brain tumor, subdural hematoma, subarachnoid hemorrhage, metabolic disorder, or peripheral lesion that could cause localizing neurologic deficit or coma according to hospital records. B. Possible (Dx code 11) la. History of rapid onset (approximately <48 hours from onset to time of admission or maximum American Heart Journal acute neurologic deficit) of localizing neurologic deficit and/or change in state of consciousness -ANDIb. Documentation of localizing neurologic deficit by unequivocal physician or laboratory finding within 6 weeks of onset with >24 hours duration of objective physician findings -ORIc. Discharge diagnoses with consistent primary or secondary codes (ICD-9-CM codes 431, 432, 434, 436, 437) -AND2. No evidence by unequivocal physician or laboratory findings of any other disease process or event causing focal brain deficit or coma other than cerebral infarction or hemorrhage according to hospital records. Unequivocal laboratory findings 1. A computerized axial tomography scan showing no definite findings of any disease process or event causing focal brain deficit or coma other than cerebral infarction or hemorrhage -AND2a. Showing a focal area of decreased or normal attenuation consistent with cerebral infarct -OR2b. Showing focal increased attenuation consistent with intracerebral hemorrhage. Criteria section Diagnostic code LA. I.B. I.C. II.A. IV.A. V.A. III.A. 01. 02. 03. 04. 05. 06. 07. I.D. IV.B. II.B. V.B. III.B. Definite fatal MI Definite sudden death due to CHD Definite fatal MI Definite nonfatal MI Definite fatal stroke Definite nonfatal stroke Definite primary cardiac arrest—with resuscitation 08. Possible fatal CHD 09. Possible fatal stroke 10. Possible nonfatal MI 11. Possible nonfatal stroke 12. Possible primary cardiac arrest—with resuscitation 98. Fatal event not due to CHD or stroke 99. Nonfatal event not due to CHD or stroke N.B. When criteria are met for two events occurring within 6 weeks of each other, the primary diagnosis will be that with the lowest diagnostic code in this hierarchy. �CHS - Surveillance Manual 5-4 Criteria for Categorizing Electrocardiogram Data At least one dated EGG must be present or the EGG will be diifined as absent. Lead groups are Anterior (V1-V5), Lateral (I, aVL, V6), and Inferior (II, HI, aVF). a. Definite EGG An evolving pattern of Q or QS changes within a lead group establishes the infarct as acute. Two or more EGG readings during the hospitalization are needed for this classification: There are eight possible sets of serial changes defined below, any one of which is sufficient: A. Evolving Q Waves (1) One EGG record showing no major Q or QS code and a later record with a diagnostic Q or QS code (Minn, code 1-1-1 through 1-2-5 and 1-2-7). (2) A minor Q code (1-2-3 or any 1-3 code) and no ST segment depression in one EGG followed by a later record showing a diagnostic Q code (1-1-1 through 1-2-5 plus 1-2-7) plus ST segment depression code 4-1 or 4-2). (3) A minor Q code and no ST segment elevation in one EGG followed by later record with a diagnostic Q code plus ST segment elevation (code 9-2). (4) A minor Q code and no T wave inversion in one EGG followed by a record with a diagnostic Q code plus T wave inversion (code 5-1 or 5-2). (5) No Q code and no ST depression (4-1, 4-2) on one EGG followed by a record with a minor Q code plus ST depression (4-1, 4-2). (6) No Q code and no ST elevation in one EGG followed by a record with a minor Q code and ST elevation (code 9-2). (7) No Q code and no T inversion in one EGG followed by a record with a minor Q code and T inversion (5-1 or 5-2). �CHS - Surveillance Manual B. b. Evolution of an Injury Current ( ) An ST segment elevation (9-2) lasting more than one day 8 and T wave progression from 5-0 or 5-4 to 5-1. Probable ECG A. Static Diagnostic Changes: either (1) or ( ) 2: (1) Minnesota Code for Q and QS pattern 1-1-1 through 1-2-5 or 1-2-7 on all records; or ( ) Minnesota Code for S-T segment elevation 9-2 plus 2 T inversion (code 5-1 or 5-2; cannot use T wave item in presence of ventricular conduction defects). B. Evolution of Repolarization Changes: any of the following: (1) No ST segment depression in one ECG record and other records with major ST segment depression (4-1). (2) No ST segment elevation in one ECG record and other records with ST segment elevation (9-2) . (3) No T wave inversion in one ECG record and other records with major T wave inversion (5-1 or 5-2). c. Equivocal ECG Any of the following'Minnesota codes: (1) Q and QS pattern 1-2-8 through 1-3-6; (2) S-T junction (J) and segment depression 4-1 to 4-3; (3) T wave item 5-1 through 5-3; (4) ST elevation code 9-2, d. Other ECG All other patterns, including normal will be included here. 9/83 5-5 �EGG Interpretation Program ft 1. Get all the EGGS's for the event. *2. Do not use ECG's which do not have a date or have no codes. 3. Code those records with 9-8-1 or 8-2-1 "UNUSED" and those with 6-8 or 8-2-6 "PACER". 3a. If all ECGs are coded "UNUSED" or "PACER" then code this ECG sequence "OTHER" and then STOP. «i. If an ECG is coded 6-1 , call it "AV BLOCK" and do not use. 4a. If all ECGS are "AV BLOCK", code this sequence "OTHER" then STOP, «p. If an ECG is codec 7-1 or 7-6, call it "LBBE" and do not use. 5a. If all ECG's are "LBBB", code sequence "OTHER" then STOP. 5. If an ECG is coded 7-4, call it "IVCD" and do not use. * 6a. If all ECGS are "IVCD", code sequence "OTHER" and STOP. 7. Now examine the "Anterior Lead Group" (VI,V5) of all remaining * individually. 7a. If only one ECG remains, 'go to 16 below. «£ODE ALL RECORDS AS FOLLOWS: 3. Q field (1-X-X codes) Qo: No 1-X-X code * Ql: Any 1-3-X or 1-2-8 ,Q2: Any code 1-1-1 through 1-2-5 or 1-2-7 *. STD field (4-X codes) STDo: No 4-X code or 4-3 or 4-4 STD1: 4-2 * STD2: 4-1 10.T field (5-X codes) To: No 5-X or 5-4 * Tl: 5-3 T2: 5-2 T3: 5-1 * ll.STE field (9-X codes) STEo: No 9-2 «, STE1: 9-2 Repeat steps 12-13 for Anterior Lead Group, Lateral Lead Group, and Inferior Lead Group if a code has not been reached for the irevious lead group. If at the end of all lead groups a code *as not been reached go to 15. 12. Lead group sequence coding: 12a. Is there any Qo followed by any Q2? * YES: go to 12h NO : go to 12b 12b. Is there a QlSTDo followed by a Q2STD1 or Q2STD2? YES: go to 12h �NO : YES: NO : YES: NO : 12c. Is there a QlTo followed by a Q2T2 or Q2T3? 12d. Is there a QlSTEo followed by a Q2STE1? go go go go go to to to to to 12c 12h 12d 12h 12e 12e. Is there a QoSTDo followed by a Q1STD1 or Q1STD2? YES: go to 12h NO : go to 12f 12f. Is there a QoTo followed by a Q1T2 or Q1T3? YES: go to 12h NO : go to 12g 12g. Is there a QoSTEo followed by a Q1STE1? YES: go to 12h NO : go to 13 12h. Does any Qo record arjpear following a Ql or Q2 record? YES: code "CODING INCONSISTENT" then NO : code "DEFINITE ECG A" then STOP 13. Are there two records more than 24 hours apart but wichin 5 days of z'ne ever.::? Are there two records on different days with STE1? .13a. Is there a record with To followed bv a record with T3? YES: continue NO : gc tc 14 YES: go to 13a NO: go to 14 YES: DEFINITE ECG B STOP NO : go to 14 14. Repeat steps 8-13 for "Lateral Lead Group" (1,L,V6); if read "go to 14", then repeat steps 8-13 for "Inferior Lead Group" (2,3,F); if again reach "go to 14" then go to 15. 15. Examine "Anterior Lead Group" sequence: 15a. Is there a record with STD2 and another record with STDo (temporal order irrelevant)? YES: PROBABLE ECG B,STO NO : go to 15b 15b..Is there a record with STE1 and another record with STEo (sequence irrelevant)? YES: PROBABLE ECG B,STO~ NO : go to 15c 15c. Is there a record with To and another record with T2 or T3 (sequence irrelevant)? YES: PROBABLE ECG NO : go to 15d 15d. Repeat 15a through 15c for Lateral and Inferior Lead Groups; if reach "go to 15d", go to 16 16. Examine all available records: 16a. Does any record have Q2? YES: PROBABLE ECG A, STOP NO : go to 16b 16b. Does any record have STE1 plus T2 or T3? YES: PROBABLE ECG A, STOP NO: go to 16c 16c. Does any record have Ql or STD1 or STD2 or code 4-3 or Tl or T2 or T3 or STE1? YES: EQUIVOCAL, STOP NO: OTHER, STOP �] 78/86 PHH? r I M. SURVEILLANCE ECG ALGORISM DEFINITE n BY ECG ALL ECGs HAVE 6-1,6-8 STOP YES 7-4,7-1,7-2-1 -2,9-8, OR 6-4-1? NO YES (1-1 THRU 1-3 PRESENT^ ! 1-1 THRU 1-2-5 i OR 1-2-7 ' PRESEf.T ON ANY ECG? No YES 1 ; SUB, ECS HAS ' 1-2-8 OR 1-3? 1-2-8 OR 1-3 or; ANY ECG? ANY ECG HAVE &-2 AND 5-1 OR 5-2? (SAME LEADS) No YES ECG n HAS NO 4-1 OR 4-2? (SAME LEADS) YES No ANY ECG HAVE 1-2-8, 1-3, 4-1 4-2, 4-3, 5-1, 5-2, OR 5-3? No ECG #1 HAS NO 5-1 OR 5-2? SUB ECG HAS 4-1 OR 4-2? (SAME LEADS) No YES SUB. ECG HAS 5-1 OR 5-2? YES YES | DEF MI DIAG ECG �RAG 1/6/86 PHHP MORBIDITY AND MORTALITY SURVEILLANCE FOR STROKE IN HOSPITAL OUT OF HOSPITAL UIS, PAS TAPE. DATE, AGE, ADDRESS, ICD-9 CODE ELIGIBLE? DEATH CERT. TAPE, DATE, AGE, ADDRESS, DIAGNOSIS, ELIGIBLE? NO YES MEDICAL RECORD I NO ASSESSED? NO ! INFORMANT ACCESSED? YES YES YES DISCH. SUMM,, CAT SCANS, NEUPO/NS CONSULTS, ARTEPIOG. COPIED VALVE SURGERY, CANCER IN PAST OR UNCONSCIOUS HEAD INJURY IN TWO DAYS? OR YEAR, FROM PAST NO PHYSICIAN REVIEW YES PARALYSIS OR OTHER LCC. NEURO DEFECT? 1, 5.3, 5.5, OR 5.6 = YES SUBARACH. HEM. ONLY, OR PRESENTLY AT. FIB., OR PROSTH, VALVE, OR TIA? NO NEW HEADACHE AND HIGH BLOOD PRESSURE9 YES TO 5.7 AND 5.8 YES NO DEF. NEW, PERSISTENT NEURO DEFECT YES DEF. STROKE NO PROB. DEFECT PLUS CAT SCAN CONFIRM YES NO PROB. DEFECT: NO CAT CONFIRM YES PROB. STROKE YES �Version 20 9/27/84 i Surveillance J CORE DATA SHEET CDS ft: Hospital I.D.: Chart #: Study I.D. Discharge Date: Admission Date: Case Disposition: Discharge Diagnoses 1-7: 1. Folder No. (If different from Chart #): 2. First three letters of patient's last name: 3. First letter of patient's first name: 4. Social Security No.: (Enter "9" in all boxes if not recorded) �HOURS MINUTES 1. A.M. 2. 5. Time of Admission: P.M. 6. Marital Status: 1. 2. 4. DIVORCED MARRIED 5. NEVER MARRIED WIDOWED 3. 9. SEPARATED NR 7. Occupation Status (current): 1. RETIRED 5. STUDENT 8. Veteran: 2. 6. 1. NOT WORKING (DISABLED) EMPLOYED FT OR PT F.O 3. NOT WORKING (OTHER) (SPECIFY OCCUPATION) 2. YES 9. NR 9. Physician discharge diagnoses as found in the Medical Record: a. Primary: b. Other: c. Other: d. Other: e. Other: f. Other: g. Other: 4. HCMEMAKER �ACCESS RECORD Instruments Included in Packet: M.I. ABSTRACTOR I 1. NO 2. YES M.I. ABSTRACTOR II 1. NO 2. YES AUTOPSY 1. NO 2. YES STROKE 1. NO 2. YES Record for all attempts: Access Attempts Date Length of Time (inmin.) Abst. I.D. DISP. NOTES 1. 2. 3. j 10. Record the following for the last attempt: 'i J A. NUMBER OF ACCESSES: <* B. i J i LftST ABSTRACT DATE: (year, month, day) 11. Record the total length of time for location and abstraction in minutes, adding time from all attempts. 12. Abstractor I.D.: 13. Transcriber I.D.: j 14. Abstraction Disposition: �FOP. ALL 410's AND All's, AND FATAL 412-414, 786.5's - CONTINUE ABSTRACTION. FOR ICD-9 DISCHARGE CODES 412, 413, 414 and 786.5 THAT ARE NON-FATAL CASES: According to the Discharge Sumnary and/or the E.R. Sheet: 1. Were there complaints of pain, heaviness or discomfort, including severe shortness of breath? NO YES 2. Was there any evidence of unexplained unconsciousness before or after admission? NO YES 3. Were there any new occurrences of ventricular tachycardia, ventricular fibrillation or frequent premature ventricular contractions/impulse (PVCs, PVIs) ? NO 1. IF NO TO ALL ABO^E - STOP FDX = NON EVENT YES 2. IF YES TO ONE OR MOPE COCTINUE ABSTRACTION �Surveillance M Y O C A R D I A L INFARCTION A B S T R A C T CDS #: J Hospital ID: .Chart #: Study ID: J Discharge Date: Admission Date: J Case Disposition: Discharge Diagnoses 1-7: • Abstractor Code: Date Abstracted: IF TRANSFER j Transcriber Code: (MA = 88) Version 26 9/26/84 I �1. Did the onset of the first cardiac episode begin on or before the time of admission? (Either prior to presentation at the hospital or in the ER)? 1.1 What was the date of onset of this episode (after admission)? 1.2 Was there any complaint of pain, heaviness, or discomfort associated with this episode? 1.3 Is the source of the pain above the waist (including chest, arm, jaw, neck, back, shoulder)? 2. Was there a second cardiac episode during this admission? 2.1 What was the date of onset of this episode? �2.2 Was there any complaint of pain, heaviness, or discomfort associated with this episode? 2.3 Is the source of the pain above the waist (including chest, arm, jaw, neck, back, shoulder)? 1. NO 2. YES 9. MR 8. NA I 3. Were any Total CPK levels recorded? 3.1 Is the screening coae 41C or 411? 1. NO 2. YES v s/ FDX = NON EVENT STOP 8. NA ED = MISSING COMPLETE 2lsT> FORM S 4. Is the ULN available for at least one Total CPK value? 2. YES 8. NA >/ ED = MISSING COMPLETE 2ND FORM FOR THE FIRST EPISODE, DESCRIBED IN Q. 1 ABOVE, RECORD UT TO 5 CONSECUTIVE TOTAL CPK AND CPK - MB VALUES REPORTED AS BEING DRAW IMMEDIATELY AFTER THE EPISODE. �1 EPISODE 1 TOTAL CPK: DATE 5.1 TIME // ULN 2 x ULN RECORDED VALUE : s I •- 5 . 2 / / : _ Z a i 5 . 3 / / : a a 5 . 4 / / ' : a a 5.5 // : a a !r ~f �EPISODE 1 CPK - ME: j 6.1 , / / DATE TIME IF PERCENT: J (NA = 8's) (NR = 9's) J [ F QUALITATIVE;] | 1. ABSENT | 2. TRACE | 3. PRESENT |[ 9. NR || 8. NA I [ | J [ 1. AM 1 6.2 _/ /. DATE TIME |IF IU/L; 2. PM j IF PERCENT: (MA = 8's) (NR = 9's) j JIF QUALITATIVE; | j l T ABSENT |( 2. TRACE || 3. PRESH7T] | 9. NR |[ 8. NA | j 1. AM | 6.3 j / / DATE TIT IE | IF I D / L i ] 2. FM IF PERCEFf: f (NA = 8's) (NR = 9's) |IF QUALITATIVE:) | 1. ABSENT \[ 2. TRACE | 3. PRESENT"] | 9. NR 1 1 8. NA | 1 1. AM | j 6.4 * / (IF IU/L; | / DATE TIME 2. PM IF PERCENT: (NA = 8's) (NR = 9's) QUALITATIVE;] | 1. ABSENT | [ T TRACE | [ . PRESEtTT | 9. NR | 8 NA | T T | f. 1 . AM | J 6.5 [ I F IU/L; __ DATE TIME 2. PM IF PERCENT: t (NA = 8's) (NR = 9's) EF QUALITOTIVE^IlVABSEJNT 1 || 2. TRACE ||3. PRESENT || 9. NR || 8. NA | �EPISODE 2; . FOR THE SECOND EPISODE ( F ANY) DESCRIBED IN Q.2 ABOVE, RECORD UP I 'TO 5 CONSECUTIVE TOTAL CPK AND CPK-MB VALUES AS FOR EPISODE 1 ABOVE. TOTAL CPK: DATE 7.1 // TIME : 7 . 2 / / : 7 . 3 / 7 : 7 . 4 / 7 : 7.5 / / ULN . X UUM RECORDED VALUE �1 I EPISODE 2 CPK - MB: 1. AM | | IF IU/L;1 / DATE 1 J / TIME 2. FM | IF PERCENT: (NA = 8's) (NR = 9's) IF QUALITATIVE; | ( T ABSENT \{~2. TRACE \\ 3. PRESENT] | 9. NR jj IB. NA | T J 1. AM | _/ /_ DATE TIME | IF IU/L; 2. PM IF PERCENT: (NA = 8's) (NR = 9's) [IF QUALITATIVE;! | 1. ABSENT \\ 2. TRACE | 3. PRESENT") | 9. NR~| I 8. NA | | f l T AM I / 8.3 DATE J I IF IU/L; [ / TIME 2. PM IF PERCENT: (NA = 8's) (NR = 9's) J [IF QUALITATIVE! |1 1. ABSENT \\ 2. TRACE ]| 3. PRESET7T | | 9. NR~] | 8. NA ;|8.4 [ 1. AM | __ DATF TIME | IF IU/L; \?._ PM I IF PERCENT: (N?. = 8's) (NR = 9's) J IIF QUALITATIVE; | fTTABSENl1 | | 2. TRACE | 3. PRESENT] [ 9. NR|| 8. NA | | 1. AM | / / . DATE TIME IF IU/L; 1 2. PM I IF PERCENT: (NA = 8's) (NR = 9's) [IF QUALITATIVE; |(1. ABSENT |[2. TRACF | 3. PRESEKT] | 9. NR 1 1 8. NA | | �9. Is at least one CPK value => 10. Is at least one CPK value : ULN? * ET^EQUIVOCAL SKIP TO 0. 15 _w 11. Are at least two CPK values available in the 96 hour period after each of the episodes defined in Q. 1 and Q. 2 above? 1. NO \' 11.1 Is the screening code 410 or 411? 1. NO 2. YE? \' . i3. NA \t 11.2 Is thjp a fatal discharqe? FDX = NON EVENT STOP ED = MISSING COMPLETE 2ND FORM FDX=NON-EVENT STOP 12. Is any form of muscle disease (ICD-9 codes 710.3, 710.4, 725, 728.0) recorded in discharge sunmary as present? E.D. = EQUIVOCAL SKIP TO Q. 15 �13. With reference to the episode(s) defined in 0. 1 and Q. 2: in the 72 hour period inmediately prior to any CPK value "^ 2ULN were any surgical procedures performed? (COMPLETE A OR B, NOT BOTH, AND CHECK NA FOR THE ALTERNATIVE WHICH DOES NOT APPLY.) A. IF ONE EPISODE (Q. 1 ONLY) ONLY B. IF AT LEAST TWO EPISODES (Q.I AND Q. 2 8. NA 1. NO TO AT LEAST ONE 2. YES TO BOTH 9. MR E.D. - ABNORMAL SKIP TO Q. 14 GO TO Q. 13.1 ! 8. NA �13.1 Record all procedures (within the 72 hour time frame of 0. 13) listed in the record using ICD-9 codes. If no ICD-9 codes are recorded, write the name of the procedure. PROCEDURE TIME DATE a. b. 13.2 Do any procedures listed in Q. 13.1 above correspond to any on the EXCLUSION LIST? 1. NO ED = ABNORMAL \1 2. YES ED = EQUIVOCAL SKIP TO Q. 15 10 �14. Is the screening code 410-411? FDX=DEF MI STOP 15. (ALL EQUIVOCALS: Q's 10, 12, 13.2) Is the screening code 410 or 411 (see label)? 15.1 Is this a fatal discharge? COMPLETE 2ND FOPM COMPLETE 2ND FOPJ* . Is pain present (YES ON Q. 1.3 or 2.3)? 1. NO Jl / FDX=NON EVENT STOP 2. YES 8. NA %f FDX=POSS MI STOP 11 �Surveillance MYOCARDIAL INFARCTION ABSTRACT Version 18 09/26/84 II I CDS #: i Hospital ID: m Chart I: Study ID: Discharge Date: m I Admission Date: Case Disposition: i I Discharge Diagnoses 1-7: Abstractor Code: i Date Abstracted: i IF TRANSFER Transcriber Code: (NA = 88) �1. What type of admission was this? (Check 'YES1 to all that apply.) YES NO a. Elective J b. Emergency c. Transfer 1.1 From where? .. SHORT-STAY HOSPITAL - NURSING! HOME PSYCHIATRIC INSTITUTION 8. NA 4. OTHER, SPECIFY: ' 9. IIR 2. I REFER TO THE FIRST EPISODE (PART I Q. 1) a. First temperature recorded after onset of first episode: NR = NA = 9 8 9 9 9 8 8 8 1. F 1. 0 8. NA 2. C 2. R 9. NR 9. NR 3. A b. Temperature recorded 72° after onset (or nearest after 72°) NR = NA = 9 9 9 8 8 8 9 8 9. NR 1. F 1. 0 3. A 8. NA 9. NR c. First blood pressure recorded after onset of first episode: SYSTOLIC NR = 9 ~9"~9~ NA = 8 8 8 DIASTOLIC 8 8 8 �3. REFER TO THE SECOND EPISODE (IF ANY) (PART I Q. 2) a. -First temperature recorded after onset of second episode: MR = NA = 9 8 9 9 9 8 8 8 1. 2. C F 9. NR 8. NA 1. 0 b. Temperature recorded 72° after onset (or nearest after 72°) NR = NA = 9 8 9 9 9 8 8 8 2. C 1. F 8. NA 2. R 1. 0 9. NR 3. A 9. NR 8. NA c. First blood pressure recorded after onset of second episode: SYSTOLIC NR = NA = DIASTOLIC 9 9 9 8 8 8 9 9 9 8 8 8 PRE-ADMISSION HISTORY 4. NO ]L History of coronary bypass surgery? 5. History of atrial fibrillation or flutter? YES | 2 ] fTl H~l POSSIBLE |3 j P~l NR |9 PH 6. History of mitral stenosis? 2 T 7. History of congestive heart failure? 2 8. History of hypertension? 2 9. History of previous MI? T" T T T 9.1 Date of most recent MI prior to current admission: MONTH NA = NR = DAY YEAR 8 9 8 8 9 9 8 8 9 9 8 9 �NO r r NR 10.1 First attack occurred how many weeks before admission? 1. 4= 2. > 8 WEEKS 11. History of cardiac arrest? 11 .1 POSSIBLE m 10. History of angina? 8 WEEKS NO r r YES YES NR ~T POSS. T Last arrest occurred how many weeks before admission? 1. £. 4 WEEKS 2. >4 WEEKS 4=. 6 WEEKS 3.> 6 WEEKS ^ 8 WEEKS 4. > 8 WEEKS 8. NA 9. NR 12. Is there evidence of any other history of cardiovascular disease in ' the record, other than those listed previously? 1. NO V r r r r r 12.1 For each expression listed below, check whether or not it was mentioned in the record. NO YES POSSIBLE NA NR a. CVD b. ASHD 3J . CAD _§_ d. Coronary [ 1 Insufficiency e. Heart Disease T 1 f. Other Specify: i. NA| |9. NR �13. Family history of heart disease, stroke or high blood pressure? 1. NO 2. YES 4 3. UNKNOWN 13.1 Specify Condition: 8. NA | 9. NR 9. NR \' V 14. Current smoker? 2. YES 1. NO 9. NR 15. Alcohol intake status: According to the Medical Record, the patient is a: (check only one box) 1. NON-DRINKER 2. PAST ABUSER 3. CURRENT DRINKER 9. NR 16. Was coronary angiography performed during this admission? 1. NO COPY THE REPORT AND ATTACH 17. Were any of the following cardiac rhythm (s) documented? "yes" to all that apply). (check NO YES a. Ventricular fibrillation [1 [2 [ b. Ventricular tachycardia [1 | 2 | c. Supraventricular tachycardia | 1 [2 | d. Sinus tachycardia [ 1 (2 | | 2 | e. Paroxysmal Atrial tachycardia | 1 (PAT) f. Atrial fibrillation | 1 [~2~1 g. Atrial flutter DO h. Asystole [~ NR 2 �18. Did the patient require resuscitation at any time associated with this admission? 18.1 Where did the resuscitation attempts occur? NO YES NA a. Outside the hospital GO TO Q. 19 b. In the hospital, but prior to admission (in emergency room, or other hospital department) c. I.C.U. T d. C.C.U. T T e. Other S.C.U. T T f. Other hospital unit after admission 18.2 Were any of these attempt(s) unsuccessful? (i.e., patient expired) 18.3 If yes, where in the hospital did the unsuccessful attempt occur? NO YES In: a. I.C.U. NA J8_ T b. C.C.U. c. Other S.C.U. _2_ d. Other hospital unit after admission T T �19. FOR THOSE PATIENTS DYING DURING ADMISSION, COMPLETE Q. 20-22 OTHERWISE SKIP TO Q. 23 20. Time patient last observed before found expired or before resuscitation attempted. 1.> 24 HOURS BEFORE DEATH 2.> 1 HOUR BUT £ 24 HOURS BEFORE DEATH HOUR BEFORE DEATH 1 GO TO Q. 21 COMPLETE Q. 20.1 20.1 Did patient have ANY of the following cardiac symptoms: fainting, dyspnea, diaphoresis, nausea/vomitting, cyanosis, and/or pain, discomfort or heaviness in the chest, neck or arms? 1. NO 2. YES 8. NA V 9. NR 20.2 Was onset of symptoms: (check one box only) 1. ^ 1 HOUR BEFORE BEING FOUND EXPIRED 2. > 1 HOUR BUT 3C 24 HOURS BEFORE FOUND EXPIRED 3. > 24 HOURS BEFORE BEING FOUND EXPIRED 8. NA ,- MONTH 9. NR DAY YEAR 21. Date patient (found) expired: NA = 8 8 8 8~ �MINUTES HOUR 22. Time patient (found) expired: NA = 1. 23. 8 8 8 AM COPY AND ATTACH ALL ECG'S AS INSTRUCTED 2. PM 8 8. NA �2/6/87 RAC PHHP INFORMANT INTERVIEW ALGORITHM I. II. III. If Q. 10A OR 11 is answered 2 (YES), AND 1 (NO) or 9 (DK) to 10B, E, F, and H, and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. AND Q. 26 is answered 1 AND Q. 29-38 are answered 1 (NO) then DSCD. If Q. 29.1 or 30.1, or 31.1 is answered 6 or 7, AND 1 (NO) to 10B, E, F, and H, and 1 (NO) to 22 or, if yes to 22, 2 (YES) to 22.1. then DSCD. If Q. 32.1 is answered 6, or 7 AND 1 (NO) or 9 (DK) to 10B, E, F and H, and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. then DSCD. IV. If Q. 34.1 is answered 6, or 7 AND 1 (NO) or 9 (DK) to 10B, E, F and H, and 1 (NO) OR 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. and NO STROKE then DSCD. V. If Q. 26 is answered 1, AND 1 (NO) or 9 (DK) to Q. 10B,'E, F and H, and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. DSCD. VI. VII. If Q. 29.1 or 30.1 is answered 5, 6, or 7 AND 1 (NO) or 9 (DK)to10B, E, F and H and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. then DFCHD. If Q. 10A is answered 2 (YES) OR Q. 11 OR Q. 13 is answered 2 (YES), AND 1 (NO) or 9 (DK) to Q. 10B, E, F, and H and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1 then DFCHD. VIII. If Q. 26 is answered 2 AND 1 (NO) or 9 (DK) to 10B, E, F, and H and 1 (NO) or 9 (DK) to 22 orTTf yes to 22, 2 (YES) to 22.1. then DFCHD. IX. If Q. 29 OR 30 is answered 2 (YES) AND 1 (NO) or 9 (DK) to 10B, E, F, and H and 1 (NO) or 9 (DK) to 22 orTTf yes to 22, 2 (YES) to 22.1. then DFCHD. X. If Q. 29.1 OR. 30.1 is answered 1, 2, 3, or 4 AND 1 (NO) or 9 (DK) to 10B, E, F, and H and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. then DFCHD. XI. If Q. 31.1 OR Q. 32.1 is answered 1-5 AND 1 (NO) or 9 (DK) to 10B, E, F, and H and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES)to22.1. then DFCHD. XII. If Q. 34.1 is answered 6 or 7 PLUS 1 (NO) or 9 (DK) to 10B, E, F and H and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. and NO STROKE, then DFCHD. XIII. If Q. 27 is answered 1 AND 1 (NO) or 9 (DK) to 10B, E, F, and H, and 1 (NO) or 9 (DK) to 22, or if yes to 22, 2 (YES) to 22.1, then DFCHD. XIV. If death certificate ICD-9 Codes are 410-414 AND not DSCD or DFQD AND Q. 10B, E, F and H are answered 1 (NO) or 9 (DK) and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. then DFdD. �2/6/87 RAC PI II IP XV. If Q. 11 is answered 1 (NO) AND Q. 13 is answered 1 (NO) OR 2 (YES) to Q. 21 OR 1 (NO) to 30.1, AND 2 (YES) to 10B, E, F, or H or 2 (YES) to 22.1: then NCE. FATAL STIOKE ALGORITHM XVI. XVII. XVIII. XIX. XX. If Question 21 is YES (2), OR Question 22.1 is 2 (YES) OR Question 23 is YES (2), AND 1CD-9 Code is not 430-437, NAS. If Question 21 is 1 (NO), OR Question 22.1 is 2 (YES) OR Question 23 is YES (2), AND ICD-9 Code is 430-437, PFS. If Question 41.1 is YES (2), OR Question 42 is YES (2), OR Question 43 is YES (2), OR Question 44 is YES (2), and 1 (NO) or 9 (UK) to 10 B, E, F AND H AND 1 (NO) or 9 (DK) to 22 OR, if yes to 22, 2 (YES) to 22.1. FS. If Question 45 is YES (2), AND Question 24 is YES (2), AND ICD-9 Code is 430-437, PFS. If Question 41.1, 42, 43, AND 44 AND both 45 AND 24 are NO (1), MAS. Priority of Diagnoses Informant Interview Algoritlim 1) Definite Sudden Death due to Coronary Heart Disease (DSCD) 2) Definite Fatal CID (DFC1D) 3) Fatal Stroke (FS) 4) Possible Fatal CID (PFCI1D) 5) Possible Fatal Stroke (PFS) 6) Non-Cardiac Event (NCE) 7) No Ascertainable Stroke 8) No Ascertainable Event �Surveillance Version 10 11/10/86 INFORMANT INTERVIEW SCREENER Death Certificate # Decedent's Name Residence Date of Death Study 3D Informant Name Address Telephone Relationship to Deceased 1. Are you familiar with prior to death? _'s medical history in the year |2. YES - Continue to Informant Interview - I] l.NO 1.1 Is there someone I could talk to concerning 's medical history? OBTAIN NAME ADDRESS Phone Relationship to Deceased 2. Are you familiar with the events at the time of death? l.NO 2. YES - Continue to Informant Interview - II T " 2.1 Do you know of someone I could talk to regarding the exact circumstances of 's death? OBTAIN NAME ADDRESS Phone Relationship to Deceased �Version 10 11/10/86 RELIABILITY OF INFORMANT NO YES Medical History 3.a Did the respondent frequently contradict (himself/herself) or give information that he/she would have no way of knowing? b Did the respondent seem to be reluctant to answer questions and thus might not have given all the information the interviewer would wish to know? Signs and Symptoms 4.a Did the respondent frequently contradict (himself/herself) or give information that he/she would have no way of knowing? b Did the respondent seem to be reluctant to answer questions and thus might not have given all the information the interviewer would wish to know? 5. On the basis of these questions, give your rating of reliability of the interview. I. - Medical History 1 | | GOOD 2 [ | FAIR POOR II. - Signs and Symptoms 1 I I GOOD 2 || FAIR POOR 6. INTERVIEWER'S NAME ID QODE �Version 10 11/10/86 FINAL DISPOSITION I - Medical History 01. Interview completed with Primary Informant 02. Interview conpleted with Tteferral Informant 03. Refusal by Informant 04. Refusal by Referral ( 05. Not Complete - Unable to Locate Primary Informant 06. Not Complete - Unable to Locate Referral II - Signs and Symptoms 01. Interview completed with Primary Informant 02. Interview completed with Referral Informant 03. Refusal by Informant 04. Refusal by Referral 05. Not Complete - Unable to Locate Primary Informant 06. Not Complete - Unable to Locate Referral �Version 10 11/10/86 CALL RECORD Call No. Date Day of Week Time Start Time Stop Length of call (Mins) Notes 10 11 12 13 14 15 Introduction Letter Sent MO DA YR MO DA YR MO DA YR Permission Form Sent Permission Form Rec'd Number of Last Call Date of Last Call Year Month Day Day of Week M T W T F S S 1 2 3 4 5 6 7 Interviewer ID: Total Length of Calls Quality Controller ID: �Surveillance INFORMANT INTERVIEW - I MEDICAL HISTORY Informant Name Relationship to Deceased Interview Conducted in: 1. | | English 2. | | Portuguese 3. | I Spanish Type of Informant: A. Primary - from Death Certificate B. Referral List Other Sources Provided Physician Name Address Physician Name Address Hospital Name Address Hospital Name Address PHHP Mort. Surv. System 1/86 - Adapted from MffiD? Version 10 12/30/86 �Version 10 12/30/86 pBTAIN RELATIONSHIP TO DECEASED] 7. Was (he/she) confined to bed at any time within two weeks before death (that is, had to spend more than half of (his/her) waking hours in bed)? 1| | NO 8. How long had (he/she) been confined to bed? 2 | j YES- ] <, 2 DAYS 5|| 2| < 1 WK 6[ < 2 WKS 8 | 4| DK I 3 |j 9j j 1j | <4 WKS < 6 WKS | .> 6 WKS | NA 9 1 | DK a resident of a nursing home at the time he/she 9. Was died? 1 I I NO Name of nursing home 2 [ " YES"I 9| | DK Address/Telephone 10. In the year before 's death, did a doctor ever say that (he/she) had the following; or did the doctor treat (him/her) for any of these conditions; or prescribe any of these medications? NO YES DK A. angina pectoris, heart pains, or was he/she taking nitroglycerin? B. abdominal aneurysm, bulging or leaking of the aorta? C. congestive heart failure, fluid in/on lungs, or was he/she taking lanoxin, digoxin, or digitalis? 1| | 2 | | 9 D. high blood pressure?. E. severe breathing problems from emphysema or chronic lung disease? F. cirrhosis of the liver or liver failure? PHHP Mort. Surv. System 1/86 - Adapted from MHHP 1[ | 2 [ | 9 11 | 2 | |9 | �Version 10 12/30/86 YES NO DK G. diabetes? 1[ 2[Z1 H. kidney failure requiring dialysis or kidney machine? 1 2EH 9 O I. weakness of heart muscle, sometimes called myocarditis or cardiomyopathy? 1 | | 21 J. rheumatic fever or rheumatic heart disease? 1 | | 2 | |9 | | | 9 |j K. mitral valve prolapse, floppy heart valve, or a clicking heart valve? 1 | |2| | 9| L. Other heart-related problems, specify Id] 2 ever have a heart attack for which (he/she) 11. At anytime, did was in the hospital for a week or more? 11 | NO 2 | | YES 9 [ | DK 11.1 Was that within the 4 weeks before he/she died? 1j [ NO 2 | | YES 8I [ NA 9 DK 12. At anytime, did ever have a stroke for which (he/she) was in the hospital for 2 days or more? | | NO 2 | I YES ! DK have coronary artery or heart surgery at any time 13. Did within the 4 weeks before death? 13.1 At any time after surgery, was (he/she) able to resume (his/her) usual level of daily activities? 1| f NO 1 | f NO 2 ~ YES—» f | 9) 2 | [ YES NA \ DK 91 |DK PHHP Wort. Surv. System 1/86 - Adapted from MHHP �Version 10 12/30/86 's death, was (he/she) 14. In the year before in the hospital for any reason and then discharged from the hospital? YES 15. Within that last year, how many times was he/she hospitalized? | | 88 | NA | 99 | 1 DK LIST MOST RECENT VISIT FIRST 16. What hospital was he/she in? Name of hospital City When was he/she discharged? Date MO DY 17. What hospital was he/she in before that? Name of hospital City When was he/she discharged? Date DY MO YR 18. What hospital was he/she in before that? Name of hospital City When was he/she discharged? Date MO DY YR 19. What hospital was he/she in before that? Name of hospital City When was he/she discharged? Date MO PHHP Mort. Surv. System 1/86 - Adapted from MHHP DY YR YR �Version 10 12/30/86 have a regular physician? 20. Did (PHYSICIAN WITH THE MOST INFOFMATICN) 1 (~~1 NO 2 |~~f YES 9 Physician's name:_ Practice/Clinic: Address/Telephone: 20.1. Did (he/she) see (his/her) regular physician within one year before death? 1 I 1 2 N0 I I YES 8 | f NA 9j | DK 20.2 Did (he/she) see any other physician within one year before death? 1 | | NO 2j | YES 8 Q NA 9[ 1 DK Physician's name: Practice/Clinic: Address/Telephone: 21. Had he/she ever had surgery for a bad heart valve? YES NO NA DK 22. Did he/she have cancer during the year prior to death? | 1 | NO nr~i YES | 8 | NA 22.1. Was it skin cancer? TJ NO [2] YES | 8 | NA PHHP Mort. Surv. System 1/86 - Adapted from MffilP DK f~9~] DK �Version 10 12/30/86 23. Did he/she have an injury to the head in the two days prior to death that knocked him/her out? YES NO 8 NA DK 24. Was he/she ever diagnosed as having high blood pressure? ( T | NO "~ | T ] YES "~ 1 8 1N A DK 25.A I would like permission to review some of the medical records. IF INFORMANT IS NEXT-OF-KIN, PROCEED. IF NOT, SKIP TO Q 25.B May I have your consent to obtain further information from the hospital/physician/both? 1 | | NO I will send you a permission form(s) to sign and mail 2 | | YES — back to me in an envelope that I'll enclose. You should receive it within a fev; days. (SKIP 25.B) VERIFY ADDRESS 8 | | NA 25.B May I have the name, address and phone number of a family member to contact for consent to obtain further information from the hospital/physician/both? 1 | | NO YES •NAME ADDRESS PHONE 8j | NA JRETURN TO SCREENER Q.2 PHHP Mort. Surv. System 1/86 - Adapted from MHHP �... :*•-«-'• N E U R 0 B E HA VI T E S T I N G 0 RA L PROTOCOL �\, 0 3. I I Introduction I The neuropsycbologica1 functioning of study participants was Iderived from a battery of tests selected to assess the specific mental a b i l i t i e s hypothesized I exposure to be impaired in subjects with Agent Orange or subjects with significant combat exposure in Vietnam. iNeurppsycholcgical tests were used due to their objective scoring, standardized administration procedures, and their sensitivity for Assessing problems t in the areas of memory, attention, dexterity, anguage, visual-spatial, and higher level mental functions. These test cores were used as a means for group comparisons rather than as •bsclute measures of these ability areas. All of these test do measure multiple abilities •Lnal score . 1 1 1 I 1 1 \ Ft'-t- (multifactorial} which can influence a subject's �Neuropsychological Assessment Second Edition MURIEL DEUTSCH LEZAK Oregon Health Sciences University and Veterans Administration Hospital Portland, Oregon New York Oxford OXFORD UNIVERSITY PRESS 1983 LIBRARY CENTERS FOR. DISEASE CONTROL ATLANTA, GEORGIA 30333 �Neuropsycho 1 og.i ca .1 Testing I n t e r i m A n a l y s i s i Medical Examination Component V i e t n a m Experience Study I, A Priori Hypotheses A. Neuropsychological/Psychological Effects of Agent Orange or Dioxin: 1. Decreased memory system functioning 2. Decreased mental control and/or attention 3. Decreased dexterity 4. Decreased arousal/activation system functioning 5. Decreased frontal/executive system functioning 6. Increased levels of anxiety, depression, scmatizaticn 7. Increased emotional lability B. Neuropsychological/Psycho logical Effects Related to Military Service in Vietnam: 1. Increased levels of PTSD and/or PTSD related symptoms 2. Increased levels of anxiety, depression, somatization 3. Increased alcohol and/or drug abuse 4. Increased psychopathology (general) 5. Decreased mental control, a t t e n t i o n , or memory The above hypotheses are based on the literature review provided in Appendix C. �$% W R A T - R R e a d i n g S u b t e s t G r a d e E q u i v a l e n t S c o r e : T h e r e a d i n g s u b t e s t f r o m t h e W i d e Range A c h i e v e m e n t T e s t - R e v i s e d c o n s i s t s o f reading of single words and is h i g h l y c o r r e l a t e d w i t h e d u c a t i o n a l background. �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES THE WIDE RANGE ACHIEVEMENT TEST (WRAT) (Jastak and Jastak, 1965) Tliis batter} 1 formal i n s t r u m e n t earns its "wide range" t i t l e by its applicability from early childhood through the middle adult years. It tests three academic skills—spelling, reading, and arithmetic—each at two age ranges or "Levels." The Level I ace range is from five through 11; Level II covers ages 12 to "-15-0 and over." The Level I Spelling test comes in three parts: copying a short set of nonsense figures and writing one's name are tasks only at Level I; a dictation task differs from the Level II Spelling test in word difficulty. Both A r i t h m e t i c levels have two parts, an orally administered section for the lowest achievement levels, and a written arithmetic test. Ten minutes are allowed for w r i t t e n a r i t h m e t i c at both levels. Reading begins with letter reading and recognition at Level I and continues w i t h a 75-word reading and pronunciation list. At Level II, Reading involves only the word list. This test is carefully standardized w i t h a full set of norms for each subtest. Level I has age norms for each half-yearly interval between ages 5 and 12. Level II age norms continue at half-yearly intervals from 12 to 16; from 16 to 20, they span l\vo-\ear intervals, and from 20 to 45 they cover five-year intervals. All raw scores can be converted to school grades, standard scores, or percentiles. Thus, this is a flexible test, adaptable for inclusion in any set of tests. The standard deviation of the WRAT is only 10 (see p. 145). With a mean set at 100. an examiner f a m i l i a r with the scoring systems of the Wechsler or Stanforcl-Binet scales may misinterpret the WRAT scores if the smaller standard deviation is not taken into account. ' All three WRAT subtests are heavily weighted with the general ability factor, and the verbal factor contributes a large component to Reading and Spelling. Arithmetic has little of the verbal factor, but a "motivation" factor is involved. The WRAT Arithmetic subtest tests the ability to perform written arithmetic. A feature of the WRAT Arithmetic test that is valuable for neuropsychological assessmerit is the variety of mathematical problems it poses. These include application of the four basic arithmetic operations to two- and three-digit numbers, to decimals, percentages, fractions, and to algebraic problems, as well as the translation of Roman numerals, weights, and measures. Problems concerning squares, roots, and some geometric constructs are also presented. Thus, when a patient's mathematical performance is defective, the examiner can determine by inspection of his worksheet whether his difficulties are due to a dyscalculia of the spatial type, a symbol or number alexia, or an anarithmetria in which number concepts or basic operations have been lost. The lower level arithmetic problems can be given when the patient is unable to do enough at the adult level for a fair sampling of his arithmetic skills. The Arithmetic subtest does have some drawbacks when used for neuropsychological purposes. Many brain damaged patients are unable to answer more than a few items within the allotted ten minutes. To evaluate a performance on the basis of the test norms, which take time into account, the examiner need only note how much of the test the patient completed at ten minutes, without disturbing the patient. Stopping the patient before he has finished may greatly restrict the amount of information that can be obtained about his ability to do arithmetic and the nature of any disability he 294 �INTELLECTUAL ABILITY TESTS 2 may have in this area. The small print and scant space surrounding each problem can create some difficulty, particularly for older patients and patients w i t h visual acuity problems. A larger scale version of this test, allowing for more compulation space around each problem, would solve this difficulty and make it easier for the examiner to follow the patient's computational elforts. The standard score and percentile norms reflect a performance decline from ages 25 to 50, but they do not take into account differences at older age levels. Children's Tests Patients with severe intellectual handicaps may give so few scorable responses to some or all of the WAIS subtests that the examiner has little opportunity to assess their capabilities or the relative strengths and weaknesses of different functions. Children's or infant's tests may enable them to display a broader range of their behavior than and preschool levels but lacks the advantages of battery tests. Four of the best known children's tests—the Wechsler Intelligence Scale for Children, The V/echsler Preschool and Primary Test of Intelligence, the Pictorial Test of Intelligence, and the Illinois Test of Psycholinguistic Abilities—are in battery form. A fifth, the Leiter, is a nonverbal counterpart of the Binet intended for use with patients who have speech and hearing handicaps. THE WECHSLER INTELLIGENCE SCALE FOR CHILDREN (VVISC and VVISC-R) (Wechsler, 1949, 1974) The WISC covers the age range from 5 to 15 years 11 months, and the age range of its revision, the WISC-R, is 6 years to 16 years 11 months. They contain the same subtests as the WAIS in an almost identical format, but all of the subtests except Digit Span begin with considerably simpler items. Although most VVISC and WISC-R items are the same, outmoded VVISC items have been dropped from the WISC-R, and some of the new WISC-R picture items have black or female subjects. The WISC-R blocks conform to the two-color (red and white) WAIS blocks, replacing the four-color VVISC blocks. The number sequences of the VVISC and VVISC-R Digit Span subtest are the same length and difficulty as those of the WAIS. There is an alternate form of Digit Symbol (called Coding on the WISC) for children under nine on the WISC, under eight on the WISC-R, and suspected mental defectives. Coding uses five geometric symbols (star, circle, etc.) instead of numbers, and the symbols to be written in are simpler than those of the more difficult VVISC version of the WAIS. Administration instructions are similar, and for many subtests, identical, to those of the WAIS. Standard score equivalents of WISC and WISC-R subtest raw scores are given for each four-month interval covered by the scale. However, in interpreting VVISC and WISC-R scores for adult patients, the examiner should use the Table of Test Age Equivalents (p. 113 of the WISC Manual, p. 189 of the WISC-R Manual), which will give the age equivalents of the patient's score on any of the VVISC subtests. The VVISC contains a maze test that has no WAIS counterpart. It consists of printed mazes (eight on the VVISC, nine on the VVISC-R) of varying sizes and complexity, \vhich are given in order of difficulty. Scoring is based on the number of errors; there 295 �Reading, Level 2 Page 4 A Two letters in name (2) city form grunt triumph tree in milk O S E R T H P I U Z Q . M animal stretch theory contemporary image ethics predatory deteriorate regime covetousness coercion longevity vehemence subtlety beatify beneficent desuetude egregious prevalence 5 enigmatic predilection ingratiating emaciated regicidal contemptuous protuberance abysmal sepulcher succinct unanimous decisive pugilist soliloquize aboard bibliography desolate peculiarity irascible toughen split conspiracy municipal benign chin tranquillity humiliate mosaic stratagem grieve eliminate rancid scald between contagions escape deny alcove himself oligarchy evanescence schism centrifugal ebullience heinous misogyny 93 internecine svnecdoche COPYRIGHT 1964 by Jastak Associates, Inc.. 1526 Gilpin Avenue. Wilmington, Delaware 19806. All rights reserved. Primed in U.S.A. 1937. 1946, 1965. 1976, 1978, 1984. Photocopying of this test li a violation of copyright law. WHAT R 2 Raw Score to Grade Equivalents READING RS 30 '' GE 35 1 Below ! 38 3 1 1 1 40 I 48 3E 1 1 4E 1 1 GE Below 3 1 I 1 '•'< GE Below 3 1 68 )5 1 38 1 1 1 1 6E 1 1 78 1 7E 20 3E 1 48 1 1 4E 5B 1 1 55 1 1 8E 88 1 1 96 1 •<--.—•..- 1 9E 5E 25 1 1 68 1 1 10B 1 1 1 toe us 1 11E 65-89 I 12B 12E Above 12 1 1 76 6E 35 30 1 1 7E 1 6B 8E 1 1 98 9E 1 108 1 10E 1 1 MB 11E 12B 36-51 1 12E Above 12 SEM - 2 ARITHMETIC RS 50 SEM = 2 SPELLING 1 1 56 58 RS M0 45 15 1 1 1 38 3E 1 1 4B 25 2° 1 4E 1 56 1. 5E 1 6B 1 6E 30 1 1 7B 1 1 7E 1 8B ?s 35 1 1 1 1 1 1 1 1 1 40-66 8E 9B 9E 108 10E 11B 11E 12B 12E Above 12 SEM = 2 �•I I - ft. WAIS-H Information Subtest Scale Score: The information gj subtsst from the V»~AIS-?. is a measure of general information which is highly correlated v;ith educational and socioeconomic background. It has JJI s also been considered as a measure of long-term memory as most of the questions require the subject to recall information typically learned in school. This test is also correlated with general IQ and verbal abi1i t ies. WAIS-R Block Design Subtest Scale Score: The block design subtest from the WAIS-R is a measure of visual-perceptual-motor, 'isual-spatial, and non-verbal reasoning abilities. This test also is orrelated with general IQ and is timed so that mental and motor speed re a component of a subject's performance. I I �INTKUJ-XTUAI. A B I L I T Y TESTS 1 sitivc to memory defect, distractibility, and motor slowing, whereas these problems are not characteristic of people who are simply dull and not organically impaired. The concrete t h i n k i n g of brain damage is distinguishable from that of psychiatric conditions in that the former tends to occur consistently, or at least regardless of the emotional meaningfulness of the stimulus, whereas the latter is more apt to vary with the emotional impact of the stimulus on the patient or with any number of factors external to the examination. Concrete thinking alone is not indicative of brain damage in patients of normal!)' low intellectual endowment or in long-term chronic psychiatric patients. A concrete approach to problem solving, which shows up in a relatively depressed Similarities score, with perhaps some lowering of Comprehension, Block Design, or Picture Completion scores, may be the most pronounced residual intellectual defect of a bright person who has had a mild brain injury. However, patients with lesions primarily involving prefrontal structures may be quite impaired in their capacity to handle abstractions or to take the abstract attitude and yet not show pronounced deficits on the close-ended, well-structured Wechslcr test questions (see pp. 78-79, 82). Other than a few fairly distinctive but not mutually exclusive patterns of lateralized and diffuse damage, the Wechsler-based evaluation of whether brain damage is present depends on whether the subtest score pattern makes neuropsychological sense. For instance, the widespread tissue swelling that often accompanies a fresh head injury or rapidly expanding tumor results in confusion, general dulling, and significant impairment of memory and concentration functions that appear on the WAIS batteries as significantly lowered scores on almost all subtests, except perhaps time-independent verbal tests of old, svell-established speech and thought patterns (Conen and Brown, 1968). Bilateral lesions generally produce changes in both verbal and visuospatial functions and involve aspects of memory and attention as well. Evaluation of organicity by pattern analysis requires knowledge of what is neuropsychologically possible and an understanding of the patient's behavioral capabilities as demonstrated on a WAIS battery and other measures of mental functions that have been examined within the context of the patient's life experiences, current psychosocial situation, and the medical history. Pattern analysis applies best to patients with recent or ongoing brain changes and is less effective in identifying organic disorders in psychiatrically disturbed patients. The Wechsler subtest score patterns of patients with old, static brain injuries, particularly those who have been institutionalized for a long time, tend to be indistinguishable from those of chronic institutionalized psychiatric patients and is less effective in identifying organic disorders in psychiatrically disturbed patients (see pp. 233-234). The Wechsler Intelligence Scales Subtests The standard examination procedure calls for the administration of the 11 subtests of the Wechster scales in the order of their presentation below. When all 11 tests are given, testing time generally runs from one and one quarter to two hours. The WAIS 253 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES and VVAIS-R Manuals give the standard administration instructions in detail (D. Wechsler, 1955, 1981). In the interests of m a i n t a i n i n g a standardized administration, the examiner should not attempt to memorize the questions but rather should read them from the manual. When questions have been memorized, the examiner is liable to insert a word here or change one there from time to time without being aware of these little changes. Ultimately they add up so that the examiner may be asking questions that differ not only in a word or two but in their meaning as well. I have found that the only way to guard against this very natural tendency is to use the manual for every administration. Administration of the 11 subtests need not follow the standard order of presentation (see p. 114). Rather, the examiner may wish to vary the subtest order to meet the patient's needs and limitations. Patients who fatigue easily can be given more taxing subtests, such as Arithmetic or Digit Span, early in the testing session. If the patient is very anxious about the tests, the examiner will want him first to take tests on which he is most likely to succeed before he tackles more difficult material. Edith Kaplan recommends alternating Verbal and Performance Scale subtests of the WAIS so that patients who may have predominantly verbal or predominantly visuospatial deficits are not faced with a series of failures but rather can enjoy some successes throughout the examination. I have found this presentation pattern very helpful in preventing buildup of tension or discouragement in these patients. Alternating between the school-like question-and-answer items of the Verbal Scale subtests and the puzzle-and-games Performance Scale items also affords a change in pace that keeps the interest of patients whose insight, motivation, or capacity to cooperate is impaired better than does presentation in the originally prescribed order. The VVAISR incorporates these advantages in a recommended order of administration that alternates Verbal Scale and Performance Scale subtests. The examiner also need not complete all subtests in one sitting but can stop whenever he or his patient becomes restless or fatigued. In most instances, the examiner calls the recess at the end of a subtest and resumes testing at some later time. Occasionally, a patient's energy or interest will give out in the middle of a subtest. For most subtests, this creates no problem; the test can be resumed where it had been stopped. However, the easy items on Similarities, Block Design, and Picture Arrangement provide some people the practice they need to succeed at more difficult items. If the examination must be stopped in the middle of any of these three tests, the first few items should be repeated at the next session so the patient can reestablish the set necessary to pass the harder items. Savage and his colleagues (1973) found that people over the age of 70 tended to be uncomfortably sensitive to failures. Negative reactions were likely to show up when the examiner was following the requirement that subtests be continued for a given number of failures. Since many older people enjoyed doing "puzzles," they tolerated failure better on Performance Scale than on Verbal Scale subtests. When faced with the choice of giving the required number of items or discontinuing early to reduce the elderly patient's discomfort, I usually discontinue. In most cases, even if the 254 �INTELLECTUAL A B I L I T Y TESTS 1 patient succeeded on one or two of the more difficult items, continuation would not make a significant difference in the score. When the patient appears to be capable of performing at a higher level than he seems willing to attempt and it is important to document this information, the omitted items can be given at a later time, after the patient has had some obvious successes or when he seems more relaxed. A verbatim record of the patient's answers and comments makes this important dimension of his test behavior available for leisurely review. The examiner who has learned shorthand has a great advantage in this respect. Slow writers in particular might benefit from an acquaintance with brief-hand or speedwriling. Many examiners routinely use only nine or ten of the eleven WAIS battery subtests (McFie, 1975; A. Smith, 1966b). Most of my examinations do not include Vocabulary because the information it adds is redundant when the other verbal subtests have been given. It also takes the longest of any of the verbal subtests to administer and score. In my examinations a vocabulary test is usually included in the paper and pencil battery or a picture vocabulary test is substituted for patients unable to read or write. Sometimes I exclude Digit Symbol and give the Symbol Digit Modalities Test instead (when I want to compare auditory and graphic response speed on the symbol substitution task and also look for tendencies toward spatial rotation or disorientation, I maygive them both). When a symbol substitution test is given to patients with pronounced motor disability or motor slowing who will obviously perform poorly on this highly time-dependent test, their low scores add no new information, making this test redundant, too. When there are time pressures, the examiner may wish to use a "short form" of the WAIS battery, that is, a set of only three, four, or five subtests selected to give a reasonably representative picture of the patient's functioning (Duke, 1967). Short forms were originally developed to produce a quick estimate of the Full Scale IQ score. Since estimation of an aggregate IQ score is not the goal of the neuropsychological examination, selection of subtests for brief neuropsychological screening need not be made on the basis of how well the combined score from the small set of tests approximates the Full Scale score. So long as the subtests are handled as discrete tests in their own right, the examiner can include or exclude them to suit his patient's needs and abilities and the requirements of the examination. "Split-half" administrations, in which only every other item is given, also save time but may lose accuracy. One study (Zytowski and Hudson 1965) found that with the exception of Vocabulary, the validity coefficients of split-half scores correlated with whole subtest scores range below .90; and of the Performance Scale subtests, only Block Design is above SO. Satz and Mogel (1962) devised an abbreviated set of scales that includes all the WAIS scales. It uses mostly split-half (odd items only) administrations excepting on Information, Vocabulary, and Picture Completion in which every third item is given. Digit Span and Digit Symbol administrations remain unchanged. The authors report that only Information (r = .89), Comprehension (r = .85), Block Design (r = .8-4), and Object Assembly (r = .79) have correlations below .90 with the whole subtests. C. G. Marsh (1973) obtained fairly comparable correlations on a cross-validation study of the Satz-Mogel format and concluded that 255 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES tin's format "is an adequate substitute for the long-form VVAIS when it is used as a test of general intelligence with neurology or psychiatry patients." She found, however, that with the abbreviated forms of Information, Comprehension, Picture Completion, and Picture Arrangement, 15-20% of the scores of the group of neurology patients and 18-30% of the scores of the psychiatry patients showed a deviation of three or more scaled scores from their whole subtest performances. Marsh cautioned against using this format when doing pattern analysis. Goebel and Satz (1975) examined the relationship between subtest scaled score profiles obtained on the Satz-Mogel abbreviation of the WAIS and profiles derived in the standard administration, using multivariate procedures. Their data suggest that the abbreviated format does generate subtest profiles that can be used with relative confidence when comparing an individual profile with a set of statistically derived clinical profile types. These findings, though, apply only to the classification of overall profiles, and do not answer the questions raised by Marsh's study regarding the clinical use of abbreviated scale scores when doing inductive pattern analysis. Neuropsychologically useful information can be gained by incorporating the facesheet identification and personal information questions into the examination proper. These questions give the examiner the opportunity of evaluating the patient's orientation in a very naturalistic—and thus quite inoffensive—manner and also of ensuring that the important employment and education data have been obtained. ("Race" or "color" is usually obvious.) Only the examiner who routinely asks patients about the date, their age and date of birth, and similar kinds of information usually taken for granted, can appreciate how often neurologically impaired patients fail to answer these questions reliably and how important it is to know this when evaluating and planning for a patient. I also always make a point of filling in my name along with the rest of the information requested at the top of the page and repeating it while I write as many patients, particularly in a large medical center where they may be examined by many people, may not remember the examiner's name and may be too embarrassed to ask. Many of the subtests present administration or scoring problems peculiar to that subtest. These will be noted in the discussion of each subtest below. Verbal Scale Subtests INFORMATION The Information items test general knowledge normally available to persons growing up in the United States. WAIS battery forms for other countries contain suitable substitutions for items asking for peculiarly American information. The items are arranged in order of difficulty from the four simplest, which all but severely retarded or organically impaired persons answer correctly, to the most difficult, which only few adults pass. The relative difficulty level of some of the WAIS items has probably changed over the years, particularly for the younger age groups. The recent ramblings of the date for celebrating Washington's birthday from year to year (see p. 256 �INTELLECTUAL A B I L I T Y TESTS 1 241), the almost universal (in the United States) inclusion of the Odyssey or the Iliad in the high school curriculum, and the increased popular interest in Islamic culture will necessarily be reflected in differences in the proportion of persons within and between the different age groups who can answer these questions correctly. In addition, increases in the level of education in the United States, particularly in the older age groups, may have raised the population mean score on the Information subtest. Certainly my clinical experience suggests that this is the case. I make some additions to Wcchslcr's instructions. When a patient taking the WAIS gives a very low or very high estimate of the height of the average American woman, I usually ask, as if it were the next question in the test, "What does average mean?" to determine whether the response represents an estimation error (see pp. 501-502) or ignorance of the concept of average. I spell "Koran" after saying it since it is a word people are more likely to have read than heard, and if heard, may have been pronounced differently. When patients who have not gone to college answer any of the items from 21 to 25 correctly so that they will be given one or more of the last four items, I usually make some comment such as, "You have done so well that I have to give you some questions that only a very few, usually college-educated, people can answer," thus protecting them as much as possible from unwarranted feelings of failure or stupidity if they are unfamiliar with the items' topics. When a patient gives more than one answer to a question and one of them is correct, the examiner must insist on the patient telling which answer he prefers to be scored as it is not possible to score a response containing both right and wrong answers. I usually ask patients to "vote for one or another of the answers." Although the standard instructions call for discontinuation of the test after five failures, the examiner may use discretion in following this rule, particularly with brain injured patients. On the one hand, some neurologically impaired patients with prior average or higher intellectual achievements are unable to recall once-learned information on demand and therefore fail several simple items in succession. When such patients give no indication of being able to do better on the increasingly difficult items and are also distressed by their failures, the examiner loses little by discontinuing this task early. If he has any doubts about the patient's inability to answer the remaining questions, he can give the next one or two questions later in the session after the patient has had some success on other subtests. On the other hand, bright but poorly educated subjects will often be ignorant of general knowledge but have acquired expertise in their own field which will not become evident if the test is discontinued according to rule. Some mechanics, for example, or nursing personnel, may be ignorant about literature, geography, and religion, but know the boiling point of water. When testing an alert person with specialized work experience and a limited educational background who fails five sequential items not bearing on his personal experience, I usually give all higher level items that might be work-related. When giving the Information subtest to a patient with known or suspected organic impairment, it is very important to differentiate between failures due to ignorance, loss of once-stored information, and inability to retrieve old learning or say it on command. (See Testing the Limits, pp. 114-115.) Patients who cannot answer questions 257 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES at levels higher than warranted by their educational background, social and work experiences, and vocabulary and current interests have probably never known the answer. Pressing them to respond may at best waste time, at worst make them feel stupid or antagonize them. However, when patients with a high school education cannot name the capital of Italy or give the direction from Chicago to Panama, I generally ask them if they once knew the answer. Many patients who have lost information that had been in long-term storage or have lost the ability to retrieve it, usually can be fairly certain about what they once knew but have forgotten or can no longer recall readily. When this is the case, the kind of information they report having lost is usually in line with their social history. The examiner will find this useful both in evaluating the extent and nature of the patient's impairments and in appreciating his emotional reactions to his condition. Should a patient acknowledge that he could have answered the item at one time, appear to have a retrieval problem or difficulty verbalizing the answer, or have a social history that would make it likely he once knew the answer (e.g., a Catholic who cannot identify the Vatican), then information storage can be tested by giving the patient several possible answers to see whether he can recognize the correct one. I always write out the multiple-choice answers so the patient can see all of them simultaneously and need not rely on a possibly failing auditory memory. For example, when patients who have completed high school are unable to recall Hamlet's author, I write out, "Longfellow (or Kipling on the VVAIS-R), Tennyson, Shakespeare, Wordsworth." Occasionally a patient taking the WAIS points to "Longfellow." If there are other indications of perseverative behavior, then this response probably gives one more instance of it; certainly it raises the suspicion of perseveration since the patient had just recently heard that name. More often, the patient identifies Shakespeare correctly, thus providing information both about his fund of knowledge (which he has just demonstrated is bigger than his Information subtest score will indicate) arid his retrieval problem. Nonaphasic patients who can read but still cannot identify the correct answer on a multiple-choice presentation probably do not know, cannot retrieve, or have truly forgotten the answer. The additional information that the multiple-choice technique may communicate about the patient's fund of knowledge raises scoring problems. Since the test norms were not standardized on this kind of administration, additional score points for correct answers to the multiple-choice presentation cannot be evaluated within the same standardization framework as scores obtained according to the standardization rules. On the other hand, this valuable information should not be lost or misplaced. To solve this problem, I use double scoring; that is, I post both the age-graded standard score the patient achieves according to the standardization rules and, usually following it in parentheses, another age-graded standard score based on the "official" raw score plus rasv score points for the items on which the patient demonstrated knowledge but could not give a spontaneous answer. This method allows the examiner to make an estimate of the patient's fund of background information based on a more representative sample of behavior, given the patient's impairments. The disparity between the 258 �INTELLECTUAL A B I L I T Y TESTS 1 two scores can be used in making an estimate of the amount of deficit the patient lias sustained, while the lower score alone indicates the patient's present level of functioning when he must retrieve verbal information without assistance. On this and other subtests, test administration adapted to the patient's deficits with double-scoring to document performance under both standard and adapted conditions enables the examiner to discover the full extent of the neurologically impaired patient's capacity to perform the task under consideration. Effective use of this method involves both testing the limits of the patient's capacity and, of equal importance, standardized testing to ascertain a baseline against which performance under adapted conditions can be compared. In every instance, the examiner should test the limits only after giving the test item in the standard manner with sufficient encouragement and a long enough wait to satisfy any doubts about whether the patient can perform correctly under the standard instructions. Information and Vocabulary are the best WAIS battery measures of general ability, that ubiquitous test factor that appears to be the statistical counterpart of learning capacity plus mental alertness, speed, and efficiency. Information also tests verbal skills, breadth of knowledge, and—particularly in older populations—remote memory. Information tends to reflect formal education and motivation for academic achievement (Saunders, 1960a). It is one of the few subtests in the WAIS batteries that can give spuriously high ability estimates for overachievers, or fall below the subject's general ability level because of early lack of academic opportunity or interest. Information (WAIS) contains ten items that are not equally difficult for men and women, the difference favoring men to a significant degree. In brain injured populations, Information tends to appear among the least affected WAIS battery subtests (K. O'Brien and Lezak, 19S1; Sklar, 1963). Although a slight depression of the Information score can be expected with brain injury of any kind, because performance on this subtest shows such resiliency it often can serve as the best estimate of original ability. In individual cases, a markedly low Information score suggests left hemisphere involvement, particularly if verbal tests generally tend to be relatively depressed and the patient's history provides no other kind of explanation for the low score. Thus, the Information performance can be a fairly good predictor of the hemispheric side of a suspected brain lesion (Reitan, 1955b; A. Smith, 1966b; Spreen and Benton, 1965). COMPREHENSION This subtest includes two kinds of open-ended questions: 11 (13 in the WAIS-R) test common-sense judgment and practical reasoning, and the other three ask for the meaning of proverbs. Comprehension items range in difficulty from a common-sense question passed by all nondefective adults to a proverb that is fully understood by fewer than 22% of adults (Matarazzo, 1972). Since some of the items are lengthy, the examiner must make sure that patients whose immediate verbal memory span is reduced have registered all of the elements 259 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES BLOCK DESIGN This is a construction test in which the subject is presented with red and white blocks, four or nine, depending on the item. The task is to use the blocks to construct replicas of two block constructions made by the examiner and eight (on the WA1S) or seven (WAIS-R) designs printed in smaller scale (see Fig. 9-3). The order of presentation differs from the order of difficulty. Diller and his co-workers (197-4) found that, for elderly subjects, the second design had a difficulty level intermediate between \VAIS designs 5 and 6. Generally speaking, at each level of complexity, the \VAIS evennumbered items are likely to be more difficult than the odd-numbered items. Designs « ft' ii! Fig. 9-3. Block Design subtest. (Reproduced by permission of The Psychological Corporation.) 276 �INTELLECTUAL ABILITY TESTS 1 1, 0, 5, and 7 (1, 4, and 6 of the WAIS-H) are made up of distinguishable block faces, mostly plain squares; diagonals occur discretely so that when patients with visuospatial disorders or d u l l or careless persons fail one of these items, it is more likely to be due to incorrect orientation of the diagonal of a red-and-white block than to errors in laying out the overall pattern. In contrast, the diagonal patterns of the even-numbered designs reach across two- and three-block spans. Concrete-minded persons and patients (particularly those with right hemisphere damage) with visuospatial deficits have particular difficulty constructing these diagonal patterns. The four-block designs have one-minute time limits and the nine-block designs two-minute limits. The subject can earn one or two bonus points for speed on the last four designs of the VVAIS, and speed credits arc given on items 3 to 9 of the WAIS-R. Unlike the example pictured in Figure 9-3, the designs to be copied should be placed directly in front of the patient, just back far enough to allow the patient room to work. (Also unlike the example depicted in Figure 9-3, the patient's working area should be free of distractions such as other test material, the examiner's booklet, etc.) All subjects begin with the first item, which is presented and demonstrated as a. blockcopying rather than a design-copying test. The first and second items can be repeated should the subject fail to produce a correct design within the time limits, and the manual allows some leeway for demonstration and explanation of these items (Wechsler, 1955, 1981). Only severely retarded or impaired adults are unable to succeed on either trial of the Brst two items. The third item of the VVAIS is much easier than the second one and is given to all subjects, regardless of their performance on items 1 or 2. No demonstrations are allowed after the first two items. The test is normally discontinued after three failures. The examiner may wish to vary the standard procedures to give the patient an opportunity to solve problems failed under standard conditions or to bring out different aspects of the patient's approach to the Block Design problems. As on the other timed tests, it is useful to obtain two scores if the patient fails an item because he exceeded the time limit. When the examiner times discreetly, the patient remains unaware that he has overrun his time so that if he completes the design correctly, he will have the full satisfaction of his success. Usually, permitting the patient to complete the design correctly means waiting an extra minute or half minute beyond the allotted time. With a very slow patient, the examiner has to decide whether waiting the five or seven minutes the patient takes to work at a problem is time well spent observing him or providing an opportunity for success; whether the patient's struggle to do a difficult or perhaps impossible task distresses him excessively; or whether the patient needs the extra time if he is to succeed at this kind of task at all. It is usually worthwhile to wait out a very slow patient on at least one design to see him work through a difficult problem from start to finish and to gauge his persistence. However, if the patient is obviously in over his depth and either does not appreciate this or refuses to admit defeat, the examiner needs to intervene tactfully before the task so upsets or fatigues him that he becomes reluctant to continue taking any kind of test. Brain damaged patients sometimes do not comprehend the Block Design task when given the standard instructions alone. An accompanying verbal explanation like the 277 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES follosving may help clarify the demonstration: "Tins lower left-hand [patient's left] corner is all red, so I put an all reel block here. The lower right-hand corner is also all red, so I put another all red block there. Above it in the upper right corner goes what I call a 'half-and-half' block [red and white halves divided along the diagonal]; the red runs aiong the top and inside so I'll put it above the right-hand red block this way (emphasizing the angulation of the diagonal)", etc. Following completion of the test the examiner can bring out any design that puzzled the patient or elicited an atypical solution and ask him to try again. The examiner can then test for the nature of the patient's difficulty by having him verbalize as he works, by breaking up the design and constructing and reconstructing it in small sections to see if simplification and practice help, or by giving the patient blocks to copy instead of the smaller sized and unlinecl printed design. The examiner can test the patient's perceptual accuracy alone by asking him to identify correct and incorrect block reproductions of the designs (Bortner and Birch, 1962). Block Design lends itself well to qualitative evaluation. The manner in which the patient works at Block Design can reveal a great deal about his thinking processes, work habits, temperament, arid attitudes toward himself. The ease and rapidity with which the patient relates the individual block sides to the design pattern give some indication of his level of visuospatial conceptualization. At the highest level is the patient who comprehends the design problem at a glance (forms a gestalt or unified concept) and scarcely looks at it again while putting the blocks together rapidly and correctly. Patients taking a little longer to study the design, who perhaps try out a block or two before proceeding without further hesitancy, or who refer back to the design continually as they work, function at a next lower level of conceptualization. Trial and error approaches contrast with the gestalt performance. In these the subject works from block to block, trying out and comparing his positioning of each block with the design before proceeding to the next one. This kind of performance is typical of persons in the average ability range. These people may never perceive the design as a total configuration, nor even appreciate the squared format, but by virtue of accurate perception and orderly work habits, many can solve even the most difficult of the design problems. Most people of average or better ability do form immediate gestalts of at least five of the easiest designs and then automatically shift to a trial and error approach at the point that the complexity of the design surpasses their conceptual level. Thus, another indicator of ability level on this perceptual organization task is the level of the most difficult design that the subject comprehends immediately. The patient's problem-solving techniques reflect his work habits. Orderliness and planning are among the characteristics of working behavior that the block-manipulating format makes manifest. Some patients always work in the same direction, from left to right and up to down, for example, whereas others tackle whatever part of the design meets their eye and continue in helter-skelter fashion. Most subjects quickly appreciate that each block is identical, but some turn around each new block they pick up, looking for the desired side, and if it does not turn up at first they will set that block aside for another one. Some work so hastily that they misposition blocks and overlook errors through carelessness, whereas others may be slow but so method- 278 �INTELLECTUAL A B I L I T Y TESTS 1 ical t h a t they never waste a movement. A b i l i t y to perceive errors and willingness to correct them arc also important aspects of the patient's work habits that can be readily seen on Block Design. Temperamental characteristics, such as cautiousness, carefulness, impulsivity, impatience, apathy, etc., appear in the manner in which the patient responds to the problems. Self-deprecatory or self-congratulatory statements, requests for help, rejection of the task and the like betray the patient's feelings about himself. The examiner should record significant remarks as well as the kinds of errors and manner of solution. For quick, successful solutions, lie usually needs to note only whether the approach was conceptual or trial and error, and if trial and error, whether it was methodical or random. To some extent, time taken to solve a design will also indicate the patient's conceptual level and working efficiency since gestalt solutions generally take less time than those solved by methodical trial and error, which, in turn, generally are quicker than random trial and error solutions. It thus makes sense that high scores on this test depend to some extent on speed, particularly for younger subjects. For example, persons under the age of 35 cannot get scores above the 75th percentile (i.e., above the average range) without earning time credits. The examiner can document the patient's difficulties, his false starts, and incorrect solutions by sketching them on the margin of the Record Form, on a piece of paper kept handy for this purpose, or on a supplemental form that provides spaces for recording the designs. Of particular value in understanding and describing the patient's performance are sequential sketches of the evolution of a correct solution out of initial errors or of the compounding of errors and snowballing confusion of an ultimately failed design (e.g., Fig. 3-4a, p. 57). Block Design is generally recognized as the best measure of visuospatial organization in the Wechsler scales. It reflects general ability to a moderate extent so that intellectually capable but academically or culturally limited persons frequently obtain their highest score on this test. Block Design scores tend to be lower in the presence of any kind of brain injury. They are likely to be least affected when the lesion is confined to the left hemisphere, except when the left parietal lobe is involved (McFie, 1975). They tend to be moderately depressed by diffuse or bilateral brain lesions such as those resulting from traumatic injuries or diffuse degenerative processes that do not primarily involve cortical tissue. Patients with diffuse loss of cortical neurons like that which characterizes Alzheimer's disease, severe damage to prefrontal cortex, or extensive right hemisphere damage that includes the parietal lobe are all likely to perform very poorly on this test, but in different ways (e.g., Luria, 1973). In the very early stages of the disease, Alzheimer's patients will understand the task and may be able to copy one or two designs. However, these patients soon get so confused between one block and another or between their constructions and the examiner's model that they may even be unable to imitate the placement of just one or two blocks. The quality of "stickiness," often used to describe the performance of organically impaired patients but hard to define, here takes on concrete meaning when patients place their blocks on the design 279 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES cards or adjacent to the examiner's model and appear unable to respond in any oilier way. Patienls with severe damage to the frontal lobes may display a similar stickiness despite assertions that they understand the task. With less severe damage, frontal lobe patients may fail items because of impulsivity and carelessness, a concrete perspective that prevents logical analysis of the designs with resulting random approaches to solving the problem or not seeing or correcting errois. Concrete thinking tends to show up in the first item, for such patients will try to make the sides as well as the top of their construction match that of the model; some even go so far as to lift the model to make sure they have matched the underside as well. These patients may be able to copy many of the designs quickly and accurately, but tend to fail item 8 (7 of the WAIS-R), for instance, by laying out reel and white stripes with whole blocks rather than abstracting the 3 X 3 format and shifting their conceptualization of the design (from the mostly squared format of the first 3 X 3 design) to a solution based on diagonals. The Alzheimer's patients and those frontal lobe patients who cannot make the blocks do what they want them to do can be properly described as having constructional apraxia. The discontinuity between intent, typically based on accurate perceptions, and action reflects the breakdown in the program of an activity that is central to the concept of apra.xia. Slowness in learning new response sets may develop with a number of conditions such as aging, a dementing process, frontal lobe disease, or head injury. The Block Design format is sufficiently unfamiliar that patients capable of performing well may do poorly at first if they have this problem. Since the first five items (four on the WAIS-R) are quite easy for persons with average or better constructional ability, they give the patient who is slow to learn a new set the opportunity to gain needed familiarity. These patients tend to display an interesting response pattern in which the Erst two items are failed or, at best, passed only on the second trial while the succeeding two or three or more items are passed, each more rapidly than the last. Those patients who are slow in learning a response set but whose ability to make constructions is good may succeed on most or even all the difficult items despite their early failure. Block Design deficits associated with lateralized lesions are usually most common and most pronounced when the lesions involve posterior, particularly parietal, areas and are on the right side (Black and Strub, 1976; Newcombe, 1969; A. Smith, 1966b). Defective block design constructions made by patients with lesions in either hemisphere or when—under experimental conditions—a "split-brain" patient can use only one hemisphere, demonstrate that each hemisphere contributes to the realization of the design: "neither hemisphere alone is competent in this task" (Geschwind, 1979). However, the nature of the impairment tends to differ according to the side of the lesion (Consoli, 1979) (See pp. 285-286 for a discussion of these differences as they show up in relationships of scores on Block Design and Object Assembly to one another and to performances on purely visuoperceptual tests.) Patients with left, particularly parietal, lesions tend to show confusion, simplification, and concrete handling of the design. However, their approach is likely to be 280 �INTELLECTUAL A B I L I T Y TESTS 1 orderly, they typically work from left to right as do intact subjects, and their construction usually preserves the square shape of the design. Their greatest difficulty is likely to be in placing the last block (which will typically be on their right) (McFie, 1975). Patients with right-sided lesions may begin at the right of the design and work left. Their visuospatial deficits show up in clisorientation, design distortions, and misperceptions. Some patients with severe visuospatial deficits lose sight of the squared or self-contained format of the design altogether (see Fig. 3-ta, p. 57). Left visuospatial inattention may compound these design-copying problems, resulting in two- or threeblock solutions to the four-block designs, in which the whole left half or one left quadrant of the design has been omitted. Both right and left hemisphere damaged patients make many more errors on the side of the design contralateral to the side of the lesion. Edith Kaplan has called attention to the importance of noting whether errors tend to occur more at the top or at the bottom of the constructions, as the upper visual fields have temporal lobe components while the lower fields have parietal components. Thus, a pattern of errors clustering at the top or at the bottom can also give some indication of the site and extent of the lesion. PICTURE ARRANGEMENT This test consists of eight sets (WAIS) or ten sets (\VAIS-R) of cartoon pictures that make up stories. Each set is presented to the subject in scrambled order with instructions to rearrange the pictures to make the most sensible story (see Fig. 9-4). There are from three to six pictures in each set. Presentation is in order of increasing difficulty. Unless the subject fails both the first and second sets, all eight WAIS sets are administered. On the WAIS-R testing is discontinued after four consecutive failures. All but seriously retarded adults can do the first set (Matarazzo, 1972). Time limits range from one minute on the easiest items to two minutes on the two most difficult items. On five of the sets in each test there are two levels of accuracy. The subject can also earn time bonuses on the last two sets of the WAIS. Below age 55, the subject Fig. 9-4. VVAIS-type Picture Arrangement subtest item. 281 �,vib-' __ .:r—-WALS--R RECORD FORM —- - •—- Wechsler Adult Intelligence Scale Revised KM. i M \:'.\\ 1 NAMI i i RUM ARKS 1 5co f ir: . 0 (V 1 •DO -.-•-•^ .\-.r.--' -•'t '»'4 fci *l i\ ' ;i A "i*1- 4 i/ A • j \ /Ji7"" A Jf 16. Itaiy [17. King i 1O C .: ' [ 2 1 . Yo.r.s: 23. Paris. .24. B!c.od -.>?.-:*•:-:? J2S. Te-n-.i^^-.:•.•::•:' I 2 f i . *-,.: VVAIS-R: For list; wi;l) thfi VV"rhsli.-r Adult lni.-l!in.->n,-. t. . " " i r i . j f i i 1081. 1SG5,19-47 by Tho Psycliolcriir;,! C. r i i r r iJ. Acl.ipTod «'infj reprot.'iicod by pt.'rnii.ssi.in FlP'LETED?" ——— YES - \'0 TEH.MINA!!- •?t~£r-~r f.^*^f^.im'jf K ^X%y^r-yv>-x^vr "•' ..-^-'** ^^BJB'J y-i|y'.'*^T6?y "/»'*"'>y*i»*«ig.--i. ii-.-y^ ^^^^i^^^iii-* *>"V*****"""'" * " » " " '">"•• »»f^»-*•*•'• -*^Aiv\^-»^*j F. ^..,^>vt.^. .^ 1 fc * — --•» ^ --*x-.-^^f»^'.-^ w • , *^'C* T* V* �-Mod. '. 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' 5 , f'o"; {T^. :3 !CO nac |: | 1 —— i •••- 10 20 30 40 5 . . TESTER CODE : 1 SCORER CODE MM ! i 0 0~JO 0 o 6" i' i ;'r i '•^'1j i .'V. i i 'V • -. •_ » ' 70, £0 ,C~ .?'. ,'s" .9 i 2 0 5 6 7 7(i 120 ad .id, 20) 33;. <id. 50: cdj .^3;. soy so 4 S6 70 JI-5S I.JO '2 2 (£• 2 'T) 2 :~2- 2 •'£_' '3* 3 (4 90 f , 2~: .5", 4 ' 4 '3 3 ^ 4 : 4 3 ! .1 f 4 '' 4 3' 14^' .1 .?, 4 ^4 ;'s"; s (If) 5 .;"?;• s (5s 16 6 f 6 '• 0 I'G 6 .^6 f e !?; 7 WO ' zb* 19 BO 60 " O . O J O ' O 9 ico 10 26; 30'- 40 GO; e'd, 70. so 90 20" 2 9 ! 1'V uu [ 10 20 30 40 50 60 i ••-• : ' -'- 2 .^£. 20 30' dO, 50, 60 2b. u 3 H I t 3 BO 60' 10 20 30 40 50 60 1 • 60" ; 4. 7 i i iw -i i ' -•! Mark the appropriate score for eacii design. 50 60 x "-." ,~' ".:'' ,"." 2a. i ; 60" 2 SCORE PassFail ! AC: SCA!.= SCORE i DLVJV_IN i_/coiui\J Discontinue niter j consecutive ranures 10 20 30 'T '2" 3* (10 BO GO 4~ '5 -'<T "f 'S" 9 '6 4 S 6 7 — -^~-—"^~DO MQ!r . JL V 1 A~\J u.\ IN THIS* SHADED AF3| MARK IIM I f l l v v ' . - V^- — "r^ / > ' (5"' 1 ..••. /^ 9 '^ 9 (9^ 9 ,'9: (T '8 70, fiO SO !8, 9 1: �,,„, This measure assesses a ^ _ ^ ^ ^ ^ ^ ^ ^ d of word r e t r l e v a i , vocabulary. A subject has to general - c . . generate as many words as possible that begins with.a specific set of IS letters IF A c, , . ' - . -:- ': • • - " • ' ' ^^S ( F 'A,S) f o r 6 0 second. This score as tne number of words across the 3 letter » �(£300-9300) / / / / . / rn JOSTA, GI ^j.. u T :j (£. T O O — 9 T OO) f / _ T 00-9 TOO > (£TOO-?TOO) QI ftrOOn-rooO) /T/O/=i/M/ !.: O T 1 <i- ..J .3 U 9 q }u\=d T O T a.4 3aoa a S T "1 D U O .V) WWX3 �P £ of 5 ft ' F' words • . 1-14 sec 1. no. of unique £.'. no. of woras incorrect worcs . 96, = don' t know 99 = refusea 3. no. of unique woras 4. no. of incorrect woras , .. •-, • '9,©, = don' t know 99 = refusea 30-44 sec 5. no. of unique woras -i : £.. no. of incorrect woras •'_/_•'' <OO4O-O04.1) 93 = don' t know , , = refusea 99 45-§0 sec 7. no. of unique woras ''_/_/ U.')04c;-0043> 8. no. of incorrect woras /_/_/ (0044-0045) 98 = don't Know 99 = refusea �I T r i r f Desruaj = £.5 3 t uop = 9£ (T900-0900) / / / (6GOO-9£00) /""/""/ SDUOM aoaa^oouT SDUOM 4.0 'ou •< anbrun 4,0 'ou v 33< pasniau = £.=, <"/5OO-9SOO) /"/""/ SDJ.OM aoau-jirouT 4.0 'ou •< D3S DaSI14SJ c/i = A(=j ^ ( uop = e6 4.0 'TCOO-OCOO^ /"/""/ SDUOM anbrun 'OU -p. I j.o - •^ I ou oss ft3-< MOUVI a «uop = RA UOOUT SDUOM .4.0 -ou -ot antarun 4.0 "ou -g "oas + 7 T - T �P <+ C-- of 5 ' S1 woras 1-14 sec 17. no. . o f . yri.iqi.ie woras IS. no, ,of woras incorrect 9Q = d o n ' t know 99 = refused l5-£9 sec 19. no. of unique woras £0. no. of incorrect woras 96 = don't know 99 = refused 30-44 sec £1. no. of unique woras iiii, no. of incorrect woras 96 = don't know 99 = refused 45-60 sec £3. no. of unique woras (0074-0075^ £4. no. of incorrect woras (0076-0077) 98 = don't know 99 = refused �I I-- '• -"^ 5 of ' v ' -Xv'' ' - • . . -~ -.-.^v->:; -/.' - .. t^O""* ; '• • - G. Hnirnaj.. 1-14 sec '•"~~ '-'-£5. no. _o_f u ri_i g u e _ I I I I I I I ^_ _ ^ / _ / __ /_ lib. no. or incorrect woras 98 = aon't know - --9.9. = re'r'Tiseo j „' • • ' - -." - 15-£9 sec £ 7, n o. C1 f .'-t f< i q '-t e wo r a s £6. no. of incorrect woras . ,-9S. = don' t know s _ 30-44 sec' £S». r'C',,v,»,t'f . unique / _'/'^./ woi-^as ' 0. n o. o f in c o r r e c 'C w o r a s 3 t( /._ / _ / 45-60 sec _ '-,:..; < 0 0 56 — '.) 0 6 9; " •" . /_/_/ <0090-0091; 3£. no. of incorrect woras / / / •- j -..: .• .:„•'. • • " c." '• •'-' : " - - T' ' ••--"• ~ <009c.'—O093) ''"'* woras . 93 = don't know '*§''•;)' = re'fus'ea §33, Comment !/_/_/_/_/_/_/-/_/_ / _ / _ / _ / _ / _ / _ / _ / _ / - / - / - / - / - / - / - / I/I /I /_/_/_/_''_/_/_/ _/'_/_/_/../_/ • • ""••-~ • - _._... -_ ; . Dt'SC^I t^c. !..... i - 93 = aon't know 99 =.reruseo. 3l. no. of unique ( w or as AiNY Ui^UburtU f-'lNDlNlJti TriM'f CuL)l_D I !'Mi~"i_Ut:il\iiJh! fHi'S "i£Sf �5) C a l i f o r n i a Verbal Learning Test; (CVLT) Total Learning Score: This test assesses active verbal learning and memory ability by requiring the subject to recall 16 words over 5 learning trials. This score represents the total number of words recalled over these 5 trials. 6) California Verbal Learning Test (CVLT) Short-Term Recall Score: This component of the CVLT assesses a subject's ability to recall the 16 words previously learned after they had been given another group of words to learn. This score is the number of tota.l words (out of 16) recalled. 7) California Verbal Learning Test (CVLT) Percent Change score from short-term recall to long-term recall: This score is a measure of long-term memory abilities. It is the percentage of the 16 original words recalled after a 20 minute period compared to the number recalled on short-term recall. Negative numbers represent the percentage decline in recall over this time period. �THE C A L 1 F O R H I A VERBAL LEARNING TEST: A D M I N I S T R A T I O N AND INTERPRETATION' D e a n C. D e l i s , Joel K r a a e r , Beth A. O b e r Martinez Veterans Adiinistration Medical Center and Edi th K a p l a n Boston V e t e r a n s A d * i n i s t r a t i o n M e d i c a l Center Notice: Preliainary Manual M a i l i n g Address: Dean C. D e l i s , PruD. P s y c h e l e g y S e r v i c e (116 S) V e t e r a n s A d a i n i s t r a t i o n !". E d i c a 1 Ce~ ' r.r 150 M u i r R o a d M a r t i n e z , C a l i f o r n i a 94553 (415) 228-6BOO x302 �T H E C A L I F O R N I A V E R B A L L E A R N I N G TEST: A D t t I N 1 S T R A T I U N AND INTERPRETATION INTRODUCTION In c l i n i c a l n e u r o p s y c h o i o g y , the »ost c o a » o n l y used t t s t i of are H i d e l y c r i t i c i z e d a s h a v i n g s e r i o u s d e f i c i e n c i e s (Lezak, 19B1; Parson I include Prigatano, «e«ory 1983; R u s s e l l , 1977). The s h o r t c o i i n g s a s c r i b e d to these tests t h e i r f a i l u r e t o assess r e t e n t i o n o f i n f o r e a t i o n for p e r i o d s longer than a few s e c o n d s , with other c o g n i t i v e a b i l i t i e s , Measures of prinary the t h e i r c o n f o u n d i n g of the a s s e s s m e n t of «eacry skills and their f a i l u r e to provide quantitative m u l t i p l e u n d e r l y i n g p r o c e s s e s of «eaory functioning. reason f o r these s h o r t c o a i n g s i s t h a t e x i s t i n g aenory tests e»ploy an a c h i e v e a e n t s c o r i n g system w h i c h q u a n t i f i e s p e r f o r a a n c e in teras of pass/fail criterion. Such an a p p r o a c h c u l » i n a t e s in a s i n g l e f a i l s to i e a s u r e d i f f e r e n t t y p e s of l e a r n i n g p r o c e s s e s , gies (see Kaplan, 1983, A score, scne and errors, and strate- for a d i s c u s s i o n of a c h i e v e m e n t versus process a n a l y s e s in n e u r o p s y c h o l o g i c a l assessment). The l a c k of s o p h i s t i c a t e d «ei>ory t e s t s in c l i n i c a l neur opsychol ogy is a s e r i o u s p r o b l e m , s i n c e a l a o s t a l l types o f b r a i n p a t h o l o g y affect the a b i l i t y to l e a r n and reseuber glass I K a p l a n , 1979), and i n f o r a a t i o n (Luria, 1981; Good- since a b r a i n - i n j u r e d patient's a b i l i t y to l i v e i n d e p e n d e n t l y and to return to his 2 aeong other f a c t o r s , w i l l i n sose w a y foraer o c c u p a t i o n w i l l largely depand, on h i s v e r b a l KBaory s k i l l s (Lezau, 1983). In a d d i - tion, the r a p i d l y d e v e l o p i n g f i a l d of c o g n i t i v e r e h a b i l i t a t i o n is ?n need of • ore sensitive procedures to (1) d e l i n e a t e the s p e c i f i c oeiaory problem of i n d i v i d u a l p a t i e n t s ; .(2) d i r e c t the r e h a b i l i t a t i o n effort; the e f f i c a c y of the i n t e r v e n t i o n . ttenory is one of the aost cesses of b r a i n f u n c t i o n i n g (Luria, -ind (3) aonitcr couples pro- 1981), and e x t a n t frrcory tests have not �pressed this c o m p l e x i t y . Designed •ental •erory l i t e r a t u r e , Appendix sures *nd t h e C a l i f o r n i a V e r b a l L e a r n i n g Test txperi- (CVLTj see A ) u t i l i z e s a p r o c e s s s c o r i n g systei t o p r o v i d e q u a n t i t a t i v e of amount the to i n c o r p o r a t e f i n d i n g s froi b o t h t h e c l i n i c a l M u l t i p l e p a r a m e t e r s of ne»iory. of v e r b a l » a t e r i a l a p a t i e n t l e a r n s , r a t e o f l e a r n i n g over several t y p e s of e r r o r s » a d e , only the b u t a l s o such p r o c e s s d a t a as the encoding strategy used, the the v u l n e r a b i l i t y of eeaory to v a r y i n g d e l a y s in t i u e and to interference c o n d i t i o n s , improves trials, The CVLT assesses not «ea- a n d t h e d e g r e e t o w h i c h aeaory w i t h a s s i s t e d r e c a l l (e.g., perforcance H h en the p a t i e n t is g i v e n c a t e g o r i c a l cues). The b a s i c f o r m a t o f t h e C V L T w a s a o d e l e d a f t e r t h e R e y A u d i t o r y Learning Test (Rey, 1964; Leialc, 1983). Verbal Rey's test e v a l u a t e s an indi- v i d u a l ' s a b i l i t y to l e a r n a l i s t of 15 u n r e l a t e d w o r d s over f i v e t r i a l s . n e w l i s t o f 1 5 u n r e l a t e d nerds i s then p r e s e n t e d o n c e , by a ianediately folloxed r e c a l l of w o r d s and a r e c o g n i t i o n t e s t for the f i r s t l i s t . tessaent of r e t e n t i o n of the f i r s t l i s t a f t e r the p r e s e n t a t i o n l i s t e n a b l e s a n e v a l u a t i o n of f o r g e t t i n g i n t h e f a c e of when retrieval i s r e q u i r e d (free r e c a l l ) a n d when t a r g e t i t e m s a n d new d i s t r a c t o r i t e n s i s r e q u i r e d The CVLT a d d s to t h i s foraat A The »s- of the second interference, discriaination both between (recognition). s e v e r a l other t e s t i n g and s c o r i n g fea- tures: ECOLOGICAL VALIDITY: person is pres2nting l i k e l y t o encounter i n h i s e v e r y d a y life. a t h e C V L T uses l i s t of r a n d o o l y selected words, could p a k e up a s h o p p i n g i or the The CVLT is d e s i g n e d to be s i a i l a r to a task, patient, list. Tims, rather itess a than which The t e s t i n g is t h e r e f o r e Bade aore r e l e v a n t and i n f e r e n c e s a b o u t ho« a p a t i e n t a p p r o a c h e s a eeoory �SHORT DELAY CUED RECALL SHORT DELAY Tell me all of the shopping items from FREE RECALL the Monday list that are: (Category) Now I'd like you to tell me all of the shopping items you can from the Monday list. TOOLS SPICES & HERBS LONG DELAY FREE RECALL 1 read some shopping items to you earlier. I'd like you to tell me all the items you can from the Monday list that was the first list 1 gave you. LONG DELAY CUED RECALL Tell me all of the shopping items from the Monday List that are: (Category) TD Q) LONG DELAY RECOGNITION I'm going to read a list of shopping items. After 1 read each item, say 'yc*' if the ncm was from the Monday list and 'no' if it was not. M TR NR TU NU o> "O O) _£5_ m SwoAt«r C Or i>00 no Flounder SPICES & HERBS • . n»a TOOLS -I— • • • • • • E — _1_ -I— Tires Peppur o 2 • • CNl Jackvt Aspirin Wax . • • —^— -- o o C/} •— • Drill — — Apr icoti Spatula • Cherries • • — —1- • • Or urn Chives Film • • • • Chisel OniHcase — . c o Pastry Tanuerlnos Clock . • Shoes . • • — —1_ - 1 a E o O • • Grapes Salmon FRUITS FRUITS CLOTHING CLOTHING • • ~ — -j- -j- Paprika Racket Ginger • • • Slacks Books • • • E 03 2 • -^— Parsley Vast Apples o • 2 Grill Plums o 'c .c Wrench Lemons • • • • • • • Tapes • • Cowl • • Hammer • • • • • • Vitamins • Pliers • • --!_ • • Nutmeg Chimes Soap — • / CORR Time of Day Short Term Cued Recall Completed: me of Day Long Term -ee Recall Begun: / TR Total Delay U c na Q. '(J /4 / TU It / NR is / P*I K ft B'i ! lL " KG 1 K\* 1. $• 1 .1i. Hull* i ttl III KL. •£ «) !! /8 ilfitti V!~ O) c .c u ra Q 0) • li �INSTRUCTIONS FOR MONDAY LIST TRIAL 1: Let's suppose you were going shopping on Monday. I'm going to read a list of items for you to buy. Listen carefully, for when I'm through, I want you to say back as many of the items as you can. It doesn't matter what order they are in — just tell me as many as you can. TRIAL 2-5: INSTRUCTIONS FOR TUESDAY LIST Now Let's suppose that you planned to go shopping again on Tuesday. I'm going to read a NEW list of items for you to buy. When I'm through I want you to say back as many as you can, in any order. I'm going to repeat Monday's shopping list. Again, I want you to say back as many items as you can, in any order, including items you may have already told me. Trial 1 Monday List Trial 2 Trial 3 Trial 4 Trial 5 Tuesday* List Drill 1 Toaster 1 Plums 2 Cherries 2 Vest 3 Halibut 3 Parsley 4 Ginger 4 Grapes 5 Pineapple 5 Paprika 6 Spatula 6 Sweater 7 Oregano 7 Wrench 8 Flounder 8 Chives 9 Sage 9 Tangerines 0 Lemons 0 Chisel Cod Jacket = Skillet Nutmeg Q Peaches Q Apricots W Salmon •W Pliers E Cinnamon E Slacks R Bowl R (Intrusion) Z (Intrusion) Z Tl __— -.-« --•» ' ~ ~m —• "• "W '""'I ' ' * ' �8) Key Osterreith Complex Figure Drawing - Copy Score: This test is a drawing test which requires the subject to reproduce a complex figure. It assesses visual-perceptual-motor, visual-spatial, planning and organizational skills. Scoring is based on the number of components in the design that are correctly drawn. 9) Rey O s t e r r e i t h Complex Figure Drawing - Short-Term Recall: This score is based on the subject's ability to redraw the design from memory after they copy it. As they are not told they will have to do this, this score is considered to test incidental learning and short-term memory of visual-spatial information. 10) Rey Osterreith Complex Figure Drawing - Percentage Change Score on long-term recall: This score is a measure of a subject's memory for the complex figure after a 20 minute delay. It compares their score on long-term recall with their score on short-term recall. A negative score represents the percentage decline in recall over time �CONSTRUCTIONAL FUNCTIONS were controlled, this test proved worthless (Heimeset al., 1980). Cultural background may also influence performance on this test (D. M. Harrison and Chagnon, 1966). THE COMPLEX FIGURE TEST (CFT): COPY ADMINISTRATION A "complex figure" was devised by Rev (1941) to investigate both perceptual organization and visual memory in brain damaged subjects. (See pp. '144—1-17 for a discussion of the complex figure in memory testing.) Osterrieth (1944) standardized Rev's procedure, obtaining normative data from the performance of 230 normal children of ages ranging from four to 15 and 60 adults in the 16-60 age range. In addition to two groups of children with learning and adjustment problems, he studied a small number of behaviorally disturbed adults, 43 who had sustained t r a u m a t i c brain injury, and a few patients with endogenous brain disease. More recently, L. B. Taylor made up an alternate complex figure for use in retesting (Milner, 1975; L. B. Taylor, 1969, 1979). Although normative data have not been obtained for the Taylor figure, its comparability to the Rev figure in design elements and complexity is reflected in the similarity of scores obtained on retest by patients with left temporal lobectomies whose drawing abilities, ordinarily, are unaffected by left temporal epileptic foci or surgery for this condition. The test material consists of Rey's complex figure (see Fig. 13-2) or Taylor's complex figure (see Fig. 13-3), blank typewriter-size paper, and five or six colored pens or pencils. The subject is first instructed to copy the figure, which has been so set out that its length runs along the subject's horizontal plane. The examiner watches the subject's performance closely. Each time the subject completes a section of the drawing, the examiner hands him a different colored pencil and notes the order of the colors. Instead of using color for tracking the subject's performance, some examiners keep a detailed record of the subject's copying sequence by reproducing the performance, numbering each unit in the order that it is drawn (Binder, 1982; Edith Kaplan, personal communication). Visser (1973) uses a "registration sheet" containing the printed Rey figure, which the examiner numbers in the order in which the subject makes his copy. This latter method is a satisfactory and effort-saving procedure except when the subject produces a drawing that deviates significantly from the original. When this happens, Visser's instructions to ignore extra lines and to deal with "wrongly placed [ l i n e s ] . . . as if they were placed correctly" can result in a confusing and misleading record. For most clinical purposes, switching colors generally affords an adequate representation of the subject's overall approach. When using the CFT for research, the technique of drawing exactly what the subject draws and numbering each segment (I use directional arrows as well) will best preserve the drawing sequence accurately. Time to completion is recorded and both the test figure ancl the subject's drawings are removed. This is usually followed by one or more recall trials. Some subjects who are dissatisfied with a poorly executed copy show improvement on a second copy trial. Osterrieth analyzed the drawings in terms of the patient's method of drawing as well as specific copying errors. He identified seven different procedural types: (I) Sub- 395 �A C O M P E N D I U M OF TESTS AND ASSESSMENT TECHNIQUES 396 �CONSTRUCTIONAL FUNCTIONS Fig, 13-3. Taylor Complex Figure (actual size). ject begins by drawing the large central rectangle and details are added in relation to it. (II) Subject begins with a detail attached to the central rectangle, or with a subsection of the central rectangle, completes the rectangle and adds remaining details in relation to the rectangle. (Ill) Subject begins by drawing the overall contour of the figure without explicit differentiation of the central rectangle and then adds the internal details. (IV) Subject juxtaposes details one by one without an organizing structure. (V) Subject copies discrete parts of the drawing without any semblance of organization. (VI) Subject substitutes the drawing of a similar object, such as a boat or house. (VII) The drawing is an unrecognizable scrawl. In Osterrieth's sample, 83% of the adult control subjects followed procedure Types I and II, 15% used Type IV, and there was one Type III Subject. Past the age of seven, no child proceeded on a Type V, VI, or VII basis, and from age 13 onward, more than half the children followed Types I and II. No one, child or adult, produced a scrawl. More than half (63%) of the traumatically brain injured group also followed Type I and II procedures, although there were a few more Type III and IV subjects in this group and one of Type V. Three of four aphasic patients and one with senile 397 �A COMPENDIUM OK TESTS AND ASSESSMENT TECHNIQUES dementia gave Type IV performances; one apliasic and one prescnile dementia patient followed a Type V procedure. In line with Osterreith's observations, Visser (1973) noted that "brain-damaged subjects deviate from the normals mainly in the fact that the large rectangle does not exist for them .. . [Thus] since the main line clusters do not exist, (parts of) the main lines and details are drawn intermingled, working from top to bottom and from left to right" (p. 23). Although, like all overgencralizations, Visser's statement has exceptions, Binder (1982) showed how stroke patients tend to lose the overall configuration of the design. By analyzing how subjects draw the structural elements of the Rey-Osterrieth figure (the vertices of the pentagon drawn together, horizontal midline, vertical midline, and two diagonals) (Fig. 13-4). Binder obtained three scores: Configural Units is the number of these five elements that were each drawn as one unit; Fragmented Units is the number that were not drawn as a unit (this is not the inverse of the Configural score as it does not include incomplete units, i.e., those that had a part missing); and Missing Units is the number of incomplete or omitted units. Fourteen patients with left brain damage tended to display more fragmentation (mean score of 1.64) than the 14 with right-sided lesions (mean score of 0.71), but the latter group's average Missing Units score of 1.71 (primarily due to left-sided neglect) far outweighed a negligible Missing Units score of 0.07 for the left CVA group. In contrast, 14 normal control subjects averaged 0.21 Fragmented Units and omitted none. These copying approaches were reflected in the low Configural Unit average of 2.57 for patients with right-sided CVAs, a higher average Configural Unit score of 3.29 for those with left CVAs, and a near-perfect average score of 4.79 achieved by the control subjects. Visser (1973) suggests that the fragmented or piecemeal approach to copying the complex figure that is so characteristic of brain damaged persons reflects their inabil- Fig. 13-4. Structural elements of the Rey Complex Figure (Binder, 1982). 398 �CONSTRUCTIONAL FUNCTIONS ity to process as much information at a time as do normals. Thus, brain damaged persons tend to deal with smaller visual units, building the figure by accretion. Many ultimately produce a reasonably accurate reproduction in this manner, although the piecemeal approach increases the likelihood of size and relationship errors (Messerli et al., 1979). Messerli and his colleagues (1979) looked at copies of the Rev figure drawn by 32 patients whose lesions were entirely or predominantly localized within the frontal lobes. They found that, judged overall, 75% differed significantly from the model. The most frequent error (in 75% of the defective copies) was the repetition of an element that had already been copied, an error resulting from the patient's losing track of what he had drawn where because of a disorganized approach. In one-third of the defective copies, a design element was transformed into a familiar representation (e.g., the circle with three dots was rendered as a face). Perseveration occurred less often, usually showing up as additional cross-hatches (scoring unit 12^ or parallel lines (scoring unit S). Omissions were also noted. Laterally differences in approach to these drawings emerge in several ways. Binder's study (1982) showed that patients with left hemisphere damage tend to break up the design into units that are smaller than normally perceived while right hemisphere damage makes it more likely that elements will be omitted altogether. However, on recall of the complex figure, patients with left hemisphere damage who may have copied the figure in a piecemeal manner tend to reproduce the basic rectangular outline and the structural elements as a configural whole, suggesting that their processing of all these data is slow but, given time, they ultimately reconstitute the data as a gestalt. This reconstitution is less likely to occur with right hemisphere damaged patients who, on recall, continue to construct poorly integrated figures (also see Chapter 14, pp. 445-446). Archibald (no date) found that, overall, patients with left-sided lesions tend to make more simplifications in their copies than do patients with rightsided lesions. These two groups differ in that the simplifications of patients with right brain damage involve partial omissions (e.g., fewer dots or lines than called for) while left brain damaged patients tend to simplify by rounding angles (e.g., giving curved sides to the diamond of the Rey figure), drawing dashes instead of dots, which are more difficult to execute, or leaving the cross of the Rey figure in an incomplete, Tshaped form. Of the 32 simplifications made by patients with left hemisphere damage, however, only five were made with the right hand, and three of these errors were made by patients %vho had residual right upper limb weakness. All others were made by the nonpreferred (left) hand of herniparetic patients. These data suggest that, for the most part, simplification errors of patients with left hemisphere damage are the product of the left hand's deficient control over fine movements; i.e., simplification in patients with left-sided lesions is a defect of execution, not one of perception or cognition. Binder's right and left hemisphere damaged patients also differed significantly in the accuracy of their reproductions. Patients with right hemisphere damage produced much less accurate copies than patients with left CVAs who, although on the whole less accurate than the normal control group, still showed some overlap in accuracy scores with the control group. Differences between patients with parietal-occipital lesions and patients with fron- 399 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES tal lobe damage were demonstrated in their failures to copy the complex figure correctly (Pillon, 19Slb). Errors made by the frontal patients reflected disturbances in their ability to program the approach to copying the figure. Patients w i t h parietaloccipital lesions, on the other hand, had difficulty with the spatial organization of the figure. When given a plan to guide their approach to the copy task, the patients with frontal damage improved markedly. The patients with posterior lesions also improved their copies when provided spatially reference points. However, use of spatial reference points did not improve the copies made by the patients w i t h frontal damage, nor did those with parietal-occipital lesions benefit from a program plan. Overall evaluations of the success of a drawing of the complex figure can be obtained by using an accuracy score based on a unit scoring system (see Tables 13-3 and 13-4). The scoring units refer to specific areas or details of the figures that have been numbered for scoring convenience. Since the reproduction of each unit can earn as many as two score points, the highest possible number of points is 36. From age Table 13-3 Scoring System for the Rev Complex Figure Units 1. Cross upper left corner, outside of rectangle 2. Large rectangle 3. Diagonal cross 4. Horizontal midline of 2 5. Vertical midline 6. Small rectangle, within 2 to the left 7. Small segment above 6 8. Four parallel lines within 2, upper left 9. Triangle above 2 upper right 10. Small vertical line within 2, below 9 11. Circle with three dots within 2 12. Five parallel lines within 2 crossing 3, lower right 13. Sides of triangle attached to 2 on right 1-1. Diamond attached to 13 15. Vertical line within triangle 13 parallel to right vertical of 2 16. Horizontal line within 13, continuing 4 to right 17. Cross attached to 5 below 2 18. Square attached to 2, lower left Scoring Consider each of the 18 units separately. Appraise accuracy of each unit and relative position within the whole of the design. For each unit count as follows: Correct 1 placed properly J placed poorly 2 points 1 point Distorted or incomplete but recognizable 1 Placed properly 1 Placed P°orlv 1 point Vi point 0 points 36 points Absent or not recognizable Maximum (From E. M. Taylor, 1959, adapted from Osterrieth, 19-14) 400 �CONSTRUCTIONAL FUNCTIONS Table 13-4 Scoring System for the Taylor Complex Figure Units 1. Arrow at left of figure. 2. Triangle to left of large square. 3. Square, which is the base of figure. 4. Horizontal midline of large square, which extends to 1. 5. Vertical midline of large square. 6. Horizontal line in top half of large square. 7. Diagonals in top left q u a d r a n t of large square. 8. Small square in top left quadrant. 9. Circle in top left q u a d r a n t . 10. Rectangle above top left q u a d r a n t . 11. Arrow through and extending out of top right quadrant. 12. Semicircle to right of large square. 13. Triangle with enclosed line in right half of large square. 14. Row of 7 dots in lower right quadrant. 15. Horizontal line between 6th and 7th dots. 16. Triangle at bottom right corner of lower right quadrant. 17. Curved line with 3 cross-bars in lower left quadrant. IS. Star in lower left quadrant. Scoring Follow instructions given in Table 13-3 for scoring the Key figure. eight onward, the average score is 30 or above; the average adult's score is 32 (see Table 13-5). The accuracy score provides a good measure of how well the subject reproduces the design, regardless of the approach he uses. Since the memory trial of the CFT is scored in the same manner, the accuracy score permits a comparison between the different trials of the test (see Chapter 14, pp. 445, 447). For example, although almost half of the 43 traumatically brain injured adult patients in Osterrieth's sample achieved "copy" scores of 32 or better, one-third of this group's scores were significantly low. On the memory trial, fewer than one-third of the traumatically brain injured group were able to achieve the normal group's mean score of 22. In general, there was a wider disparity between the copy and memory scores of the brain injured group than in Osterrieth's normal group of 60 persons ages 16 to 60. Four patients performed relatively better on the memory than' the copy task, suggesting delayed perceptual organization or slowed ability to adapt to new tasks. Seven patients diagnosed as having severe psychiatric disorders were the only adults to add Table 13-5 Percentile Norms for Accuracy Scores Obtained by Adults on the Copy Trial of the Complex Figure Test Percentile 10 20 30 40 50 60 70 80 90 100 Score 29 30 31 32 32 33 34 34 35 36 (Adapted from Osterrieth, 1944) 401 �A C O M P E N D I U M OF TESTS AND ASSESSMENT TECHNIQUES bizarre embellishments to their drawings, interpret details concretely, or Oil in parts of the design with solid color. No behavior of this kind appeared among the brain damaged patients. THE BENTON VISUAL RETENTION TEST (BVRT): COPY ADMINISTRATION (Benton, 197-1) The three alternate forms of this test permit the use of one of them for a copy trial. (See pp. 447-4-48 for a description and picture of the test.) The copy trial usually precedes the memory trials, which allows the subject to familiarize himself with the test and the test materials before undertaking the more difficult memory tests. Benton's normative population of 200 adults provides the criteria for evaluating the scores. Each patient's drawings must be evaluated in terms of his estimated original level of functioning. Persons of average or better intelligence are expected to make no more than two errors. Subjects making three or four errors who typically perform at low average to borderline levels on most other intellectual tasks have probably done as well as could be expected on this test; for them, the presence of a more than ordinary number of errors does not signify a visuographic disability. On the other hand, the visuographic functioning of subjects who achieve a cluster of test scores on other kinds of tasks in the ranges above average and who make four or five errors on this task is suspect. The performance of patients with frontal lobe lesions differs with the side of injury: those with bilateral damage average 4.6 errors; with right-sided damage, 3.5 errors; and with left-sided damage the average 1.0 error is comparable to that of the normative group (Benton, 1968). Other studies tend to support a right-left differential in defective copying of these designs, with right hemisphere patients two or three times more likely to have difficulties (Benton, 1969a). However, in one study that included aphasic patients in the comparisons between groups with lateralized lesions, no differences were found in the frequency with which constructional impairment was present in the drawings of right and left hemisphere damaged patients (Arena and Cainotti, 1978). MISCELLANEOUS COPYING TASKS Since any copying task can produce meaningful results, the examiner should feel free to improvise tasks as he sees fit. He can learn to reproduce a number of useful figures and then draw them at bedside examinations or in interviews when his test material is not available. Hecaen and co-workers (1951) and Warrington (1970) give some excellent examples of how easily drawn material for copying, such as a cube, a Creek cross, and a house can contribute to the evaluation of visuographic disabilities (see Fig. 13-5). Bilaterally symmetrical models for copying such as the cross and the star in Figure 13-5, or the top left and bottom designs from the Stanford-Binet Scale (Fig. 14-2, p. 444) are particularly suited to the study of unilateral inattention. Another simple copying technique that is sensitive to visual inattention as well as 402 �TEST NO. PARTICIPANT NUMBER TESTER CODE REY OSTERRIETH COMPLEX FIGURE SCORER CODE PARTICIPANT NAME ©©©©©©©© ®©©©©®©l 10000000 ®@®©®®©i ®®@®®®®j ©0000000 OMAY I/'TN f£\ /^\ /^\ S^T\ S^T\ /^T\ /^\ ©©©©©©©© '*•», O J © © ® © © © © ! OJUL !©©©©©©© ®®®®®®© !©©©©©©© O AUG © (T "5 "'*•-..*•». OSEP •i' v OOCT OMOV IPDEC \ i®@®@|®@®@ ^ I" .v_' •^— • y- • \ 6'' \ ? /.. L 7 REMARKS ^ •- • —y b..':^ _,'' '. I"' i N. ^ « 5'' / ' s u \ / ^** ^"•v/~\ « 'V*^7s^>v [ '* .• (9 •fl.....„_':# x ]''''(*?) : "£ 1 f ^ . ' . •"' fc- ! "* N. . -— f .«. *« f i MEMORY COPY DELAYED IMMEDIATE Cross upper left corner, outside of rectangle !©©0®i ®@O®i i©@©@i Large rectangle ®©0©i ®©0®l ®©0@! l@©0©i !®®0©l @©0®! !®©O®! !®©0®l I®®®® !@©0@! i®©0©! |®©0®i |@©0®i ©©0© Diagonal cross Horizontal midline of 2 ®©0®l Vertical midline l®©0®! l@©0© Small rectangle, within 2 to the left Small segment above 6 ©©0© Four parallel lines within 2, upper left Triangle above 2 upper right Small vertical line within 2, below 9 @©0®i ®®0©l ®©0®l ©@0© Circle with three dots within 2 ®©0© ©©0© Five parallel lines with 2 crossing 3. lower right @©0© ®©0® ®®0© Vertical line within triangle 13 parallel to right vertical of 2 ®©0© ©©O© Horizontal line within 13, continuing 4 to right l®©0® ®®Q© Sides of triangle attached to 2 on right Diamond attached to 13 @©0© Cross attached to 5 below 2 TOTAL 1 TOTAL TOTAL 1. SCORING I ©@© Consider each of the eighteen units separately. Appraise accuracy of each unit and relative position within the whole of the design. For each unit count as follows: Absent or not recognizable Maximum \ placed properly 2 points 1 placed poorly Distorted or incomplete but recognizable 1 point ) placed properly 1 placed poorly |®©0®i ®©O® Square attached to 2, lower left Correct !®©O©| 1 point '/' point 0 point 36 points 1 . �10. 13) Paced Serial Addition Test: This is a measure of mental control, mental speed, computational and attentional abilities. The subject is required to mentally add a sequence of numbers in rapid succession. �PACED AUDITORY SERIAL ADDITION TEST (PASAT) (Gronwall and Sampson, 1974; Gronwall and Wrightson, 1974) This sensitive test simply requires that the patient add 60 pairs of randomized digits so that each is added to the digit i m m e d i a t e l y preceding it. For example, if the examiner reads the numbers "2-S-6-1-9," the subject's correct responses, beginning as soon as the examiner says "8," are "10-14-7-10." The digits are presented at four rates of speed, each differing by 0.4 seconds and ranging from one every 1.2 seconds to one every 2.4 seconds. Precise control over the rate at which digits are read requires a taped presentation. Gronwall begins the tape with a brief repetition task that is followed by a ten-digit practice series presented at the 2.4-second rate. Sixty-one digits are given at each rate. The performance can be evaluated in terms of the percentage of correct responses or the mean score (see Table 17-4; the data are rounded to the nearest whole number). Postconcussion patients consistently perform well below control group averages immediately after injury or return to consciousness. The overwhelming tendency is for their scores to return to normal w i t h i n 30 to 60 days. Based on an evaluation of how the PASAT performance was associated with performances on memory and attention tasks, Gronwall and Wrightson (1981) concluded that the PASAT is very sensitive to deficits in information processing ability. By using the PASAT performance as an indicator of the efficiency of information processing following concussion, the examiner can determine when a patient is able to return to a normal level of social and vocational activity without experiencing undue stress, or when a modified activity schedule would be best (Gronwall, 1977). Although this technique was developed for taped presentation in order to control the presentation rate, with practice the examiner should be able to deliver the numbers at a reasonably steady one or two second rate. The task can also be presented at Table 17-4 Average PASAT Percent Correct and Mean Scores Made by Control Croup at Four Presentation Rates Presentation rate (seconds) 1.2 1.6 2.0 2.4 Average percent correct 51 66 73 32 Mean score ( ± SD) 22 ± 5 32 ± 3 40 ± 7 46 ± 6 (Adapted from Cronwall and Wrightson, 1974; Gronwall, 197 A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES the subject's response rate (i.e., unpaced), in which case the examiner should record pauses of five seconds and longer. Although the paced delivery format identifies patients whose responses are slowed as well as those who have a tracking disability, the unpaced delivery is more likely to identify those patients whose defective performance is due to a tracking defect. �® ® ® ® © 0 ® © © © © © ® ® ® ®i@© Jo • WHOM; 4 7 10 9 13 II 1 3 12 14 11 8 i © © © © © © © 4 G 9 4 8 2 14 G 1 1C 17 10 i i 7 1 6 4 23 3 7 74 5 £ 25 G 11 2G 5 11 20 27 Z © 14 15 11 , ! 8 G 3 G 9 4 9 D 3 7 6 1 4 7 8 9 8 fi 14 9 9 ID 2 15 11 2D 4 13 30 7 31. 3 1 ; 1 © © © © © © © © 4 32 2 3 33 6 8 34 n 9 35 4 36 8 12 37. 9 17 38. 5 14 39 1 6 10 2 3 11 8 1 9 43 2 3 14 5 7 45 3 8 46 a © © © 12 . 17 G 15 48 4 10 '19 3 7 COMPLETED? ©YES ©N'l i© I® i® j® ;© I® © I© © J© 1 | 17 13 G M 1 15 3 A r 18 " i 20 2 22 G 24 2 7 9 7 3 i 10 13 ' : 5 23 © 9 I 25. 3 8 11 27 •1 12 28 2 —I 1 3 30 9 10 31. 8 17 11 32. 3 33 5 11 C> 9 8 il. 4 12 JH. 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HI f.l'ONM IILSI'ONSr 1 4 2 8 3 1 G 1-1 2 8 5 2 <) li 9 11 7 3 12 8 4 1 S 5 ! 9 10 8 1 13 7 . ._ 11 1 12 6 13 3 9 14 8 16 G ! 16 L 18 19 9 .. „._ ! r 10 ^ T © G I I 1 0 j. _ ® G 0 i t ! i© | 10 | 23 8 : © © ©""© © G © G © 0 © © © G © 0 © 0 © 0 © © ©_© 17 10 7 4 9 27 G 10 28 3 9 29 C fl 30 3 | 31 2 i 32 9 11 33. 1 10 34 8 G 13 4 9 3G G 9 13 38 G 15 39 2 8 40 4 G 41. 3 7 42. 5 8 43 8 13 44 1 9 45. 5 G 45. G 11 47. 9 15 48 8 17 49 3 11 50 1 4 5 I i 3 1 C 9 G 10 0 11 G © © 0 0 © 0 © © Q G © © © 0 (0 8 I 3 1 2 G .4 .'( G u :i ! n i 13 •1 23 : :i ; !® © © i© ©• •r"::" ; 13 " 7 ©•' i© ©; 9 9 t'j •0 © G © "© © 11 '© ©: L> 10 0 ©' "r, " 7 " [ " • 1 I! !l 7 3 1 11 " 12 ©! ©' © © I© ©; 13 III © .© "® :© 15 'If 29 : ! © "0 © ©i i© ©1 b 13 2 11 © 0 B 0__0 1-1 36 1 37 3 4 39 4 39 2 : 7 -^ r G © © ® ® ® © 1® © i® 0! G G| © © G O© G ©© G ©@ G 0© © © G ® 5 9 12 2 D 14 3. G 11 4 8 14 45 1 S 4G G 7 47. 4 10 !© © 48. 9 13 2 11 3 5 1© i© 1® 0| G ©1 49 0. i 1— © © 3 1. i®® ©i H 16 1 ' 14 i f 1 12 1) : 13 1!. ftl'.ll! G© !©© !© ©• i©®; ;© ©; ,0© i© © i © 1® ©! 0 !@ ©' ©' i© G ®. © ©: _..©; ® 0. 17 1 n ©: © ©; I© . 11 12 33. i All •.-.« 1(0 I 14 12 34 © © © © © © © © © © © © © © © © ! 1© i® 0: !©..._©; '"•> r ~ H ©0 0® 0© 0© © © © © © " 4 8 ....." r 7 7 13 ©@ ! 9 111 1 " " © G J© © ! ,o,. 1 8 . .„ 4 \MillM ©000© 37 ! (i It 9 9 3 4 5 SCOIItS ' ' H""'HI ! 1 3 2 » - 'A"OM(, ©000O l 1 2 17 © © © © © © „„.„ 9 26 © ©1 © G © G 22 5 1 1i © G ©©! © 0 00 © 0 ©©' G 0 ©© © © ©© © © G © © © © ©I © 21 2'j (ill, HI © ~©l 20 2 lOIAl PAHT CII'A\T S lir il'ON'til cottiucr HI bl'ONSI fit HILJj 4 SCOI1ES © © 0 2 4 Nff ill © 0 1® 11 1.1 8 G 5 17 1 - © © 12 4 0 • VVKOiMG © © © ^M 1 - I ] I �12) Wisconsin Card Sorting Test: This test is designed to assess concept f orrr.at lor., problem solving, and the use of feedback. The score used is the number of cards (out of 128) that a subject used in order to make 6 categorical sorts based on the examiners feedback. �WISCONSIN CARD SORTING TEST t /^ N —• 1 1 Rl'MARKS COLOR I.H l\'f) J ] f 0 ; ?'• f^T' 00 ••.-, -. /-;» ._ '"^. ,--><:. '.„. - s_. N ,'?' :"; ,^~", ". C: ( "^i '-•!.} , -., /'"N ^_^' s „ ,- "• t \i' SORTS: C, F, 10GGGGGJ 230©©© 2 © © G ©''3 24©©®© GG! © Gi 2 5 © © @ 0 ©0, /7s '"'^ • 2 6 0 0 G © ©Oi , 30©©@©G 4©©©©'©0| 5 ©©©©'© ©| 2 7 0 0 0 0 0.^1 VX- —' 23000®. 7©©©©GG| 7T0G00GG 3©G0@0®| 29©©0© 3 G 0 ^! (^ 'v£, i i 72 5 3GS0GG1 ;- ©-t: -J - Vl-' v_/ ' 9©GG©GG| ,,©©00001 !i2©0©©:©0i •7\ 55000 -i f- ^^ .'T', / J \^/ V__• m^-. ^P vl-/ ^l-' ^ .^' '^^ ' ,' J J ^y 'O-' ^O' 34©©®@©0! 55000 13 © © © © © ©i 3500®©.©©! 570 730G Q00G 14©©®©!©©' 3G©©©@©0! 530 79© 1 5 © © ® ©•© © 37©G©©©0! 16©©®©!©© 3 8 © © ® ©®0| 53 ©'© G 60000' 33 : 17©©®©!©© 39©©®©©G| 18©©®©®© i fn\ /^ /Til 19©©®©'©© 20©©®©!©© 21©©®©!©( 22©©®©©© O'ri:- 1 •' ?, 0 . •^-s 1 1 .,_ X s /'"" V E GGGGGGG G ©.• t GGGGGG© O-. GGGGGGG' OGGGGO0G ;GGGGGG© c.-.. F E t , 6 ©©©©:©©! | i ^p rr, v:~) G 0 W C; C ^n G 35 0 ('0 3) p i ": "i •^..' © G /• G 3) 0 GG G G i^i) G I'""! © ©© : } 0 C?) G f ; }*vll ' 0 v © © y^,' GG O P-' . 1 © G 0 ; r, _i GG /r . 'G G -©. ©G i • * G 0 GG v^. © G. GG {--. /*-> G ^' .._G : ,0 G G. w f^\ G G G G G G © G ,T>, , "} /TV © 'O' ..:- vj. rr. 0; GG ©GG .©©©©©'©©' GGGGGGG GOGGGGG GGGGG0G 42©©©©.®G • — x.^' '^^- '^^ >—' ; •—' **—f j 6100© 930GG0G0; ioo©©©0©0! 'vi'^' o 62 ©0© 0GG 63 © G © 0 © : ^ 64 ©©© ! 65 © © © •^©G © GG 3200 33 © 0 123©©®@ : @0 0©©G! 103 CD© © © • © © ©G®G| 1 0 4 © © ® © - © © ©@© ©GG 35©^ )G 105©©@©©Gi 1060©©©©©! 12S©©®©'©G !27©©®@i@© 107©G(^ 123©©©©®© G| '©©© GGG ©G '~'©G © ©Gi QG)(G_); ! (5) (3)1 COMPLETED? ©YES © TERMWATED 125 C£ ©©•©Gi ®@' GGG ! ©G 124 ©© 34 © 0 44©©®©'©©l ©@© 121 122©©®©©© 00 310© ® © © 0 : 1 1200©©©©© OREFUSED �«and. tne Each Left Hand: o£ ^ ^ P = ys IHLO a grooved them of seconds lt to compiete �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES identical. Goldberg and Smith's criteria for each 60 second condition is simply two times the 30 second criterion for that condition. Performances are considered indicative of brain damage when one or more score below criterion occurs on both the first and the second trial for one or more 30 second conditions, or occurs on the 60 second trial for one condition. A 60 second score achieved by the nonpreferred hand that exceeds the preferred hand's score by three or more points indicates a lesion contralateral to the preferred hand. A 30 second score for the preferred hand that exceeds the 30 second score of the nonpreferred hand by five or more points suggests that the lesion is ipsilateral to the preferred hand. Like many other useful neuropsychological instruments, the Purdue Pegboard Test varies greatly in the efficiency with which it identifies brain impairment. T. E. Goldberg and A. Smith (1976) report that, using their norms based on two trials for each condition, this test identified 80% (10% false positive, 10% false negative) of a large group of normal subjects and neurological patients correctly. Also using these norms, Berker and his colleagues (1982) found that in a group of 223 diagnostically mixed brain damaged persons, a larger number had motor than sensory deficits (using the Face-Hand Sensory Test, see p. 378), although both kinds of deficits are usually present with lateralized lesions. However, Heaton and his co-workers (1978) report that the proportion of correct differentiations between organic and various groups of psychiatric patients made by this test alone ranges from 16% to 46%. These are not very good odds on which to attempt a screening program. GROOVED PEGBOARD (KWe, 1963; Matthews and Klave, 1964) This test adds a dimension of complex coordination to the pegboard task. It consists of a small board containing a 5 X 5 set of slotted holes angled in different directions. Each peg has a ridge along one side requiring it to be rotated into position for correct insertion. It is part of the Wisconsin Neuropsychological Test Battery (Harley et al., 1980; Matthews and Kleve, 1964) and the Lafayette Clinic Repeatable Neuropsychological Test Battery (R. Lewis and Kupke, 1977) (see p. 566). Its complexity makes it a highly sensitive instrument for studying improvement in motor functions following stroke (Meier, 1974) and hemispheric components of motor performance (Haaland et al., 1977; Haaland and Delaney, 1981). Time to completion is scored. Data have been handled in a variety of ways. Matthews and Haaland (1979) give the mean time averaged for both hands in a small (n — 16) group of mostly middle-aged (55 ± 5) control subjects as 35 seconds. One group of 14-year-old boys and girls performed the task in 66.5 ± 13.3 seconds using their preferred hands and 70.1 ± 7.5 seconds with the nonpreferred hand (Knights and Moule, 1968). Another group of 14 year olds, all male, took longer and showed much greater variability, performing the task in 78 + 40.5 seconds with the preferred hand and in 81 ± 23.8 seconds with the nonpreferred hand (Trites, no date). R. Lewis and Kupke (1977) report that average scores for the preferred hand only were in the range of 71-79.5 seconds for epileptic patients under different drug conditions. 532 �p 1 of Grooved Peqooarcj -i- (label) / 6 /rt/ 0 / 1 / EXMfl CODE (OUUI--OOO4) (OOO5-O011) Part ici pant ID Partcipant Name Month (OO14-0015) Year (0016-0017) hour (0018-0019) Mi n Time started (001£-0013; Day Date <OO£0-OO£1) Interviewer ID (O0££-O0c:5) Supervisor ID (OO£6-OOc.'9) 1. For most of your daily tasks, do you prefer to use your rignt hand, your lefr hand, or Co you use either hand? 1 = right haviC £ = left hand 3 = either hand 8 = don't know S = refused (0030) �I P £ of r* wnen you were a ^ounfl £Qi.4.5, you prefer to use your iright hand, your left hand, or d i d you use either hand? IB 1 = right hand £ = left hand 3 = either nand J 8 = don' t know 9 = refused J 3. First Hand Tested J 1 = ri gnt nano c.1 = left hand 7 = not appiicaoie 8 = don* t know 9 = refusea Note: TEST THE RIGHT HP.ND FIRST, IF THERE IS NO i-i EXPLfilN IN THE SECTION Ii- TriE PREFERRED hftND IS NOT TESTED FIRST .Completion time / First hand I minutes seconds I <0033-O034) (OO3S-0036) 97 = not applicaDle 98 = aon 1 t know 93 = refused i tf No. of pegs dropped / t-iiTSt nand 97 = not applicaple 9d = don't know 99 = refused <0037-OO38; �iNf,r'T,'tv, -"A.-J": -^ ' •HJ*" v -••"•- • .„ » -.. '•*. ,." "W i; » • *" : 6. Conip 1 et i on t i m e 4 / isgcong minutes /_/_/ seconds • / _ / _/ 57 = not applicaolc 98 = aon' t know S'3 = refused 7. No. of pegs dropped / becond nana /_/_/ 97 = not applicable 98 = don' t know 99 = refused S. Comment /_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/._/_/_/_/_/_/_/_/ /I / _ / _ / _ / _ / _ / _ / ' _ / _ / _ ''_/._/_ / _ / _ DESCRIBE ftNY UNUSUHu FlNiJlNGS "i HMT COUL.D llMr'LUENCE THiri "I'Eb'T NON-DOM INftNT HftND TESTED FIRST, INTERFERING NDISt, DID NOT DIRECTIONS, ETC. ( E. 6. , �-•v i- 1-3 - . , . - . .,. : :v * . , • '. v• •.,--,, , •'•• . , , . . . , . - . . . . . - . . - . _•-.•. .-,-.. ...-,.•-. . . , . . , . . . . . . ...... ^ . 16) Handedness Laterality Rating: This score represents the subject's handedness index as assessed by the Edinburgh Handedness inventory. A scored 1 .00 represents a 'pure' right hander, while' a 0.00 is someone who reports only left hand use. �LOVELACE MEDICAL CENTER - VETERAN'S HEALTH STUDY ALBUQUERQUE, NM Please indicate your preference in the use of hands in the following activities by putting a check ( V ) in the appropriate column. Some of the activities require both hands. In these cases, the part of the task or object for which hand preference is wanted i< clearly indicated. Please try to answer all of the questions, and only leave a blank if you have no experience at all of the object or task. — Always Left Usually Left Either Hand Usually Right Always Right (2) (1) (0) (1) (2) 1. Writing 2. Drawing 3. Throwing 4. Scissors 5. Toothbrush 6. Knife (without fork) 7. Spoon 8. Top hand when holding the handle of a shovel. K. Striking a match r 10. Twisting off the lid of a jar This space for department use only TOTALS LQ= R-L X100 = 20 rticipant No. Technician Test Date Participant Name .Technician No. .Completion Debriefer _Test No. _ Form No. 10-051 (Rev. 5/85) Modified Edinburgh Handedness Inventory 1-Yes; 2-No; 7-Terminated; 9-Refused Scorer No. : �Reprinted Irom Journal of Occupational Medicine Volume 27, No. 3, March 1985 A Computer-Administered Neurobehavioral Evaluation System for Occupational and Environmental Epidemiology Rationale, Methodology, and Pilot Study Results Edward L. Baker, M.D., M.P.H.; Richard Letz, Ph.D.; and Anne Fidler, M.Sc. To facilitate the conduct of, epidemiologic studies of populations at risk for or suffering from central nervous system (CNS) dysfunction due to environmental agents, a computer-administered neurobehavioral evaluation system has been developed. The system includes a set of testing programs designed to run on a microcomputer and questionnaires to facilitate interpretation of results. Standard tasks evaluating memory, psychomotor function, verbal ability, visuospatial ability, and mood were selected and adapted for computer presentation following the recommendation of an expert committee of the World Health Organization and the National Institute (or Occupational Safety and Health. In two pilot surveys, test performance was found to be influenced by age, education level, and socioeconomic status in ways consistent with prior research findings. Performance on tests of short-term memory and reaction time was negatively correlated with intensity of organic solvent exposure among industrial painters. In view of the ease of administration and data handling, high subject acceptability, and sensitivity to the effects of known neurotoxic agents, computer-based assessment of CNS function holds promise for future epidemiologic research. iNeurobehavioral tests have been used widely to evaluate cognitive function following human exposure to From the Occupational Health Program, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115 (Dr. Baker for further correspondence). This study was supported in part by Occupational and Environmental Health Center grant ES00002-21 from the National Institute of Environmental Health Sciences, the William F. Milton Fund of Harvard University, and a Mellon Foundation Faculty Development Award. 206 neurotoxic agents.' These studies have shown a variety of adverse effects on the central nervous system (CNS) that have been reviewed in detail elsewhere. 3 - 3 Although somewhat similar techniques were used in many of these studies, significant variability in testing procedures between studies unfortunately has made comparison of results difficult. Furthermore, the procedures used require extensive interviewer involvement, with attendant error due to variation in testing procedures. Such error impairs the ability of the study to detect subtle health effects. J Additionally, systematic error introduced by interviewer bias may further distort study results. An additional concern exists regarding the intelligibility of the results of past studies. Since a wide variety of tests have been used in past investigations, health professionals lacking formal training in psychology or a related discipline have great difficulty in interpreting study findings. Also, because neurobehavioral epidemiology is being used with increasing frequency to establish standards of occupational and environmental exposures to neurotoxic agents, intelligibility of test results is an important consideration for standard setting. Finally, the variability in test procedures among studies precludes the pooling of data on unexposed individuals in an attempt to explore the effects of extraneous factors (e.g., age, education level, and sex) on test performance. Clearly, our ability to use these tests to evaluate exposed populations is dependent on our understanding of the determinants of test performance in unexposed groups. In a recent review of neurobehavioral studies of populations exposed to organic solvents, Cherry and Waldron5 indicated that prospective evaluations of working populations hold particular promise for future epidemiologic Computerized Neurobehavioral Testing/Baker et al �work. We concur in this assessment of the need for prospective studies and feel that, in this context, tests with maximum rcproducibility are needed. For this and other reasons, we have adapted certain tests of neurobehavioral function to a computer-administered format. In choosing tests for inclusion in our set, we have reviewed the previous literature in which lest sets for use in epidemiologic investigations have been specified. An extensive set is that developed at the Finnish Institute of Occupational Health.'• More recently, an expert committee convened by the World Health Organization (WHO) and the National Institute for Occupational Safety and Health (NIOSH) proposed a core set of neurobehavioral tests for use in occupational epidemiologic studies and a list of supplemental tests suitable for certain situations.-" This is the only core set developed by an international group with specific experience in epidemiologic study of occupational groups. Clearly, the process of specifying a test set is an evolving one that will be facilitated by further experience. For our current choice of tests to adapt for computer administration, we were guided significantly by the views of the WHO-NIOSH group, as well as by our prior experience." The tasks that we have chosen include ones adapted from clinical neuropsychology that have also been used widely in prior field studies of workplace neurotoxic agents. As a result, most of our tests are recognizable to practitioners in the field since they are adaptations of preexisting instruments. In selecting our set of tests, we were guided primarily by clinical and epidemiologic experiences rather than theoretical considerations from the field of cognitive psychology. We feel strongly that there is an important role for other sets of tests that derive directly from current psychological theory (e.g., Force et al") in evaluating populations exposed to environmental neurotoxic agents. Such tests will prove particularly useful in exploring mechanisms of neurotoxin action and will undoubtedly be found to be useful in combination with other techniques for evaluating CNS function. The testing system described herein is designed for use in epidemiologic field studies of human populations exposed to neurotoxic agents in the workplace or the general environment. Our approach offers techniques that can be administered on portable equipment by technicians with minimal training. The tests chosen evaluate a broad range of CNS functions, including psychomotor function, memory, visuospatial ability, verbal ability, and mood. We have not selected tests of sensory function, which should be included in most evaluations of populations exposed to workplace or environmental neurotoxic hazards. Further development of such tests is needed. We do not feel that the current set of tests should be considered as a fixed battery to be used in all situations. Rather, a more appropriate approach is one in which tests are selected from those noted for use in specific circumstances. Computer-administered behavioral testing techniques offer certain advantages and disadvantages that should be carefully considered prior to their use. The primary advantages of a computer-administered system include the reproducibility of testing conditions, ease of data handJournal of Occupational Medicine/Vol. 27, No. 3/March 1985 ling, ease of scoring, and immediate reporting of results to individuals participating in the testing session. Immediate feedback of test results, if properly performed, improves the level of motivation of persons being lested. Furthermore, ihc use of a computer alters the dynamics of the testing situation in a way that provides a nonthreatening challenge to the individual, which thereby encourages participation. Some disadvantages of computer-administered system are the cost and availability of equipment as well as the unusual quality of the interaction between the person being tested and the computer itself. Although many persons in the past were quite unfamiliar with the use of computers, this situation is rapidly changing with the proliferation of home computers, computerized banking machines, and video games. Therefore, interacting with a computer is not as unusual in developed countries today as it was a few years ago. Since the computer systems being considered for this application may also be used for other applications by scientific groups, including the analysis of data from surveys and word processing, the costs of obtaining a computer system for neurobehavioral testing can be justified for other reasons. Furthermore, with the advent of powerful, affordable systems, the versatility of the available hardware has made field testing using these units quite feasible. Although the use of computers does increase somewhat the complexity of the testing situation, some existing tests included in the WHO core test battery and supplementary tests 7 do require electronic equipment for their performance. Therefore, it appears that a place exists for the use of computer-administered neurobehavioral tests in the monitoring and study of populations exposed to neurotoxic agents. Such a battery has been field tested by our group and found useful in field studies of several population groups. Rationale for Test Selection Our automated neurobehavioral evaluation system currently includes 12 separate tasks (Table 1); others are under development. All tests listed have been successfully administered in field surveys of working populations. Five of the tests (Table) are modifications of tests within the seven-test WHO core battery.7 The two other tests in the WHO core battery do not lend themselves to computer administration. In addition, we have implemented programs for the verbal paired-associate learning and the continuous performance tests that were specified as suitable supplements to the WHO core set. The Sternberg memory-scanning test and the vocabulary test were adapted from existing tests, not listed by the WHO committee, to evaluate memory and verbal ability. The pattern recognition and pattern memory tests are similar to existing computer-administered screening tests. 10 Only one totally new test, the hand-eye coordination task, was developed for inclusion in the set. Further discussion of the rationale and process of test selection is provided in previous publications.a -"-' a Description of Individual Tests and Rationale for Their Selection Psychomotor Performance—7. Symbol-Digit Substitution Test—This task is a modification of the Digit-Symbol Sub207 �Computer-Administered Neurobehavioral Evaluation S y s t e m Test Function Psychomotor performance Speed/coding ability Dexterity Speed Attention/speed Memory Memory/attention Verbal memory (short-term and intermediate) Visual memory Visual memory Memory processing Verbal Verbal ability Mood Mood Visuospatial ability Cognitive ability Administration Time, min Symbol-digit't Hand-eye coordination! Simple reaction time'! Continuous performance!! 6 4 5 6 Digit span'! Paired-associate learning} (with delayed recall) Visual retention* Pattern memory! Memory scanning! 10 12 2 10 5 10 Vocabulary Mood scales*! 7 Pattern recognition! 5 * WHO core test ! Suitable for repeated measures design \ WHO supplemental test 40 r- £ 30 B 20 ^ b <= K 20 I? <° i I 'I^ 6L 1-1-1 360 400 440 480 520 MEAN CPT LATENCY 560 600 (msec) Fig. 1 — Distribution mean response latencies on continuous performance test of 68 unexposed bricklayers. stitution test from the Wechsler Adult Intelligence Scale. 15 A computerized version of the symbol-digit task has been found to be of value in automated screening of psychiatric patients. 10 In addition to being included in the WHO core set/ the Digit-Symbol test, which evaluates speed and coding ability, has been found useful in prior epidemiologic studies of individuals exposed to lead, carbon disulfide, and solvent mixtures.- In our adaptation, nine symbols and digits^ire paired at the top of the screen and the subject has to press the digit keys corresponding to a reordered test set of the nine symbols. The time required to complete each symbol-digit set and the number of digits incorrectly matched are recorded. Four sets of nine symbol-digit pairs are presented in succession. The pair- 208 4 8 12 JL 16 20 MEAN FATIGUE SCALE SCORE Fig. 2 — Distribution of scores of 68 unexposed bricklayers on fatigue scale from mood scale. ing of symbols with digits is varied between sets to avoid learning. 2. Hand-Eye Coordination Test—The individual is asked to use a joystick to trace over a large sine wave pattern on the video display terminal. A cursor moves horizontally at a constant rate, while the individual controls only the vertical motion of the cursor with the joystick. Deviations from a set line (mean absolute error and root mean square error) are recorded and constitute measures of coordination ability. This task evaluates dexterity, a function found to be disrupted in previous studies of various neurotoxic agents.2-n'11' 3. Simple Reaction Time—In this test, the individual is Computerized Neurobehavioral Testing/Baker et al �asked to press n button when seeing a large "0" on the screen. The inlcrstimulus interval is varied randomly between 2.5 and 7.5 s to reduce anticipation effects. Data are recorded as individual reaction times over the presentation of 60 stimuli and the response latencies are averaged over blocks of 12 trials. Reaction time testing has been a widely used technique for monitoring exposed workers.' r 4. Continuous Performance Test (CPT}—'\h\s test measures sustained visual attention by having the subject press a button upon seeing a large letter "S" when it is projected onto a video display terminal. 1 " A series of l e t t e r s , 20% of which are the letter "S," flash briefly (for about 50 ms) on the screen at a rate of one per second for five minutes. Recording and storage of individual response latencies allow for computation of mean reaction time, learning effects noted during (he early stage of the task, and variability in attention that occurs during the latter part of the test. Omission and commission errors are also recorded. Previous research has utilized this form of testing extensively in evaluating solvent"'' ir and lead neurotoxicity." A report of CRT results can be graphically displayed to the subject at the end of the entire testing session. Memory—7. Digit Span—This widely used clinical test is a part of the VVechsler Adult Intelligence Scale'"- and VVechsler Memory Scale.- 0 The individual must enter into the computer progressively longer series of digits following visual presentation at a rate of one per second by the computer. After incorrectly responding to two trials at a Span length, the task changes such that the individual must enter a new digit series in reverse order. Previous studies of solvent and lead toxicity have utilized this test as a measure of short-term memory and attention.-•'>-2' 2. Paired-Associated Learning Test (With Delayed Recall)— In a standard task- 0 of short-term verbal memory, word pairs are read from the visual display screen by the interviewer at a rate controlled by the computer. The acceptable response time is also computer controlled. The series of words is presented three times with varying internal order, and scores, consisting of the number of correct associations, are given for each trial. An additional trial containing the same words is given at the end of the testing session, following a delay of more than 30 minutes, as a test of memory encoding and intermediate recall. This is the only task within our set requiring direct interviewer participation. 3. Visual Retention Test—The Benton test of visual memory is administered in many standard neuropsychological batteries." We have developed a similar approach in which the machine presents the test figure(s) followed by four similar figures from which the individual must select the figure(s) previously seen. The computer records the number correct and the response times for correct and incorrect responses. 4. Pattern Memory Test—In this task, a pattern consisting of several geometric figures formed by small blocks is presented for a brief period. The pattern is then removed and replaced by three similar patterns, one of which is identical to the original stimulus. The task is repeated with different stimulus and choice patterns to a total of 15 trials. Journal of Occupational Medicine/Vol. 27, No. 3/March 1985 Task difficulty may be increased by increasing the degree of correspondence of the incorrect patterns to the correct one. The computer records number of correct responses and latency time for correct and incorrect responses. Since the pattern composition is varied randomly, this test of visual memory is suitable for repeated administration. A similar task has been described previously. 10 5. Memory-Scanning Test—The subject is shown a scries of digits and must indicate whether a digit presented subsequently comes from a previously presented set." Responses are scored as correct/incorrect and response latencies are recorded. The set size of digits to be presented can be varied from two to five and regression techniques used to assess total cognitive encoding and motor processing time, difference in mean response time for positive and negative trials, and memory-scanning time. The computer program used to administer the tests is modified from that used by Smith and Langolf.- J The test measures the actual processing time required to recall previously stored (i.e., learned) information and has been shown to be sensitive to chronic mercury exposure.-' Verbal Abilities—7. Vocabulary— In our modification of a vocabulary subtest from the Armed Forces Qualifying Test, 12 25 words are presented and the subject is asked to select, from a set of four words, the synonym for the presented word. This test is said to provide an index of stable CNS function. 11 In developing this test some new sets of words were created to increase task difficulty as discussed below under "Pilot Testing." Mood—7. Mood Scales—This presentation modifies a selfadministered questionnaire 2 - 1 in which subjects rate themselves with respect to their feelings during the previous seven days. This mood survey has been used successfully in the evaluation of the efficacy of psychotherapeutic drugs and in classifying individuals with various neurobehavioral disorders. 24 Our adaptation is limited to 25 items and yields a five-dimensional mood profile (tension, depression, anger, fatigue, and confusion) by combining ratings on individual items. Our prior studies of lead toxicity have shown that a mood survey is useful and sensitive in the evaluation of CNS effects of occupational lead exposure.19 Visuospatial Ability—7. Pattern Recognition Test— In this task, three patterns similar to those generated for the pattern memory task (described above) are presented on the screen at the same time. Two are identical. The task consists of identifying which of the three is different. Number of correct responses and individual response latencies are recorded. As with the pattern memory test, the method of generating the patterns is such that repeated trials can be performed. The test appears to evaluate the higher processes involved in the organization of visual material, i.e., visuospatial ability." A similar task has been described.1" Computer Configuration Hardware—The software used for test administration was developed using an IBM personal computer (PC). The speed and power of the 16-bit 8088 microprocessor allow millisecond accuracy while working in an interpreted language. A joystick as well as two push buttons provide input for cursor controls. Field testing in our offices and 209 �in pilot projects utilixed the IBM PC. More recent testing has utilized the COMPAQ Computer (COMPAQ Computer Corp., Houston), which is totally compatible; with IBM. spftwarg and hardware,. Vj.dc.O_ djsplay is performed through a built-in 9-in monitor. Use of this microcomputer permits testing with a portable, 28-lb test system. The programs run on some other IBM PC-compatible computers. Software—The software that administers these tests is written in IBM's Advanced BASIC. Input/output statements and functions standard in this implementation of the language allow the flexibility of an interpreted language with great speed of graphic presentation. Separate files are developed for each subject, containing some identification data and the test results. Each lest in the battery is individually administrate. Minimal training time is necessary for interviewers because they are given the option, through a screen menu, of choosing the tests and test order to be administered to each subject. A default Option can provide a fixed set of tests established by the investigator. Timing of response latencies is accomplished by a software clock. Timing resolution is about 0.5 ms. Standard communications software permits data transfer over telephone or dedicated communication lines to larger computers for analysis using standard statistical software packages. A summary of test results can be displayed on the screen or printed out immediately after testing. Mode of Presentation—After the procedures are briefly explained by a research technician, all additional instructions are read from the video screen. Instructions have been simplified to avoid complicated passages and ambiguous phrases. With the exception of the Paired-Associate Learning Task, little interaction occurs between the technician and the tested individual until the testing sequence is completed, unless assistance is needed in understanding the task. The computer is programmed to monitor inappropriate responses (e.g., holding down the joystick button too long or continuously failing to respond to appropriate stimuli) and to instruct the individual to modify his approach to the testing session. Practice trials are performed on certain tests to ensure that the tests are understood-.Testing procedures are described below under pilot studies. Pilot Testing Background—Development of our system has occurred incrementally as programs were written, field tested, and evaluated for subsequent use. The two pilot studies were performed at a stage when only a portion of the current test set (Table) had been developed. The purposes of these studies were (1) to evaluate the portability and subject acceptability of our computer-based system, (2) to determine training requirements of interviewers and to clarify their role during testing, (3) to develop a strategy for evaluation and control of extraneous factors that might alter test performance, and (4) to examine the distribution and determinants of test performance in a working population unexposed to neurotoxic agents in their jobs. Methods—Before coming to the test site, each person completed a detailed work-health questionnaire regarding prior health conditions, prior jobs and job-related chemical exposures, current and past habits (i.e., alcohol and 210 cigaretle consumption history), and current symptoms; the questionnaire was reviewed for accuracy and completeness by an interviewer. Immediately before test administration, a pretest questionnaire designed to evaluate transient conditions (e.g., physical injuries, alcohol or drug consumption, sleep deprivation, and emotional trauma) was also administered. Those persons found to be acceptable for neurobehavioral testing were then provided brief instructions by an interviewer and left alOnc to proceed with the test series. The interviewer remained nearby to monitor the session and to be available if questions or problems arose. At the completion of the tasks, the interviewer displayed the subject's results on the continuous performance task (CPT) on the video display terminal. A written report of test results was provided with appropriate explanations several weeks later by mail. Test Selection—Six tests were used from the system: the mood scales, CPT, hand-eye coordination, digit span, simple reaction time, and the vocabulary subtest from the Armed Forces Qualifying Test. The choice of tests was determined by an interest in evaluating mood, psychomotor ability, memory, and verbal ability and by the stage of development of our system. Statistical Analysis—Simple frequency distributions of each variable were derived and histograms for selected tests were constructed. Multiple regression analyses designed to evaluate the impact of selected predictor variables on test performance were executed using a computer software package (Statistical Analysis System, Gary, N.C.) run on an IBM mainframe computer. Unexposed Population Study Procedure—In April, 1982, a group of union bricklayers was evaluated as part of a multiphasic health evaluation that included, in addition to neurobehavioral evaluation, pulmonary function testing, chest roentgenography, and other clinical tests. We excluded data for persons with evidence of acute alcohol or drug consumption, poor English comprehension ability, or incomplete information, leaving data for 68 individuals for analysis. Results—The 68 bricklayers whose data were analyzed were typical of U.S. working males: they had a mean age of 47.8 years, with a mean of 11.6 years of schooling; their parents were of lower socioeconomic class using the scale of Hollingshead and Redlich 25 (class 4, out of five classes); they reported consumption of an average of 2.4 alcoholic drinks per day. The distributions of raw scores on the six tests were generally Gaussian (Figs. 1 and 2). Log transformation of the scores of the hand-eye coordination test (root mean squared deviation from pattern line) was required to yield an approximately Gaussian distribution. A ceiling effect was observed with the Armed Forces Qualifying Test vocabulary test such that 25% of those tested had either zero or one error of the 25 items. We have subsequently modified our vocabulary test to address this problem. Multiple regression analyses showed that performance on tests of psychomotor function (i.e., CPT, simple reaction time, and hand-eye coordination) consistently were negatively correlated with age, as anticipated from previous literature.' 011 Vocabulary test performance was pos- Computerized Neurobehavioral Testing/Baker et al �itively correlated with number of yenrs of schooling (p = 0.03)/which was also consistent with prior research. Memory test results correlated best with number of years of education (p = 0.09 for digit span, backward). Alcohol consumption history (average number of drinks per occasion) did not show a clear pattern of association with test performance in this group. Exposed Population Study Procedures—In April, 1982, we evaluated another group of construction trade workers: industrial painters and drywall tapers. The painters were exposed to a variety of organic solvents that previous reports" 1 have indicated may effect neurobehavioral function both transiently and persistently. In contrast, dry-wall tapers, although exposed to asbestos in the past, have not been exposed to organic solvents or other workplace neurotoxic agents. Following exclusions for reasons described above for the other pilot Study, 66 workers were available for analysis. In view of the small number of dry-wall tapers (N = 17), their data were combined with those of the painters and used in a multiple regression analysis. In this analysis, two exposure terms were used to estimate the intensity of solvent exposure: the number of hours worked with paints during the past year and whether the individual had worked with paints during the past month. Both indices were derived from union records. We also asked individuals to recall their work experience, and their reports correlated well with union records (/• = 0.75). Other terms in the multiple regression model were age, number of years of education, and parental socioeconomic status (as measured by the Hollingshead Index). In view of the high correlation between number of years worked as a painter and age, we did not include this term in the model to avoid poor parameter estimation due to colinearity. Significance levels (two-tailed p values) for each coefficient were calculated using the t statistic. Results—As observed in the bricklayers' pilot study, we noted associations between test performance and age and education level, as anticipated on the basis of previous reports'2: older individuals demonstrated significantly worse p e r f o r m a n c e on the continuous p e r f o r m a n c e t e s t (p = 0.005), hand-eye coordination test (p = 0.0003), and backward digit span (p = 0.02); those with better education performed better on the vocabulary test (p = 0.0001), forward digit span (p = 0.02), and the continuous performance test (p = 0.05); parental socioeconomic status showed modest correlations with test performance but of a magnitude, that was less striking than those noted for age and schooling. As seen with the pilot study of bricklayers, chronic alcohol use was not found to be significantly associated with te.st performance. Some associations were noted between the two measures of painting frequency and test performance. Recent heavy exposure to paints during the month prior to testing was associated with reduced forward digit span (p = 0.08), whereas the amount worked during the past year was correlated with lower performance on simple reaction time (p = 0.05). Discussion The computer-based neurobehavioral evaluation sysJournal of "0"ccupational~MeuTcme,'Vo]; 27, No. 3/March 1985 tem described herein offers several advantages over current conventional approaches, including a battery that we have recently described." Computer administration improves the rcproducibility of test conditions and facilitates data handling and scoring. Portable computers are now available that permit the use of these systems in field locations. A minimum level of training is required for technicians who operate the system. Validation studies are now under way to compare our computer-administered tasks with conventional methods of test administration, to evaluate the rcproducibility of the tests, and to assess the effect of alcohol consumption on test performance. Our pilot studies demonstrated a high degree of acceptability of this portable computer-based system among blue-collar workers. The experience of using the computer was found to provide a nonthreatening, positively motivating format for evaluating neurobehavioral function. Minimal interviewer involvement was found to be necessary. Statistical analyses showed that test performance was correlated with age, education, and parental socioeconomic status in a fashion consistent with prior research findings. Exposure to solvents among industrial painters was associated with performance decrements on certain tests. Despite the promise of this system, we are concerned about its potential misuse. The ease of test administration using the computer system could lead to widespread use by individuals unqualified in interpretation of test results. An even more significant concern, recently discussed in an editorial in Science,™ is that the system will be used inappropriately to make decisions concerning employment status. Since cultural and demographic factors influence performance on tests such as ours, using these tests in an employment decision could discriminate against certain groups. For these reasons, we feel that the system should be limited to the use of trained medical professionals for application in a comprehensive program designed to prevent or treat disease or health impairment. Our primary goal has been to provide tools for screening populations at risk for CNS dysfunction resulting from overexposure to neurotoxins in the workplace or the general environment. Clearly, other applications exist for the use of this system beyond our intended application, particularly in clinical medicine as a tool for evaluating the efficacy of treatment regimens and as a diagnostic aid. We feel that the development of computer-based systems such as ours will extend and enhance the capabilities of clinical neuropsychologists, as recently discussed," and will provide an important tool for epidemiologists evaluating the effects of environmental neurotoxic agents. Acknowledgment ). Preston Harley, Ph.D., Benjamin J. Murawski, Ph.D., Roberta F. White, Ph.D., Marcia Lyndon, Candace Pidcock, Diane Planlamura, and Stuart Shalat assisted in the development of this system. Anne Ahern prepared the manuscript. References 1. Johnson BL, Anger WK: Behavioral toxicology, in Rom WR (Ed.): Environmental and Occupational Medicine. Boston: Little Brown & Co., 1983. 2. Anger WK, Johnson BL: Chemicals affecting behavior, in O'Donaghue JL ( E d . ) : Neurotoxicity of Industrial and Commercial Chemicals. Boca Raton, Fla.: CRC Press Inc., 1985. 211 �3. Feldman KG, Kicks Nl, Baker LI: Neuropsychologic.il e f f e c t s of industrial toxins: A review. Am I Ind Mud 1:211-228, 1'JOO. •4. Monson RR: Occupalion.il Epidemiology. Boca Raton, Fla.: CRC Press Inc., 1900. 5. Cherry N, Waldron HA (Eds.): The Neuropsychologit.il E f f e c t s of Solvent Exposure. Havant, Hampshire, United Kingdom: The Colt Foundation, 1903. 6. H.inninen II, Lindstrom K: Behavioral Test Battery (or Toxic Psychological Studies. Helsinki: I n s t i t u t e of Occupational Health, 1979. 7. Prevention of ts'eurotoxic Illness in Working Populations. Geneva: World Health Oiganization, in press. 8. Baker EL, Feldrnan RC, White KF, el al: Monitoring neuroloxins in industry: Development of a neurobehavioral test battery. / Occup Mcd 25:125-130, 1983. 9. Foree DD, Cckemian DA, Elliott SL: An adaptable microcomputer-based testing system. liehav Res Moth Inslrum. in press. 10. Acker A: A computerized approach to psychological screening: The Bexley-Maudsley Automated Psychological Screening and the Bexley-Maudsley Category Sorting Test. / / ) ( / Man-Machine Stud 18:361369, 1982. 11. Lezak MD: Oxford University Press, Neuropwchological Assessment. New York: 1976. 12. Jensen AR: Bias in Mental Testing. New York: The Free Press. 1900. 13. Hanninen H: Psychological test methods: Sensitivity to longterm chemical exposure at work. Neurobehav Toxicol Ksuppl 1):157161, 1979. 1-1. Valciukas JA, Lilis R: Psychometric techniques in environmental research. Environ Res 21:275-297, 1980. 15. Wechsler D: Wechsler Adult Intelligence Scale Manual. New York: Psychological Corporation, 1955. 212 16. Baker EL, Smith 1): Evaluation of exposure to organic solvents, in Harrington |M ( C d . ) : Recent Advances in Occupational Health No. 2. London: Churchill Livingstone, 190-1. 17. Gamberale F, K|ellberg A: Field studies of the acute e f f e c t s of exposure to solvents, in Cherry N. Waldron HA (Eds.): The Neuropsychologic.il E f f e c t s ol Solvent Exposure. Havant, Hampshire, United Kingdom: The Colt Foundation, 1983. 18. Rosvold H, Mirsky A. Sarason I, el al: A continuous performance test of brain damage. / Consult Clin I'sychol 20:3-13-350, 1956. 19. Baker EL, Feldman RG,White RA, et al: Occupational lead neuroloxicity — a behavioral electrophysiologic evaluation: I. Study design and year one results, lir I Ind Mod, 41:352-361, 198-1. 20. Wechsler D: A standardized memory scale for clmic.il use. I Psychol 19:87-95, 19-15. 21. Baker EL: Neurological disorclers, in Rom WN (Ed.): Environmental and Occupational Medicine. Boston: Little Brown and Co., 1983. 22. Sternberg S: Memory-scanning: Mental processes revealed by reaction-time experiments. Am Sci 57:421-457, 1975. 23. Smith TJ, Langolf CD: The use of Sternberg's memory-scanning paradigm in assessing the effects of chemical exposure. Human Factors 23:701-708, 1981. 24. McNair DM, Lorr M, Dropleman LF: EITS Manual—Profile of Mood States. San Diego: Educational and Testing Service, 1971. 25. Hollingshead AB, Redlich FC: Social Class and Mental Illness. New York: |ohn Wiley & Sons, 1958. 26. Matarazzo JD: Computerized psychological testing. Science 221:323, 1983. 27. Psychological assessment by computer. Editorial. Lancet 1:10231024, 1983. Computerized Neurobehavioral Testing/Baker et al �SOFT TISSUE SARCOMA CLASSI FlCATION �INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS No. 3 HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS F. M. ENZINGER Head, WHO International Reference Centre or the Histological Definition and Classification of Soft Tissue Tumours f in collaboration with R. LATTES H. TORLONI Professor of Surgical Pathology, Columbia University, College of Physicians and Surgeons, New York, USA Medical Officer, Cancer, World Health Organization, Geneva and pathologists in fourteen countries TUFTS UNIVERSITY HEALTH SCIENCES LIBRARY 145 HARRISON AVENUE BOSTON, MA 02111 WORLD HEALTH ORGANIZATION GENEVA 1969 �LIST OF COLLABORATORS WHO International Reference Centre for the Histologtcal Definition and Classification of Soft Tissue Tumours (established 1958) Head of Centre:* Dr F. M. ENZINOER, Chief, Soft Tissue Branch, Armed Forces Institute of Pathology, Washington, D.C., USA Collaborating Centres Professor B. J. P. BECKER, Head, Department of Pathology and Microbiology, University of the Witwatersrand Medical School, Johannesburg, South Africa Dr J. CAMPOS, R. de C., Professor of Pathology, Faculty of Medicine of San Fernando, Universidad Nacional Mayor de San Marcos, Lima, Peru Professor E. ISHIKAWA, Department of Pathology, The Jikei-Kai University School of Medicine, Atago-cho, Shiba, Minato-ku, Tokyo, Japan Dr R. LATTES, Columbia University, College of Physicians and Surgeons, New York, USA Professor C. SIRTORI, National Institute for the Study and Treatment of Tumors, Division of Anatomy and Pathological Histology, Milan, Italy Reviewers Professor W. W. BONGELER, University Institute of Pathology, Munich, Federal Republic of Germany Professor F. CABANNE, Department of Pathological Anatomy, Ecole Nationale de M6decine, Dijon, France Professor D. F. CAPELL, Pathology Department, The Western Infirmary, University of Glasgow, Scotland Professor G. M, EDINGTON, Pathology Department, University College Hospital, Ibadan, Nigeria Professor K. FARKAS, Director, National Institute of Rheumatism and Medical Hydrology, Budapest, Hungary Dr G. A. FUERTES, Director, National Registry of Pathology, Mexico D.F., Mexico Professor J. MICHALANY, Department of Pathology, Escola Paulista de Medicina, Sao Paulo, Brazil Professor E. E. PANTANGCO, Department of Pathology, University of Santo Tomas, Manila, Philippines Dr D. W. PENNER, The Winnipeg General Hospital, Department of Pathology, Winnipeg, Manitoba, Canada Dr J. D. RHD, Pathology Department, Public Hospital, Wellington, New Zealand • From December 19S8 onto Jane 1960 the Had of die Centre w«j Dr D. J. Window. �PREFACE Among the prerequisites for comparative studies of cancer are international agreement on histological criteria for the classification of cancer types and a standardized nomenclature. At present, pathologists use the same histological description for tumours of different primary sites, while conversely different terms are applied to the same pathological entity. An internationally agreed classification of tumours, acceptable alike to physicians, surgeons, radiologists, pathologists and statisticians, would enable cancer workers in all parts of the world to compare their findings and would facilitate collaboration among them. In a report published in 1952,1 a subcommittee of the WHO Expert Committee on Health Statistics discussed the general principles that should govern the statistical classification of tumours and agreed that, to ensure the necessary flexibility and ease in coding, three separate classifications were needed according to (1) anatomical site, (2) histological type, and (3) degree of malignancy. A classification according to anatomical site is available in the International Classification of Diseases, the foundations of which were laid as long ago as 1853 when the first international statistical congress was held in Brussels. Responsibility for the decennial revision of the international lists of causes of disease and death was taken over in 1924 by the Health Organisation of the League of Nations and since 1947 has passed to the World Health Organization. The 1965 revision - contains a much more detailed classification of neoplasms by anatomical site than its predecessors. The question of establishing a universally accepted classification by histological type has received much attention during the last 20 years and a particularly valuable Atlas of Tumor Pathology—already numbering more than 30 volumes—is being published in the USA by the Armed Forces Institute of Pathology under the auspices of the National Research Council. An Illustrated Tumour Nomenclature in English, French, German, Latin, Russian and Spanish has also been published by the International Union Against Cancer (U1CC). » WU Hltk Of». ttcbi. Hep. Sa^ 1932. No. 33, p. 45. •World Health Organization (1967) Manual of rV International Statistical Classification of Dlteaui, lifrrtti o»d Cauut of Death, 1965 revfcion, Geneva. �10 INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS The World Health Organization was brought into the picture in 1956 when the WHO Executive Board passed a resolution * requesting the Director-General to explore the possibility that WHO might organize centres in several places in the world and arrange for the collection of human tissues and their histological classification. The main purpose of such.centres would be to develop histological definitions of cancer types and to facilitate the wide adoption of a uniform nomenclature. This resolution was endorsed by the Tenth World Health Assembly in May 1957* and the following month a Study Group on Histological Classification of Cancer Types met in Oslo to advise WHO on its implementation. The Group recommended criteria for selecting tumour sites for study and suggested a procedure for the drafting of histological classifications and their rigorous testing. Briefly, the procedure is as follows : ries, salivary glands, thyroid, skin, male urogenital tract, jaw, uterus, stomach and oesophagus, and intestines, as well as oral precancerous conditions and the leukaemias and lymphomas. This work involves at present 160 pathologists from 42 countries. It is planned to designate another 5 centres for tumours of the liver, eye, central nervous system, upper respiratory tract and endocrine glands. The International Reference Centres for Lung, Breast, Soft Tissues and Oropharyngeal Tumours have already completed their work, and the centres dealing with tumours of bones, salivary glands and jaws are exacted to have their classifications ready in the near future. The World Health Organization is deeply indebted to the many pathologists who have collaborated and are collaborating in this large undertaking, especially to the heads of the international reference centres and the collaborating laboratories. Grateful acknowledgement is also made to the many other international and national organizations whose pioneer work in the field of histological classification of tumours has greatly facilitated the task undertaken by WHO. Finally, WHO wishes to record its appreciation of the co-operation of the International Council of Societies of Pathology (1CSP), which has undertaken to distribute copies of the classifications, with corresponding sets of microscope slides, to national societies of pathology all over the world. L For each tumour site, a tentative histopathological typing and classification is drawn up by a group of experts, consisting of up to ten pathotogists working in the field in question. 2. An international reference centre and a number of collaborating laboratories are then designated by WHO to evaluate the proposed classification. This is done by exchanging histological preparations in the form of microscope slides and paraffin blocks, accompanied by clinical histories and the histological typing in accordance with the proposed classification. Subsequently, one or more technical meetings are called by WHO to facilitate an exchange of opinions. If necessary, the classification is then amended to take account of criticisms. 3. The international reference centre then prepares sets of microscope slides covering all the proposed histological types and sends these with the 'evised classification to not more than ten independent pathologists for 'heir comments and suggestions. 4. When replies have been received from all these reviewers, the classiication is again revised in accordance with their comments. The inter\ational reference centre then prepares 100 sets of microscope slides of the 'orious histological types and also drafts a text explaining the basis of he classification. In addition, photomicrographs are taken of the appronote fields for the preparation of 35-mm transparencies and colour lates. Since 1958, WHO has established 16 international reference centres tvering tumours of the lung, breast, soft tissues, oropharynx, bone, ova' Off, Kec. WW BM> Orr, 19*, tt, 14 (Rctoiotion EB 17.R.40). •Off. See. WUBhh Org., 1957, 79, 467 (Rotolution WHO 10.18). * * The WHO International Reference Centre for the Histological Definition and Classification of Soft Tissue Tumours was established in 1958 at the Armed Forces Institute of Pathology, Washington, DC. At a meeting in Geneva in 1959 attended by Dr B. J. P. Becker, Johannesburg ; Dr J. Campos R. de C., Lima ; Dr J. Clemmesen, Copenhagen; Dr R. Lattes, New York; Dr N. O. E. Ringertz, Stockholm; Dr C. Sirtori, Milan ; Dr A. J. Stmkov, Moscow ; and Dr D. J. Winslow, Washington, DC., a tentative classification of soft tissue tumours was drafted. This was then evaluated by the International Reference Centre and its Collaborating Centres, a list of which will be found on p. 5. Subsequently, the International Reference Centre began to distribute material (clinical information and unstained slides) from selected cases of soft tissue tumours and related conditions to the five Collaborating Centres for histological typing according to the tentative classification. The histological and clinical material on soft tissue tumours available from the files of the Armed Forces Institute of Pathology, Washington, DC., was ,. I * 11 Hi, mi, UJ ILL, ITT �12 INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS extremdy valuable in this work. A total of 520 tumour cases have been studied by the International Reference Centre and its Collaborating Centres. All the histological preparations from these cases were reviewed at meetings held in 1962 and 1965 and attended by the heads of the centres. At a final meeting in 1966, the tentative classification was adopted. This classification was then reviewed by ten pathologists who had been designated by WHO (see p. 5). In the light of the criticisms and suggestions received, the Head of the International Reference Centre, assisted by Dr R. Lattes and Dr H. Torloni, prepared the final classification, together with explanatory notes and colour photomicrographs. The latter are reproduced as colour plates in the book and are also available as a collection of transparencies intended especially for teaching purposes. In view of the large variety of soft tissue tumours and tumour-like lesions it was decided to group them in the following broad categories : fibrous tissue, adipose tissue, muscle tissue, blood vessels, lymph vessels, synovial tissue, mesothelial tissue, peripheral nerves, sympathetic ganglia, paraganglionic structures, pluripotential mesenchyme, embryonic structures, extragonadal germ cell origin, and disputed or uncertain histogenesis. An additional category comprising non-neoplastic and questionable neoplastic lesions of soft tissue has been included because of the resemblance of these lesions to true neoplasms. It will, of course, be appreciated that the classification reflects the present state of knowledge and modifications are almost certain to he needed as experience accumulates. Furthermore, it necessarily represents a majority view, from which some pathologists may wish to dissent. It is nevertheless hoped that, in the interests of international co-operation, all pathologists will try to use the classification as put forward. Criticisms and suggestions for its improvement will be welcomed. The World Health Organization is greatly indebted to Dr F. M. Enzinger, Head of the International Reference Centre, for his constant support and collaboration, and wishes also to thank the Director of the Armed Forces Institute of Pathology for making available the facilities needed for the work of the Centre. The assistance given by Dr R. Lattes is also gratefully acknowledged. GENERAL GUIDE TO THE TYPING OF SOFT TISSUE TUMOURS Although knowledge of soft tissue tumours has increased greatly in recent years, there is still much confusion concerning their incidence and behaviour and the best mode of therapy. This confusion is due not only to the wide morphological range and the relative rarity of soft tissue tumours but also to the lack of a standardized and widely accepted nomenclature and classification. Terminology For the purposes of this classification " soft tissues " are defined as including all non-epithelial extraskeletal tissues of the body with the exception of the reticuloendothelial system, the glia, and the supporting tissues of specific organs and viscera. The neuroectodermal tissues of the peripheral and autonomic nervous system are also included because the tumours of this group pose similar problems in diagnosis and treatment. The terms " tumour" and " neoplasm" are used here to indicate " an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissue and persists in the same excessive manner after cessation of the stimuli which evoked the change ** (R. A. Willis). A cellular proliferation the neoplastic nature of which is in doubt is designated as a " growth ", " process ", or " lesion ". A decision as to the neoplaslic or non-neoplastic nature of a given soft tissue growth is often exceedingly difficult, if not impossible. The terms " malignant " and " sarcoma " are used throughout this classification to denote that the tumour is capable of metastasis. These terms, however, give little information as to the likelihood and speed of metastasis. Some malignant soft tissue tumours, such as the myxoid liposarcoma, metastasi/e only rarely and at a late stage of the disease, while others, . such as the alveolar rhabdomyosarcoma, produce melastases—blood-borne and via the lymph stream—in virtually all cases and without much delay. These notable differences in the clinical course exist not only between neoplasms of different histogenetic type but also between morphologically different subvarieties of certain soft tissue tumours. Liposarcoma, for instance, shows such a wide range in its pattern and behaviour that the term liposarcoma alone without reference to its histological subtype is quite meaningless for prognosis and adequate therapy. 13 �14 HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS INTERNATIONAL HISTOLOOlCAL CLASSIFICATION OF TUMOURS The terms " well differentiated " and " poorly differentiated " are used to indicate the relative maturity of the tumour cells as judged by their more or less pronounced resemblance to the cells of normal adult tissue. In most instances the degree of differentiation is a reliable index of the future clinical behaviour. But sometimes differentiation is misleading. Certain leiomyosarcomas, for example, may metastasize widely despite their relatively high degree of differentiation. Fibrosarcomas, on the other hand, when occurring in infants and small children, tend to pursue a less aggressive clinical course than one would expect from their immature histological appearance. Moreover, in evaluating the prognostic significance of the degree of differentiation it must be remembered that some soft tissue tumours display a fairly wide range in their morphological picture making it mandatory to examine several sections taken from various portions of the tumour whenever possible. Principles of classification In the preparation of this classification the attempt has been made to list all recorded and generally recognized primary neoplasms of soft tissues regardless of their relative incidence. Hamartomas and certain lesions of questionable neoplastic origin are included because of their importance for differential diagnosis and the difficulty of establishing clear boundaries between these lesions and true neoplasms. Malformations as well as granulomatous, reparative and inflammatory lesions are excluded. To facilitate histological identification of each entity, brief definitions and illustrations are appended. The classification is based on the type of tissue of which the tumour is composed, whenever this can be determined. Accordingly, tumours and tumour-like lesions of the following tissues are distinguished : fibrous tissue, adipose tissue, muscle tissue, blood vessels, lymph vessels, synovial tissue, mesothelial tissue, peripheral nerves, sympathetic ganglia, paraganglionic structures, pluripotential mesenchyme, and embryonic structures. Three additional categories comprise tumours of possible extragonadal germ cell origin, tumours of disputed or uncertain histogenesis, and lesions of oon-neoplastic or questionably neoplastic type of interest because of their resemblance to true neoplasms. Most of these broad categories are subdivided into a benign and a •naiignant group. This subdivision is not meant to imply that malignant soft tissue tumours tend to originate from their benign counterparts. In act, malignant transformation of soft tissue tumours is an exceedingly are event, with the exception perhaps of the occasional transformation of leurofibromas into malignant Schwannomas. Subtypes are given where thdy are believed to be of value in predicting he clinical behaviour. A combination of histogenetic and descriptive terms • I I I I I • • 15 (e.g., pleomorphic liposarcoma) is used to designate these tumours. Eponyms and synonyms are employed only if they have been widely used in the literature or if their use is considered to be important for an understanding of the disease: in such cases, the preferred term is given first, followed by the synonym in square brackets. In some instances, outdated or imprecise names have been changed if the premises for their original designation are no longer acceptable; thus, M granular cell myoblastoma " has been changed to " granular cell tumour " because the muscle origin of this tumour has been disputed by most investigators. In addition to the tumours of known histogenesis, there are tumours of typical morphology that fail to give any clue as to their tissue type (categories XIV and XV). Classification of these tumours has been tentatively based upon some other characteristics, such as the size, the shape and the staining characteristics of the tumour cells and their arrangement and pattern (e.g., alveolar soft part sarcoma). Finally, there are soft tissue tumours of unusual or bizarre morphology that will not fit readily into any of the suggested tumour categories and for the time being will have to be designated as " tumour type unclassified ". Perhaps 10-15% of malignant soft tissue tumours and a smaller number of benign tumours fall into this category. Terms such as spindle-cell sarcoma or round-cell sarcoma should be avoided in classifying tumours of unknown type, because such terms are meaningless for the correlation of morphology with clinical behaviour. Difficulties in typing soft tissue tumonrs Classification of soft tissue tumours on a histogenetic basis is not always easily accomplished. It is simple with benign soft tissue tumours because the cytological characteristics and the specific products of the tumour cells closely resemble those of normal tissue. Thus, lipornas or leiomyomas composed of only slightly modified fat or smooth muscle cells usually pose no particular problem. Classification of malignant soft tissue tumours, however, is often difficult. The cells of malignant tumours frequently differ in appearance and function from those of the prototype tissue and sometimes are recognizable only by their superficial resemblance to some phases of normal embryonic tissue development. Most soft tissue tumours consist of a tissue type that is normally present at their anatomic site of origin, but this is not invariably the case. Some soft tissue tumours, particularly malignant ones, produce tissue types apparently foreign to the part of the body from which they arise. Rhabdomyosarcomas, for example, occur in the bile duct region and the vagina, i.e., in areas where striated muscle tissue is normally not formed. Synovial sarcomas develop occasionally in the abdominal wall far removed from any normal synovial structure. Most likely these tumours arise from • • • I I t • • �16 INTERNATIONAL HKTOLOGICAL CLASSIFICATION OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS persisting or newly formed foci of multipotential mesenchyme or from some incompletely differentiated kinds of tissue. Caution in the interpretation of the tissue type must be exercised if the cells are associated with collagen production. Various types of tumour cells, such as synovioblasts, mesothelial cells, Schwann cells and histiocytes. are capable of producing collagen fibres and the mere association of cells and collagen does not necessarily indicate that the cells are fibroWasts. Likewise, the presence of lipid in tumour cells or tissue is a fairly common occurrence, yet the finding of this feature alone does not warrant the diagnosis of lipoma or liposarcoma. In fact, lipid in tumours is frequently the result of altered cellular metabolism associated with early tissue degeneration. treatment of the sections prior to staining with diastase or hyaluronidase assists in arriving at a diagnosis. The former procedure, combined with the periodic acid Schiff (PAS) reaction, helps to separate glycogen from other PAS-positive material; treatment with hyaluronidase combined with various mucin stains allows distinction of the acid mucopolysaccharides produced by Hposarcomas (and other soft tissue tumours) from the sulfated mucopolysaccharides elaborated by chondroid neoplasms. Other histochemical and enzymatic techniques, many still in their experimental stage, may also be useful in the localization of specific structural elements. Methods that may be helpful in the study of soft tissue tumours also include phase contrast and electron microscopy, small-angle X-ray diffraction, fluorescent antibody techniques, and microangiography. Tissue culture in vitro often allows recognition of the prototype cells, even if the parent tumour is poorly differentiated. This method is of practical value in differential diagnosis of neuroblastoma and Ewing's sarcoma. Chemical analysis of tumour tissue or of isolated cellular elements may also yield information regarding the products of the tumour cells or their function and so may lead to a more precise histogenetic classification. In addition to histological study, detailed inspection of the gross specimen and information as to the operative findings, particularly the relationship of the tumour to skin, fascia, tendon sheath, bone or joint, are essential to diagnosis. Sometimes, however, too much reliance upon the gross inspection may be misleading; such features as encapsulation, poor circumscription, and infiltration may be deceptive as to the true growth potential of the tumour and may invite inadequate or excessive therapy. Shelling out or enuclcation of apparently well circumscribed or encapsulated malignant soft tissue tumours should be discouraged. Such procedures are bound to lead to recurrence and complications, since often satellite nodules or groups of viable tumour cells are situated about the main tumour mass or in the capsular tissue. Evidence of infiltrative growth may also be an unreliable guide to the clinical behaviour. Nodular fasciitis, proliferative myositis and other innocuous lesions insidiously infiltrate neighbouring tissues in a sarcoma-like manner and yet these lesions are perfectly benign and are treated effectively by simple excision. In most cases, therefore, it is best to plan definitive therapy only after the diagnosis has been established by open biopsy. The delay in treatment caused by the biopsy procedure is insignificant compared with the therapeutic hazards of an erroneous diagnosis. Accurate diagnosis requires adequate material representative of the main characteristics of the tumour. Such material can be obtained by incisional or excisional biopsy, and occasionally by needle biopsy. In most instances, particularly if major surgery depends upon an accurate diagnosis, examination by open surgical biopsy is to be preferred. Biopsy should be sufficiently deep, and should include viable tumour tissue as well as portions of the surrounding tumour bed. Incisional biopsy has been condemned by some because of the supposed but unproven danger of promoting the spread of malignant cells ; if surgical trauma is kept to a minimum, the merits of open incisional biopsy certainly outweigh its risks. Frozen-section diagnosis is useful in those rare cases in which immediate therapeutic action is required. This method as applied to soft tissue tumours requires judgement and experience in order to avoid serious errors and, in our opinion, should be used only by specially qualified pathologists. Likewise, needle or aspiration biopsy of soft tissue may be useful in the hands of a competent pathologist but it seems doubtful whether it can effectively replace open biopsy as a routine procedure. Obviously those tumours that are already difficult to diagnose with adequate material are more liable to be misinterpreted if only a minute and possibly non-representative portion of the lesion can be examined. Exfoliative cytology has its special and established place in the diagnosis of mesotheliomas. Paraffin sections of adequately fixed material stained with haematoxylin and eosin will usually suffice for diagnosis, but selective staining procedures may be necessary in the evaluation of occasional problem cases. In studying soft tissue tumours, such staining procedures are used for myofibrils, lipid, glycogen. melanin, mucin, acid and sulfated mucopolysaccharides, retfculum. elastic fibres, iron, and others. At times, 17 Correlation between histological and other findings Accurate classification of soft tissue tumours requires close correlation between clinical features and histology. The information provided by the clinical history, physical examination, radiography and laboratory studies �18 INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS is important and sometimes indispensable for a correct diagnosis. Knowledge of the age and the sex of the patient and the localization of the tumour may be significant. For reasons that are still poorly understood, virtually every well-defined soft tissue tumour has a predilection for certain age periods and anatomic sites; moreover, some soft tissue tumours occur more frequently in men, others in women. These interrelationships between tumour type and certain clinical features are well illustrated by the predominance of embryonal rhabdomyosarcoma in children, the predilection of juvenile aponeurotic fibroma for the palmar region of the hand, and the almost exclusive occurrence of juvenile angiofibroma in male patients. The clinical behaviour of some tumours varies according to the anatomic site. Thus, fibromatosis is more likely to recur and behave in an aggressive manner when it is situated in the muscles of the shoulder or neck region than when located at other sites. Environmental and genetic factors, revealed by careful history-taking, may also contribute to the understanding of the disease. The specific role of these factors is evident from the occurrence of mesothelioma following exposure to asbestos dust, the occasional development of sarcomas secondary to radiotherapy or prolonged lymph stasis, the familial incidence of neurofibromatosis, and the association of mesenteric fibromatosis and familial intestinal polyposis in Gardner's syndrome. Vital information may be obtained from certain laboratory studies. Thus, the demonstration of catecholamine derivatives in the urine may suggest the presence of phaeochromocytoma or, as more recently shown, the presence of neuroblastoma, ganglioneuroblastoma, or ganglioneuroma. Obviously, the fact that histology is to date the most reliable guide for making an accurate diagnosis and for predicting the clinical behaviour does not preclude the need for clinical information. Only integration of all morphological and clinical data, achieved by close co-operation between clinician and pathologist, assures the ultimate goal of reaching a correct diagnosis and providing adequate therapy for the patient. HISTOLOGTCAL TYPING OF SOFT TISSUE TUMOURS I. TUMOURS AND TUMOUR-LIKE LESIONS OF FIBROUS TISSUE A. FlBROMAS 1. 2. 3. 4. Fibroma durum Fibroma molle [fibrolipoma] Dermatofibroma [histiocytoma, sclerosing haemangioma] Elastofibroma (dorsi) B. FIBROMATOSIS 1. Cicatricial fibromatosis 2. Keloid 3. Nodular fasciitis [pseudosarcomatous fibromatosis] 4. Irradiation fibromatosis 5. Penile fibromatosis [Peyronie's disease] 6. Fibromatosis colli 7. Palmar fibromatosis 8. Juvenile aponeurotic fibroma [calcifying fibroma] 9. Plantar fibromatosis 10. Nasopharyngeal fibroma [juvenile angiofibroma] 11. Abdominal fibromatosis [abdominal desmoid] 12. Fibromatosis or aggressive fibromatosis [extra-abdominal desmoid] 13. Congenital generalized fibromatosis C. DERMATOFIBROSARCOMA PROTUBERANS D. FlBROSARCOMA n. TUMOURS AND TUMOUR-LIKE LESIONS OF ADIPOSE TISSUE A. BENIGN 1. Lipoma (including fibrolipoma, angiolipoma, etc) 2. Intramuscular lipoma [infiltrating lipoma] �20 INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS 3. 4. 5. 6. 7. Hibernoma Angiomyolipoma (of renal origin) Myelolipoma Lipoblastomatosis [foetal lipoma] Diffuse lipomatosis B. MALIGNANT 1. Liposarcoma a. predominantly well-differentiated b. predominantly myxoid [embryonal] c. predominantly round-cell d. predominantly pleomorphic (poorly differentiated) e. mixed type (combining features of a, b, c, or d) HI TUMOURS OF MUSCLE TISSUE A. SMOOTH MUSCLE 1. Benign a. Leiomyoma b. Angiomyoma [vascular leiomyoma] c. Epithelioid leiomyoma [bizarre leiomyoma, leiomyoblastoma] 2. Malignant a. Leiomyosarcoma HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS IV. TUMOURS AND TUMOUR-LIKE LESIONS OF BLOOD VESSELS A. BENIGN 1. Haemangioma a. Benign haemangjoendothelioma b. Capillary haemangioma [juvenile haemangioma] c. Cavernous haemangioma d. Venous haemangioma e. Racemose [cirsoid] haemangioma (arterial, venous, arteriovenous) 2. Intramuscular haemangioma (capillary, cavernous or arteriovenous) 3. Systemic haemangiomatosis 4. Haemangiomatosis with or without congenital arteriovenous fistula 5. Benign haemangiopericytoma 6. Glomus tumour [glomangioma] 7. Angiomyoma [vascular leiomyoma] 8. " Haemangioma" of granulation-tissue type [granuloma pyogenicum] B. MALIGNANT 1. Malignant haemangioendothelioma [angiosarcoma] 2. Malignant haemangiopericytoma V. TUMOURS AND TUMOUR-LIKE LESIONS OF LYMPH VESSELS B. STRIATED MUSCLE 1. Benign a. Rhabdomyoma 2. Malignant A. BENIGN : a. Rhabdomyosarcoma (1) predominantly embryonal (2) predominantly alveolar (3) predominantly pleomorphic (4) mixed (combining the features of (1). (2). or (3)) 21 1. Lymphangioma a. capillary b. cavernous c. cystic [hygroma] 2. Lymphangiomyoma 3. Systemic lymphangiomatosis �22 B. MALIGNANT 1. Malignant lymphangloendothelioma [lymphangiosarcoma] 23 H1STOLOGICAL TYPING OF SOFT TISSUE TUMOURS INTERNATIONAL HISTOLClGICAL CLASSIFICATION OF TUMOURS B. MALIGNANT 1. Malignant Schwannoma [neurogenic sarcoma, sarcoma] 2. Peripheral tumours of primitive neuroectodenn neurofibro- VL TUMOURS OF SYNOVLAL TISSUES A. MALIGNANT 1. Synovial sarcoma [malignant synovioma] a. predominantly biphasic (spindle-cell and epithelioid patterns) b. predominantly monophasic (spindle-cell or epithelioid pattern) IX. TUMOURS OF SYMPATHETIC GANGLIA A. BENIGN 1. Ganglioneuroma B. MALIGNANT 1. Neuroblastoma [sympathicoblastoma, symphathicogonioma] 2. Ganglioneuroblastoma B. BENIGN 1. Benign synovioma VIL TUMOURS OF MESOTHELIAL TISSUE A. BENIGN MESOTHEUOMA 1. predominantly epithelioid 2. predominantly fibrous (spindle-cell) 3. biphasic B. MALIGNANT MESOTHELIOMA 1. predominantly epithelioid 2. predominantly fibrous (spindle-cell) X. TUMOURS OF PARAGANGLIONIC STRUCTURES A. PHAEOCHROMOCYTOMA 1. Benign 2. Malignant B. CHEMODECTOMA [non-chromaffin paraganglioma] 1. Benign 2. Malignant C. PARAGANGLIOMA, UNCLASSIFIED 3. biphasic VTJL TUMOURS AND TUMOUR-LIKE LESIONS OF PERIPHERAL NERVES XI. TUMOURS AND TUMOUR-LIKE LESIONS OF PLURIPOTENTIAL MESENCHYME A. BENIGN A. BENIGN i 1. Traumatic neuroma [amputation neuroma] 2. Neurofibroma 3. Neurilemoma [Schwannoma] 4. Neurofibromatosis [von Recklinghausen's disease] 1. Mesenchymoma B. MALIGNANT 1. Malignant mesenchymoma �24 HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS INTERNATIONAL HISTOLOG/CAL CLASSIFICATION OF TUMOURS 2. Malignant granular cell tumour [malignant (nonorganoid) granular cell " myoblastoma "] 3. Chondrosarcoma of soft parts 4. Osteosarcoma of soft parts 5. Malignant giant-cell tumour of soft parts 6. Malignant fibroxanthoma [malignant histiocytoma] 7. Kaposi's sarcoma 8. Clear-cell sarcoma of tendons and aponeuroses XH. TUMOURS OF VESTIGIAL EMBRYONIC STRUCTURES A. BENIGN 1. Chordoma B. MALIGNANT 1. Malignant chordoma . TUMOURS OF POSSIBLE EXTRAGONADAL GERM-CELL ORIGIN A. BENIGN 1. Teratoma [dermoid cyst] B. MALIGNANT 1. Teratocarcinoma 2. Embryonal carcinoma 3. Qioriocarcinoma XIV. TUMOURS OF DISPUTED OR UNCERTAIN fflSTOGENESIS A. BENIGN 1. Granular cell tumour [granular cell " myoblastoma "] 2. 3. 4. 5. 6. Chondroma of soft parts Osteoma of soft parts Nasal glioma [ganglioglioma] Pacinian tumour Adenomatoid tumour of genital tract 7. Myxoma 8. Melanotic progorioma [retinal anlage tumour, melanotic neuroectodermal tumour of infancy] 9. Fibrous hamartoma of infancy B. MALIGNANT 1. Alveolar soft-part sarcoma [malignant organoid granular cell " myoblastoma "] 25 XV. NON-NEOPLASTIC OR QUESTIONABLY NEOPLASTIC LESIONS OF SOFT TISSUES, OF INTEREST BECAUSE OF THEIR RESEMBLANCE TO TRUE NEOPLASMS A. XANTHOMA GROUP 1. Fibroxanthoma [fibrous histiocytoma] a. Atypical fibroxanthoma 2. Xanthoma 3. Juvenile xanthogranuloma [naevoxanthoendothelioma] 4. Retroperitoneal xanthogranuloma (Oberling) 5. Nodular tenosynovitis [giant-cell tumour of tendon sheath] and pigmented villonodular synovitis B. GANGLION C. LOCALIZED MYXOEDEMA D. Mvosms OSSIFICANS E. PROLIFERATIVE MYOSITIS XVI. SOFT-TISSUE TUMOUR, UNCLASSIFIED �HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS 27 and is found mainly in Negroes. Unlike hypertrophic scars, which do not show the characteristic thick, glassy collagen bundles, the lesion tends to recur. EXPLANATORY NOTES I. TUMOURS AND TUMOUR-LIKE LESIONS OF FIBROUS TISSUE A. FlBROMAS 1. Fibroma durum. A benign and frequently pedunculated, well circumscribed dense growth of fully matured and richly collagenous fibrous connective tissue occurring on the body surface and mucous membranes. Many so-called "fibromas" are examples of hyperplastic fibrous tissue rather than true neoplasms. 2. Fibroma moUe [fibrolipoma]. A benign and usually pedunculated growth made up of a mixture of mature fibrous connective tissue and adult-type fat occurring on the body surface. 3. Dermatofibroma [histiocytoma, sderosing haemangioma]. A benign, non-encapsulated, superficial lesion, characterized by an intimate mixture of histiocyte and fibroblast-like cells associated with varying amounts of collagen and thin-walled blood vessels. Frequently, lipid macrophages and siderophages are prominent features of the lesion. 4. Elastofibroma (dorsf). A slow-growing, benign, poorly circumscribed fibrous growth, which is characterized by the association of collagen bundles and homogeneous acidophilic fibrillary or globular material staining similarly to elastic tissue. The lesion is deep-seated and affects almost exclusively the subscapular region of elderly individuals. Bilateral involvement has been observed. B. FlBROMATOSIS 1. Cicatridd fibromatosis. A non-metastasizing progressive overgrowth of fibrous tissue arising in association with a scar. 2. Keloid. A superficial nodular, parvicellular, fibrous growth, characterized by well-defined interlacing broad bands of homogeneous, acidophilic collagen. The lesion usually follows some form of injury to the skin — 26 — 3. Nodular fasciilis [pseudosarcomatous fibromatosis]. A benign and probably reactive fibroblastic growth extending as a solitary nodule from the superficial fascia into the subcutaneous fat or, less frequently, into the subjacent muscle. Confusion with a sarcoma is possible because of its cellularity, its mitotic activity, its richly mucoid stroma, and its rapid growth. Other fibroblastic proliferations, such as proliferative myositis (XV/E), are probably akin to this lesion. Nodular fasciitis is most common in the upper extremity, the trunk and the neck region of young adults. 4. Irradiation fibromatosis. A benign, infiltrating and often aggressive growth of richly collagenous fibrous connective tissue consequent to tissue injury by radiation. The frequent presence of bizarre cells should not be mistaken for evidence of malignancy. Differentiation from the rare postirradiation fibrosarcoma might be difficult. 5. Penile fibromatosis [Peyrom'e's disease]. A dense, infiltrating, fibrous growth affecting the fascial structures and the fibrous septa of the corpora cavernosa and the corpus spongiosum of the penis. The condition occurs chiefly in adults between 40 and 65 years of age and is occasionally associated with palmar and plantar fibromatoses. Secondary ossification has been observed occasionally. 6. Fibromatosis coili. A benign, poorly circumscribed fibrous growth of unknown histogenesis arising in the sternocleidomastoid muscle of infants and small children. Contraction of the fibrous tissue may lead to wry-neck or torticollis. Bilateral forms have been observed. 7. Palmar fibromatosis. A benign, nodular, infiltrating, fibrous lesion of variable cellularity originating in the palmar aponeuroses and leading to contracture of the fingers [Dupuytren's contracture]. Multiple lesions involving the feet as well as the hands are observed occasionally (see I/B/9, plantar fibromatosis). 8. Juvenile aponeurotic fibroma [calcifying fibroma]. A rare infiltrating fibrous growth affecting chiefly the muscles and the subcutaneous fat of the volar aspects of the hands. The growths apparently occur exclusively in children, adolescents and, rarely, young adults. Characteristically, the infiltrating collagenous tumour is associated with irregular foci of calcification and chondroid metaplasia. Local recurrence is frequent �28 HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS 9. Plantar fibrornatosis. A benign, nodular, infiltrating fibrous lesion of variable cellularity originating in the plantar aponeuroses and leading to contracture of the toes. This lesion is found mainly in adults. Multiple lesions involving the hands as well as the feet are observed occasionally (see I/B/7, palmar fibrornatosis). 10. Nasopharyngeal fibroma [juvenile angiofibroma]. A locally invasive growth of more or less mature fibrovascular tissue arising in the wall of the nasopharynx and its vicinity and affecting almost exclusively male patients between 10 and 25 years of age. Spontaneous regression has been observed. 11. Abdominal fibromatosts [abdominal desmoid]. A locally aggressive infiltrating tumour-like fibroblastic growth of unknown pathogenesis arising from the musculo-aponeurotic structures of the rectus muscle and the adjacent muscles of the abdominal wall. It differs from a fibrosarcoma mainly in its uniform growth pattern, the abundancy of collagen, and the paucity of mitotic figures. The lesion occurs most commonly in women during or following pregnancy but has also been observed in men and in small children of both sexes. 12. Fibromatosis or aggressive fibrornatosis [extra-abdominal des~ moid]. A non-metastasizing tumour-like fibroblastic growth of unknown pathogenesis involving voluntary muscle as well as aponeurotic and fascia! structures. Histologically, it is indistinguishable from an abdominal fibromatosis (I/B/11). The lesion has a strong tendency to local recurrence and aggressive, infiltrating growth. It is most common in the shoulder girdle, the thigh, and the buttock of young adults.1 13. Congenital generalized fibromatosis. An extremely rare mesenchymal and predominantly fibroblastic growth developing simultaneously at multiple sites prior to birth or during the first year of life. Fatal cases with widespread visceral involvement have been observed. Familial incidence has been recorded. C. DERMATOFIBROSARCOMA PROTUBERANS A cellular tumour of disputed histiocytic or fibroblastic origin composed of small, uniform cells arranged in a cartwheel pattern. It usually forms a protruding nodular or multinodular mass by infiltration of the entire dermis and the subcutaneous fat. The tumour has a tendency to recur locally after simple excision. Cases with metastases have been recorded. * The tttocttttoa of flbromatotU, CunilUl IntMtlnd polypoii«, oneotmu and cutaneoui epithelial cyiti li known a» Gtrdner't (jrndrorae. 29 D. FIBROSARCOMA A malignant circumscribed or infiltrating tumour composed of reticulin and collagen, which produces predominantly spindle-shaped cells showing no evidence of other forms of cellular differentiation. The histological picture consists chiefly of interlacing, densely cellular fascicles of more or less uniform spindle cells, often forming a herring-bone pattern. A characteristic feature is the close relationship between cells and reticulin fibres. Mitotic figures are a constant feature of fibrosarcoma. It is possible that some ill-defined pleomorphic sarcomas are of fibroblastic origin. The tumour is capable of metastasis, chiefly via the blood stream. II. TUMOURS AND TUMOUR-LIKE LESIONS OF ADIPOSE TISSUE A. BENIGN 1. Lipoma (including fibrolipoma, angiolipoma, etc.). A benign growth made up exclusively of mature adipose tissue cells showing no evidence of cellular atypia. Lipomas arising in the panniculus adiposus are usually encapsulated; those arising elsewhere are frequently unencapsulated and less well demarcated. Lipomas undergoing myxoid changes should not be confused with a well-differentiated myxoid liposarcoma. 2. Intramuscular lipoma [infiltrating lipoma]. A benign proliferation of mature adipose tissue infiltrating striated muscle. The absence of cellular atypia serves to distinguish the lesion from a well-differentiated liposarcoma. 3. Hibernoma. A benign, lobulated, and encapsulated tumour made up of granular or vacuolated, round, acidophilic cells having the appearance of brown fat. Hibernoma usually involves the shoulder or neck region of young adults. 4. Angiomyolipoma (of renal origin). A benign neoplasm of hamartomatous nature consisting of a mixture of adipose tissue, thick-walled vascular structures, and smooth-muscle elements. The neoplasm is generally unencapsulated. This term is used here exclusively for tumours arising from the renal cortex. Angiomyolipoma is sometimes a feature of the tuberous sclerosis complex. 5. Myelolipoma. A rare, benign, unilateral or bilateral lesion made up of an intimate mixture of haematopoietic tissue and mature fat. It occurs in the adrenal gland or, less frequently, in the soft tissue of the retroperi- �31 INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS toneum and the pelvis. Unlike extramedullary haematopoiesis, the lesion is unassociated with haematopoietic disorders. c. Epithelioid leiomyoma [bizarre leiomyoma, leiomyoblastoma]. A peculiar smooth-muscle tumour, characterized by predominantly rounded or polygonal cells with acidophilic cytoplasm and a clear space partially or completely surrounding the nucleus. Mitotic figures are scanty or absent in most cases. Transitions towards typical elongated smooth-muscle cells are seen occasionally. The tumour, which sometimes reaches an enormous size, usually arises from the muscle coat of the stomach wall of adult patients. Less commonly it occurs in the mesentery, the omentum, or other areas. The behaviour 5s very difficult to predict. The great majority of epithelioid leiomyomas follow a benign clinical course; a few, however, are known to have metastasized. 30 6. Lipobtastomatosis [foetid lipoma]. A benign, lobulated, lipoblastic growth resembling typical foetal fat. The lesion, which is easily confused with a myxoid liposarcoma, predominates in children during the first year of life and presents either as a localized, lipoma-like growth or as a diffuse infiltrating process. Maturation towards a typical lipoma has been observed in consecutive biopsies. 7. Diffuse lipomatosu. A diffuse, infiltrating proliferation of mature adipose tissue showing no evidence of cellular atypia. Large examples of this lesion may involve sizable portions of an extremity or the trunk. It chiefly affects children and is exceedingly rare during adult life. B. MALIGNANT 1. Liposarcoma. A malignant infiltrating neoplasm, characterized by the presence of atypical lipoblasts in varying stages of differentiation. The histological picture of liposarcoma varies from well-differentiated to cellular or extremely pleomorphic types. Whenever possible liposarcoma should be subtyped according to the predominant cell pattern (II/B/l/a, b. c, d and e). The biological behaviour varies with the degree of differentiation. Metastases are more frequent among the less differentiated (round-cell and pleomorphic) types. in. TUMOURS OF MUSCLE TISSUE 2. Malignant a. Leiomyosarcoma. A malignant, occasionally richly vascular neoplasm of elongated, acidophilic cells containing a varying number of nonstriated myofibrils and showing frequently a perinuclear clear space. The cells tend to be arranged in sharply intersecting bundles and fascicles. Helpful criteria for differential diagnosis from leiomyoma are the greater degree of cellularity, the presence of cellular pleomorphism, including tumour giant cells, and, most important, the presence of typical and atypical mitotic figures. Occasionally the parallel arrangement of the reticulin fibres may be helpful in distinguishing the tumour from fibrosarcoma. Leiomyosarcomas may occur at any site, including the wall of large vessels. B. STRIATED MUSCLE 1. Benign A. SMOOTH MUSCLE 1. Benign a. Leiomyoma. A benign and occasionally richly vascular tumour of smooth muscle cells showing little variation in their appearance and characterized by the presence of non-striated myofibrils within their cytoplasm. Collagen formation, present in all leiomyomas, may be excessive and at times may obscure the basic structure of the tumour. The tumour occurs in superficial and deep locations. b. Angiomyoma [vascular leiomyoma]. A benign, well-circumscribed and frequently tender or painful tumour, consisting of convoluted thick-walled vessels associated with bundles of well-differentiated smoothmuscle elements. The tumour occurs most commonly in the wrist and ankle region. I I ! a. Rhabdomyoma. A benign tumour generally consisting of polygonal, frequently vacuolated (glycogen-containing) cells having a finely granular deeply acidophilic cytoplasm. Cells with cross-striations are fairly common. The tumour is rare and the majority of cases have been observed in the upper neck region, the tongue, the pharyngeal wall, and the vicinity of the larynx. 1. Malignant a. Rhabdomyosarcoma. A highly malignant tumour of rhabdomyoblasts in varying stages of differentiation with or without intracellular myofibrils, and with or without cross-striations. Cytology and growth pattern vary greatly and three types can be distinguished: predominantly embryonal (including the botryoid type), alveolar and pleomorphic I I �33 INTERNATIONAL HBTOLOGICAL CLASSIFICATION OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS (HI/B/2/a, 1, 2 and 3). The two, .former types prevail in children and adolescents. Mixed forms may occur. The embryonal and alveolar types of the tumour may arise in sites where skeletal muscle is not normally present. Special staining techniques may be necessary for the demonstration of cross-striations. Lymphatic and blood-borne metastases are rornmon. 3. Systemic haemangiomatosis. A condition involving one or more organs or tissues and characterized by multicentric or diffuse haemangiomatous lesions. Rendu-Osler-Weber disease, Sturge-Weber disease, the Mafucci syndrome, the Bourneville syndrome, and Hippel-Lindau disease are forms of systemic hemangiomatosis. 32 IV. TUMOURS AND TUMOUR-LIKE LESIONS OF BLOOD VESSELS i. BENIGN 1. Haemangioma. A benign non-circumscribed lesion consisting of roliferaled blood vessels of various types. In the lesions belonging to this roup, distinction between tissue malformations (hamartomas) and true unours is especially difficult. a. Benign haemangioendothelioma. A benign and largely solid mass \ endotfadial cells of typical appearance identifiable by the formation of ;pillaries or other vascular structures in some places. Frequently, this yon is not dearly separable from capillary haemangioma. The growth most common in the head and neck area of small children. Reticulin tins often help in the recognition of these lesions. b. Capillary haemangioma [juvenile haemangioma]. A benign ion composed predominantly of small vascular channels, mostly of Hilary size, lined by a single layer of endothdial cells. c. Cavernous haemangioma. A benign lesion composed predomi?tfy of cavernous vascular structures lined by a single layer of endotial cefls. d. Venous fuemangioma. A benign lesion composed of irregular Iran- to large-sized vessels, predominantly of the venous type. Isolated oth muscle elements, fibrous tissue, and fat may be associated with the w. e. Racemose [cfryoid] haemangioma (arterial, venous, arterionts). A lesion resembling a malformation composed of tortuous, thicked blood vessels of the venous and arterial type. Those that are ominantly arterial are generally found in the region of the head. .. Intramuscular haemangioma (capillary, cavernous or arterio>us). A benign, non-systemic, poorly circumscribed vascular growth sely infiltrating striated muscle. Either capillary or cavernous struci may predominate. The lesion is found chiefly in young adults. It Id not be confused with malignant vascular tumours. 4. Haemangiomatosis with or without congenital arteriovenous fistula. Regional or diffuse proliferation of capillaries or thin-walled vascular structures with or without a congenital arteriovenous fistula. Sometimes this lesion is accompanied by overgrowth of fat and/or bone. 5. Benign haemangiopericytoma. A tumour characterized by the proliferation of round, oval or spindle-shaped cells of rather uniform size, surrounded by reticulin fibrils and arranged about vascular spaces lined by a single layer of endothelial cells. The tumour is uncommon, and a clear separation from other well-vascularized mesenchymal tumours is often difficult and may cause a considerable problem in the differential diagnosis. It is not always easy to predict the clinical course on the basis of the histological findings. 6. Glomus tumour [glomangioma]. A benign tumour made up of acidophilic. epithelioid, round cells of uniform size with large oval nuclei, probably derived from the neuromyoarterial glomus. The cells are usually intimately associated with vascular structures of varying size and often blend with smooth muscle tissue. The tumour may occur anywhere, but is most common in the distal portions of the extremities. 7. Angiomyoma [\vsndar leiomyoma]. A benign, wefl-circumscribed and frequently tender or painful tumour consisting of convoluted thickwalled vessels associated with bundles of well-differentiated smoothmuscle elements. The tumour occurs most commonly in the wrist and ankle region and is frequently tender or painful. 8. " f/aemangioma" of granulation-tissue type [granuloma pyogenicum]. A benign, solitary, raised lesion of the skin and mucous membranes having the microscopic appearance of a lobulated capillary haemangioma or richly vascular granulation tissue. Secondary features, such as surface ulceration, chronic inflammation, and fibrosis are common. The initial rapid growth and the tendency of the lesion to occur during adult life help to distinguish it from capillary haemangioma. B. MALIGNANT 1. Malignant haemangioendothelioma [angiosarcomaj. A highly malignant neoplasm characterized by the formation of irregular anastomosing �34 INTERNATIONAL HISTOLOOICAL CLASSIFICATION OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS vascular channels lined by one or more layers of atypical endothelial cells, often of immature appearance. The female breast is one of the commonest sites of the tumour. Metastases are usually blood-borne. tures lined by one or more layers of endothelial cells showing a varying degree of cellular atypia. So far this tumour has been observed exclusively in conjunction with chronic lymph stasis, usually secondary to radical mastectomy. 2. Malignant haemangiopericytoma. A malignant tumour characterized by the proliferation of rather uniform, round, oval or spindle-shaped cells about vascular spaces of varying size lined by a single layer of endotbelial cells. Clear separation from other well-vascularized mesenchymal tumours, such as synovia! sarcoma, mesothelioma, and malignant fibroxanthoma, is often exceedingly difficult and may cause a problem in the differential diagnosis. V. TUMOURS AND TUMOUR-LIKE LESIONS OF LYMPH VESSELS A. BENIGN 1. Lymphangioma. A benign growth composed exclusively of lymph vessels of various size lined by a single layer of endothelial cells. The lesion is often congenital and is probably the result of a tissue malformation during the early development of the lymphatic system. Lymphangiomas should be typed as capillary, cavernous, or cystic (V/A/l/a, b and c). The cavernous and cystic forms [hygroma] of this tumour are most frequent in the cervical, mediastinal, and retroperitoneal regions of infants and children. Capillary lymphangiomas are exceedingly rare and are difficult to distinguish from capillary haemangiomas. 2. Lymphangiomyoma. A growth composed of bundles of smoothmuscle tissue about cavernous or slit-like, endothelial-lined lymph spaces. Aggregates of lymphocytes may or may not be found in association with the smooth-muscle tissue. The tumour has been observed only in the mediastinum and retroperitoneum in close association with the thoracic duct and its tributaries. Chylothorax and pulmonary complications are common. 3. Systemic lymphangiomatosis. A condition in which one portion of the body is altered by excessive growth of lymphangiomatous structures often causing deformities. Children are almost exclusively affected. B. MALIGNANT 1. MaKgnant lymphangioendothdioma [lymphangiosarcoma]. A malignant neoplasm marked by the formation of irregular lymphatic struc- •i 35 VI. TUMOURS OF SYNOVIAL TISSUES A. MALIGNANT 1. Synovial sarcoma [malignant synovioma]. A malignant neoplasm showing a biphasic cellular pattern composed of clefts or acinar structures lined by epithelial-like cells, with or without formation of mucoid material, and separated by reticulin- and collagen-forming fibrosarcoma-like spindle-cell areas of varying cellular density. Calcification and hyalinization are frequent features. There is also a monophasic form in which the gland-like spaces are exceedingly rare and can be found only after careful examination of multiple sections; this often makes it very difficult to distinguish the tumour from a fibrosarcoma. Synovial sarcoma is capable of metastasizing through the blood stream and less frequently through the lymphatics. Most synovial sarcomas occur in young adults and usually arise from tissues in the vicinity of large joints (for subtypes see VI/A/I/a and b). B. BENIGN 1. Benign synovioma. Whether true benign tumours of synovial tissues exist is controversial. Nodular tenosynovitis and pigmented villonodular synovitis are discussed on page 43 (XV/A/5). VII. TUMOURS OF MESOTHELIAL TISSUE (MESOTHELIOMAS) Tumours arising from the mesothelial lining of the coelomic cavities and consisting of a variable mixture of epithelioid and spindle-cell elements. Whenever possible, the predominant cell characteristics should be specified (for subtypes see VII/A/1, 2 and 3 ; VHI/B/l, 2 and 3). Characteristically, the tumours form a tubular, papillary, or tubulo-papillary growth pattern, but occasionally they are difficult to distinguish from fibromas or fibrosarcomas. Diffuse and localized forms occur. Patients with mesothelioma frequently give a history of exposure to asbestos dust �» 36 » * * I 1 fc I I INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS Vin. TUMOURS AND TUMOUR-LIKE LESIONS OF PERIPHERAL NERVES 2. Peripheral tumours of primitive neuroectoderm. These are a closely related group of tumours occurring outside the central nervous system and simulating neural crest tissue in various stages of development. Some are indistinguishable from their central nervous system counterpart. They include neuroepitheliomas. medulloepttheliomas, medulloblastomas, ependymomas, and olfactory neuroepitheliomas [olfactory neuroblastomas]. Neuroepitheliomas. medulloepitheliomas, medulloblastomas and ependymomas are malignant tumours capable of metastasis, but metastasis of olfactory neuroepithelioma is very rare. A. BENIGN 1. Traumatic neuroma [amputation neuroma], A benign non-neoplastic overgrowth of nerve fibres, Schwann cells, and scar tissue occurring at die proximal end of a severed nerve trunk. 2. Neurofibroma. A benign localized or diffuse tumour consisting of a mixture of Schwann cells and fibroblasts accompanied by loosely arranged coOagen fibres and mucinous material. Plexiform neurofibromas are the result of growth within and about a preformed nerve, giving the nerve trunk a tortuous, thickened, and plexiform appearance. Neurites can be frequently demonstrated within these tumours. Malignant transformation of neurofibromas occurs. 3. Neurilemoma [Schwannoma]. A benign and usually well demarcated or encapsulated tumour, most probably of nerve-sheath origin. Characteristically, an Antoni type A pattern, with regimentation of the nuclei in twisted rows or palisades (Verocay bodies), and an Antoni type B pattern, with loosely arranged cells within a wide-meshed, microcystic fibriDar stroma, can be distinguished. Perivascular hyalinization is common. Secondary features, such as haemorrhage, thrombosis, phagocytosis of lipid and haemosiderin, and cystic changes are frequent findings, usually occurring in tumours that have been present for many months or years. 4. Neurofibromatosis [von Recklinghausen's disease]. A hereditary systemic disease characterized chiefly by the presence of one or more neurofibromas and multiple cafe"-au-lait spots. Associated lesions include skeletal deformities and elephantiasis. 8. MALIGNANT i 1. Malignant Schwannoma '[neurdgenic sarcoma, neurofibrosarcoma]. \ malignant and usually densely cellular tumour consisting of rather plump spindle-shaped or ovoid cells of Schwannian origin, generally showing little cellular pleomorphism and often accompanied by collagen fibres. Nuclear palisading, as well as an arrangement of the cells in groups, nests, cords, or whorls are features helpful in differential diagnosis. Origin in a pre-existing neurofibroma is frequent, but origin in a neurilemoma, if it ever occurs, must be exceedingly rare. For this reason the term malignant neurilemoma should be avoided. Distant metastases are frequent in the highly cellular form of this tumour. 37 IX. TUMOURS OF SYMPATHETIC GANGLIA A. BENIGN 1. Ganglioneuroma. A benign tumour composed of mature ganglion cells (with or without Nissl granules and satellite cells) associated with well-differentiated neurofibromatous elements. B. MALIGNANT 1. Neuroblastoma [sympathicoblastoma, sympathicogonioma]. A highly malignant tumour of undifferentiated neuroblasts (sympathicoblasts). The neuroblasts are usually of small size with darkly staining nuclei and indistinct cytoplasm. Arrangement of the cells in spheroid groups about a central tangle of fibrillary material (Homer-Wright rosettes) is a characteristic feature. The tumour occurs predominantly in children under the age of 4 years, usually in close association with the adrenal medulla or the sympathetic chain. 2. Ganglioneuroblastoma. A tumour of varying degrees of malignancy made up of a mixture of neuroblasts (sympathicoblasts) and ganglion cells in various stages of differentiation. Some of the tumours show a fairly uniform distribution of the tumour cells; others display a composite picture with alternating differentiated and undifferentiated areas. As in neuroblastoma, the majority of these tumours occur along the thoracolumbar sympathetic chain or in the adrenal gland. Ganglioneuroblastomas are most common in children under 5 years of age. Rarely regression of the tumour or maturation into a ganglioneuroma occurs. Increased catecholamine levels and diarrhoea have been observed in patients with ganglioneuroma, ganglioneuroblastoma, and neuroblastoma. �38 INTERNATIONAL HlSTULUUIUAl, ULASSIW^AIIUIN Uh 1UMUUKS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS X. TUMOURS OF PARAGANGLIONIC STRUCTURES A. PHABOCHROMOCYTOMA. A benign or malignant neoplasm of chromaffin cefls arising from the adrenal medulla, aberrant adrenal medullary tissue, or from the organ of Zuckerkandl or similar paraganglia. It is characterized by its distinctive organoid growth pattern, the presence of intracellular chromaffin granules,1 and the secretion of catecholamines. Paroxysmal or persistent hypertension and other vasomotor disorders are often associated with the tumour. It is difficult to predict the behaviour of this tumour from its morphology. B. CHEMODBCTOMA [NON-CHROMAFFIN ?ARAOANGLIOMA]. A generally benign tumour of non-chromaffin, chemodectal tissue (carotid body, glomus jugulare, aortic body, intravagal body, etc.) showing an organoid growth pattern with nests of cells separated by vascular structures and connective tissue. These tumours can be multicentric. Malignant behaviour is exceedingly rare. As in most tumours of endocrine type, the presence of free tumour cells in blood vessels is not by itself a sign of malignancy. C. PARAGANOLIOMA, UNCLASSIFIED. A tumour of the paraganglionic structures that cannot be clearly identified as of the chromaffin or nonchromaffin type. XI. TUMOURS AND TUMOUR-LIKE LESIONS OF PLURIPOTENTIAL MESENCHYME (MESENCHYMOMAS) Benign or malignant tumours consisting of two or more clearly identifiable mesenchymal elements in addition to fibrous tissue. The mixed mesodermal tumours of the genito-urinary tract are not included in this group. XH. TUMOURS OF VESTIGIAL EMBRYONAL STRUCTURES (CftORDOMAS) Chordoma has been Included in the classification because rare examples have been observed in which bone origin could not be demonstrated. Chordoma wfll be discussed in the volume dealing with tumours of the skeletal system. of intnccttabr chromalBn granule* requires immediate fixation in a chromium uh I 39 XIII. TUMOURS OF POSSIBLE EXTRAGONADAL GERM-CELL ORIGIN A. BENIGN 1. Teratoma [dermoid cyst] B. MALIGNANT 1. Teratocarcinoma 2. Embryonal carcinoma 3. Choriocarcinoma These neoplasms are included because they may occur as primary tumours in the retroperitoneum and pelvis. They will be discussed in the volume on tumours of the urogenital tract. XIV. TUMOURS OF DISPUTED OR UNCERTAIN HISTOGENESIS A. BENIGN A. Granular cell tumour [granular cell " myoblastoma"]. A benign tumour of unknown histogenesis made up of large round or polygonal, finely granular, acidophilic cells with small dense nuclei. Superficially located tumours are often accompanied by pseudo-epitheliomatous hyperplasia of the overlying squamous epithelium. Recent evidence speaks against a myoblastic origin. 2. Chondroma of soft parts. A benign cartilage-forming tumour that shows no evidence of other cellular differentiation and is unassociated with the skeleton. Some of the smaller examples of this lesion are difficult to distinguish from chondroid metaplasia. 3. Osteoma of soft parts. A benign, bone-forming tumour unassociated with the skeleton and showing no evidence of other cellular differentiation. Osseous metaplasia and late stages of myositis ossificans may be difficult to distinguish from this entity. 4. Nasal glioma [ganglioglioma]. A malformation consisting of glial tissue occasionally admixed with ganglion cells, occurring as a subcutaneous mass at the base of the nose or as a polypoid lesion attached by a pedicle to the roof of the nasal cavity. The lesion probably consists of cerebral tissue of the frontal lobe growing through a defect in the cribri- �H i l t HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS form plate or the ethmoidal bone. A connexion with the brain may or may not be demonstrable a\ the time or removal. The absence of a fluidfined space distinguishes the lesion from an anterior encephalocele. 5. Pacinian tumour. A still ill-defined benign tumour, probably of neuro-ectodermal origin, containing structures resembling Pacinian corpuscles. Neurofibromas with Meissner-Wagner corpuscle-like structures and blue naevi should be distinguished from this tumour. 6. Adenomatoid tumour ized by irregular gland-like vacuolated mesothelium-like of the epididymis, spermatic mesonephric origin. of genital tract. A benign tumour characterstructures or spaces lined or associated with cells. The tumour predominates in the region cord, and Fallopian tube, suggesting possible * 41 cells surrounded and separated by thin-walled, cleft-like vascular spaces. Typically, many of the cells contain crystalline, diastase-resistant PASpositive material. This feature helps to distinguish this entity from paraganglioma. The tumour is often mistaken for a metastatic renal cell carcinoma. 2. Malignant granular cell tumour [malignant (nonorganoid) granular cell " myohlastoma "]. An exceedingly rare malignant form of granular cell tumour differing from its benign counterpart merely in its slight cellular pleomorphism, its mitotic activity, and its potential to develop metastases. 7. Myxoma. A benign but often infiltrating growth of unknown histogenesis characterized by rather small inconspicuous round, spindle, or stellate cells within a matrix containing abundant mucoid material, chiefly hyaluronic acid, a loose meshwork of reticulin and collagen fibrils, and scanty vascularity. The large muscles of the shoulder and thigh are the most common sites. 3. Chondrosarcoma of soft parts. An extraskeletal malignant nodular tumour consisting of cords, rows, and nests of chondroblasts within a mucinous matrix rich in sulfated acid mucopolysaccharides. There is evidence that chondrosarcomas of soft parts are less malignant than those that arise from the skeleton. They can be distinguished from mixed tumours of salivary or adnexal origin by the complete absence of glandular or ductal structures. 8. Melanotic progonoma [retinal anlage tumour, mdanotic neuroectodermal tumour of infancy], A rare benign tumour made up of irregular pigmented melanin-containing cuboidal cells forming nests and alveolar spaces accompanied by a dense fibrocollagenous stroma. The histogenesis is obscure, but the available evidence seems to give strong support to a neural crest origin. The .tumour has been observed in the head, mediastinum, shoulder, and testis, as well as in the maxilla. 4. Osteosarcoma of soft parts. An extraskeletal malignant tumour composed of atypical mesenchymal cells producing osteoid or bone. The irregular manner of bone formation, as well as the absence of other cellular differentiation, distinguishes the tumour from other forms of sarcoma showing foci of osseous metaplasia. It is important to distinguish this tumour from myositis ossificans and analogous benign bone-forming lesions of soft parts. 9. Fibrous fiamartoma of infancy. A benign and probably hamartomatous growth characterized by an organoid mixture of (1) well-defined trabeculae of dense fibrous connective tissue, (2) whorls or aggregates of loosely arranged stellate or spindle-shaped cells of immature appearance, and (3) mature adipose tissue. The lesion is always located between the epidermis and the superficial fascia and tends to occur in infants between birth and two years of age. The regions of the axilla, the shoulder, and the upper arm are most commonly involved. 5. Malignant giant-cell tumour of soft parts. An ill-defined malignant extraskeletal neoplasm of uncertain histogenesis, somewhat resembling a giant-cell tumour of bone. Transitions towards a fibrosarcoma-like pattern have been observed. The tumour is frequently associated with the fascial structures of the thigh. Distant blood-borne metastases are frequent. Superficial atypical fibroxanthomas should not be confused with this entity. B. MALIGNANT 1. Alveolar soft-part sarcoma [malignant organoid granular cell " myoblastoma"].1 A malignant tumour of unknown histogenesis characterized by small organoid aggregates of polygonal, coarsely granular • The term " malignant oon-chromaffin paraganglioma " has sometime* been applied to this tumour, but ft b eooriderad mdetirable since the etiolocr h "ill not clear. 6. Malignant fibroxanthoma [malignant histiocytoma]. An ill-defined, usually deep-seated malignant neoplasm probably of histiocytic origin. This tumour shows varying degrees of pleomorphism and is characterized by a focal cartwheel or storiform pattern, multinucleated giant cells of the Touton type, xanthoma cells, siderophages, and nests of chronic inflammatory elements. The collagenous fibrillar ground substance is unevenly distributed and is less abundant than in fibrosarcoma. Metastases may occur. This tumour will be illustrated in the volume dealing with skin tumours. �42 INTERNATIONAL fflSTOLOGICAL CLASSIFICA-nON OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS 7. Kaposfs sarcoma. A potentially malignant tumour made up of irregular vascular channels and spaces, formed and surrounded by slender spindle-shaped cells with prominent, deeply staining nuclei, superficially resembling leiomyoblasts. The lesions are usually multiple and may occur in the skin as well as in the viscera. Haemosiderin pigment is frequently found. The histogenesis is obscure. The tumour is occasionally associated with malignant lymphoma. 3. Juvenile xanthogranuloma [naevoxanthoendothelioma]. A benign cellular growth of childhood occurring as a tan-to-brownish nodule in the skin and deeper tissues, principally of the head, neck, and trunk. Characteristically, the lesion consists of a mixture of small, often lipid-bearing oval or spindle-shaped cells, presumably histiocytes, Touton-type giant cells and, in the superficial lesions, occasional eosinophils. The lesion is selflimiting and in the majority of cases disappears spontaneously. It is not known to be associated with elevated serum lipid levels. 8. CleoT'ceU sarcoma of tendons and aponeuroses. A rare malignant tumour of unknown histogenesis characterized by groups and short fascicles of uniform pale staining, rounded or fusiform cells, with vesicular nuclei and prominent nucleoli. The tumour affects chiefly young adults and tends to be firmly attached to tendons or aponeuroses; it is most common in the foot and knee region of young adults. XV. NON-NEOPLASTIC OR QUESTIONABLY NEOPLASTIC LESIONS OF SOFT TISSUES, OF INTEREST BECAUSE OF THEIR RESEMBLANCE TO TRUE NEOPLASMS A. XANTHOMA GROUP 1. Fibroxanthoma [fibrous ftistiocytoma]. A benign, unencapsulated and often richly vascular growth made up of histiocytes and collagenproducing fibroblast-like cells, which are arranged in a whorled or cartwheel pattern. Frequently, the growth contains lipid-carrying macrophages. It may occur anywhere but is most common in the dermis. a. Atypical fibroxanthoma. A probably benign growth, which is closely related to fibroxanthoma but shows a much greater degree of cellular pleomorphism with multinucleate giant cells and occasional giant cells of the Teuton type as well as numerous mitotic figures, including atypical forms. The relatively small size of the lesion (generally less than 3 cm), its prevalence in the sun-damaged or irradiated skin of elderly individuals, and the fact that it is usually well-circumscribed, help in the difficult differential diagnosis from malignant fibroxanthoma (XIV/B/6). 2. Xanthoma. A benign growth made up chiefly of xanthoma cells (lipid-carrying histiocytes), occasional Touton-type giant cells, and varying amounts of fibrous connective tissue. The lesion may be solitary or multiple and is often associated with high levels of serum cholesterol and phospholipids (hypercholesteraemic xanthomatosis). 43 4. Retroperitoneal xanthogranuhma (Oberling). A mixture of xanthoma cells, acute or chronic inflammatory elements, and varying amounts of fibrous connective tissue occurring as an infiltrating tumour-like lesion in the retroperitoneum. Lesions of similar histology may also occur at other sites. Xanthogranulomatous pyelonephritis may mimic the picture of a retroperitoneal xanthogranuloma. Differential diagnosis from liposarcoma may be exceedingly difficult. 5. Nodular tenosynovitis [giant cell tumour of tendon sheath] and pigmented villonodular synovitis. A slowly growing localized or diffuse process composed chiefly of histiocyte-like stroma cells, with or without deposits of haemosiderin, xanthoma cells, and multinucleated giant cells. Collagen is a constant feature of the lesion but variable in amount. The process may arise from either tendon sheaths or the synovial membrane of joints. It most commonly affects the fingers and the knee. Erosion of the underlying bone is occasionally observed. B. GANGLION. A more or less cystic, fluid-filled lesion, possibly resulting from mucoid degeneration of collagen. The lesion is frequently associated with aponeuroses or tendons, but seldom communicates with synovial cavities. The cystic space is not lined by synovial cells. The non-cystic parts of a ganglion may bear a close resemblance to a myxoma. C. LOCALIZED MYXOEDEMA. A tumour-like dermal accumulation of hyaluronidase-sensitive mucinous material, frequently but not always associated with thyroid dysfunction. D. MYOSITIS OSSIFICANS. A benign, pseudo-neoplastic, reactive process made up of a mixture of collagen-producing, cellular, fibrous connective tissue and osteohlastic tissue engaged in orderly osteoid and bone formation. Characteristically, the formation of mature bone is most prominent in the periphery of the lesion, and this is the main criterion for differentiation from an osteosarcoma. Mitotic figures are frequent. About half the cases give a history of preceding trauma. �• 14 * - - * „ . _ _ INTERNATIONAL HISTOLOOICAL CLASSIFICATION OF TUMOURS 5. PROHFERATTVE MYOSITIS. A rapidly growing, poorly circumscribed, probably reactive proliferation of fibroblasts and ganglion-cell-like giant iclls involving chiefly the connective tissue framework of striated muscle :issue. In contrast to myositis ossificans, a history of preceding trauma is infrequent and the lesion occurs chiefly in patients older than 45 years. Ihe lesion is benign and should not be mistaken for a rhabdomyosarcoma or some other malignant neoplasm. XVI. SOFT-TISSUE TUMOUR, UNCLASSIFIED Any primary tumour of soft tissue that cannot be placed in one of the categories described above. Fig. 1. Fibroma molle l/A/2 Female, scapular region No recurrence (4-year follow-up) H&E x 190 Abbreviations used in the captions to the colour photomicrographs reproduced on the following pages: H & E: AMP: FTAH: PAS: Haematoxylin-eosin • Colloidal iron (acid mucopolysaccharides) Phospbotungstic acid haetnatoxylin Periodic acid Schiff reaction The code references on the right-hand side refer to the various categories of the histokjgical classification given on pages 19-25. Fig. 2. Dermatofibroma Female, 27 years, shoulder region No recurrence (5-year follow-up) l/A/3 �"NO T i v N i w y ~3 ± fa" N 3 a y n a A a o a a d D i - s '/. 'e ' �SERUM DIOXIN (2.3.7.8 - TCDD) TESTING Testing for serum dioxin levels is a highly technical and exacting procedure with at least the following requirements: • Standardization and quality control in the collection, processing, and shipping of specimens; and • Specialized laboratory facilities for measurement of serum TCDD levels (i.e., High Resolution Gas Chromatography/High Resolution Mass Spectrometry or HRGC/HRMS). These two major areas of specimen collection processing and laboratory measurement will be discussed. 1) Specimen Collection and Processing Two major issues must be addressed in the collection and processing of blood specimens for serum dioxin (TCDD) testing: a) the amount of blood required for the assay, and b) the necessity of standardization and quality control of procedures. At the present time, given the state of the science for dioxin testing, one (1) unit of blood is required for the assay (see Patterson et al, 1987 for discussion). The requirement for this amount of blood places constraints on how it will be obtained. Blood must be collected by trained personnel, working under the direction of a qualified, licensed physician. The donor must be monitored and never left unattended during or immediately after the collection of the blood. Further, precollection screening must include a medical history to rule out hepatitis, AIDS, or other serious illnesses, and a physical exam to determine the temperature, pulse, blood pressure (below 180/100 is acceptable) and hematocrit (41 is acceptable for males and 38 for females.) These requirements for safe collection of the blood specimen rule out an in-home collection protocol even using trained personnel. Further requirements for standardization and quality control of specimen processing and shipping also rule out an in-home protocol. Specific specimen processing and shipping requirements include: �• • • • • • • collection bags must have no anti-coagulant; blood-pack must be allowed to clot at room temperature for 3 hours before spinning to separate serum; blood-pack must be spun down, using a Beckman Centrifuge Model #J-6M or equivalent; at 4,000 RPM for 10 minutes at 4 degrees C. serum is then transferred into a 300 ml transfer pack using a "Plasma Extractor"; serum is again centrifuged as above and transferred to (4) Wheaton bottles using a plasma transfer set; serum samples are stored at -20 degrees C or less until shipment; and samples are labeled according to specifications and shipped on dry ice to the laboratory via a 24hour delivery service (e.g., Federal Express). The full CDC protocol and specifications are attached. These very specific requirements for processing of specimens prior to shipment necessitate collection at central sites where processing and preparation for shipment could be carried out. A feasible and already tested system for specimen collection, processing, and shipment is to contract for service with the Red Cross. Most importantly, the Red Cross is currently performing this work for the Ranch Hand Study, is aware of the special requirements and the necessity for standardization and quality control, and has been performing satisfactorily according to CDC specifications. Further, Red Cross personnel are qualified and appropriately supervised for collection of a unit of blood and have the equipment and facilities for the required processing and shipment of the serum specimens. Contact with Ms. Natalie Gerace of the National Red Cross, Blood Operations Support Office indicated that the organization was willing and able to perform this work for the proposed study. Since the subjects for dioxin testing will most likely be dispersed throughout the country, it will be necessary to arrange for blood collection at a potentially large number of Red Cross offices. Ms. Gerace indicated that this could be arranged through service contracts with the regional offices (up to 56 service contracts may be required depending on geographic location of the subjects). In addition to negotiating service contracts, training of the Red Cross personnel in the special requirements of specimen collection,processing and shipping will be necessary to ensure standardization of procedures. Training of personnel at the �three Red Cross sites for the Ranch Hand Study was provided by CDC personnel from the Special Activities office. Brenda Lewis from this office indicated that CDC would prefer and would be available to provide this training of Red Cross personnel for the proposed study. However, unlike the Ranch Hand Study, use of a large number of collection sites is anticipated. Two alternatives for training personnel were considered: 1) providing centralized training at selected regional sites across the country; or 2) training several technicians who would,in turn, provide training at local collection sites. Because it is necessary to train all personnel who will be involved in any aspect of the protocol, and because several people may be involved at any one site, the first alternative is not feasible. Further, it has been CDC's experience that on-site training is most effective. Therefore, a "train the trainer" technique is proposed. A number of Red Cross technicians (number to be determined by the number of collection sites required) will be trained and evaluated by CDC staff from the Special Activities Office. These technicians will then train the local Red Cross personnel onsite, using the CDC protocol. To ensure standardization and quality control, it is further proposed that CDC personnel make on-site visits to randomly selected local collection sites to monitor implementation of the protocol during the course of the specimen collection period. 2) Serum Assay At the present time CDC has the only laboratory in the country capable of carrying out the serum dioxin assay. Housed in the Division of Environmental Health Laboratory Sciences, Center for Environmental Health, the Toxicology Branch has made its own analytical standards to provide an accuracy base for the assay, has three high resolution mass spectrometry machines, has programmed and debugged the system, and has established thorough quality control procedures. Since CDC is currently performing serum assays for TCDD and since it would take at least a year to set up a laboratory in another facility, it is both time- and cost-efficient to use CDC laboratory for the assays for the proposed study. �A detailed description of the assay is contained in the attached article by Patterson et al (1987) and therefore is not repeated here. An assay on an individual specimen takes 1 1/2 days to complete. Throughput is slow, related to the complex cleaning required for each specimen. At maximum capacity, CDC could complete 75 assays per week and more reasonably 60 assays per week. �RANCH HANDS PILOT STUDY FOR SERUM DIOXIN CASE 87-0006 DIVISION OF ENVIRONMENTAL HEALTH AND LABORATORY SCIENCES CENTER FOR DISEASE CONTROL Prepared: 11/14/86 �RANCHHAND PILOT STUDY FOR SERUM DIOXIN ANALYSIS I. PREPARATION OF WORK AREAS A. Materials Needed Per participant 1. 2. 15% aqueous soap swab 10% acetone in 70% alcohol ( : ) swab 19 3. Tincture of iodine solution swab A. 5. 6. 7. 8. 9. 10. 11. 12. 13. 1A. 15. Gauze, sterile, individually wrapped, 4"x4" Tourniquet 500 mL blood bag WITHOUT anticoagulant (Travenol) Fenwal centrifuge bag 300 mL transfer pack (Travenol Plasma extractor Plasma transfer set (Travenol) Hand scale or vacuum assist device Clamps Hemostats Pliers Preprinted labels II. COLLECTION OF BLOOD ***VERY IMPORTANT;*** Blood collection for serum differs in two ways from standard blood collection for plasma. 1. 2. A. Collection bags must have NO anti-coagulant. The blood-pack must be allowed to clot at room temperature for 3 hours before spinning to separate serum. Introduction Blood shall be collected from donors by trained personnel, working under the direction of a qualified, licensed physician. The donor shall never be left unattended during or immediately after collection of blood. Blood collection must be made by aseptic methods, utilizing a sterile closed system, and a single venipuncture. If more than one skin puncture is needed, another container and donor set must be used. B. Preparing Venipuncture Site 1. Blood should be drawn from large firm vein in area free from skin lesions. 2. Apply tourniquet, select vein. �-2- 3. Release pressure, prepare skin site. a. b. c. d. e. Scrub with 1ST. aqueous soap or detergent for 30 seconds. Remove soap with 10% acetone in 70% alcohol (1:9) and allow to dry. Apply tincture of iodine solution and allow to dry. Remove iodine with acetone/alcohol mixture and allow to dry. Cover the site with dry sterile gauze until ready to perform venipuncture. After skin has been prepared, it must NOT be touched again. C. Unit Collections (Large Volumes) IT IS IMPERATIVE THAT THE PHLEBOTOMY BE ..PERFORMED INTO BLOOD-PACKS WITHOUT ANTICOAGULANT. 1. 2. Check bag without anticoagulant for defects. Bag may be gravity filled or vacuum filled. If gravity filled, use a hand scale to monitor volume; if vacuum filled, a vacuum assist device is used. 3. The bags should be affixed with the label showing the participants ID number and identified "Blood Collection Bag". A. Select vein. Prepare skin site. Reapply tourniquet. 5. Remove cover from needle. Do venipuncture immediately. 6. Open tubing. If using vacuum assist device, turn on. 7. Tape tubing to hold needle in place. 8. Fill to desired amount. Release tourniquet. 9. Remove needle from arm. Cover with gauze. Apply steady pressure for about 15 minutes. 10. Check arm, apply bandage when bleeding stops. D. Care of Donor 1. Have donor recline in donor chair under close observation. 2. After a few minutes, allow donor to sit up. 3. If there is any adverse reaction to giving blood, the blood bank physician should be notified immediately. 4. At the first sign of adverse reaction during phlebotomy, remove tourniquet, and withdraw needle from arm. �—3— III. PROCESSING BLOOD A. Processing Units LET THE BLOOD-PACK CLOT AT ROOM TEMPERATURE AT LEAST 3 HOURS BEFORE SPINNING. 1. Use Beckman Centrifuge Model #J-6M or equivalent. 2. Place bag containing blood into Fenwal Centrifuge bag. A collection bag filled with water is used for balancing if only one bag of blood is processed. 3. Spin bags at AOOO RPM for 10 minutes at 4 °C. 4. Transfer serum into 300 niL transfer pack using a "Plasma Extractor". 5. Clamp tubing with 2 clamps about 1 inch apart. Cut between clamps. 6. Repeat steps 2 through 5. 7. Using the preprinted labels provided, label each of the Wheaton bottles as follows: Size/Type Bottle 4 4 6 10 8. oz oz mL mL Wheaton Wheaton Wheaton Wheaton bottle bottle bottle bottle Bottle Label 87-0006-0001-Sl-Serum 87-0006-0001-S2-Serum 87-0006-0001-S3-Lipid 87-0006-0001-S4-Serum Dioxin Dioxin Profile Reserve Use a plasma transfer set to transfer serum to Wheaton bottles. a. Insert the sharp end into one of the outlet ports in top of the bag. b. Close tubing with thumb roller on tubing. c. Press bag with "Plasma Extractor". d. Hold open end of tubing over open pre-labeled Wheaton bottles. e. Open tubing and put 5 mL in "S3" bottle, 10 mL in "S4" bottle and divide the rest into the 4 oz bottles. f. Extract only the serum being careful that cells do not ent°!r the bottle. g. Log in the serum samples and store at -20 °C or less until shipment. �-4- IV. SHIPMENT OF SPECIMENS TO CDC, ATLANTA, GA A. Beginning of Study and General Instructions 1. 2. For all shipments, do not pack shippers with frozen specimens and dry ice until just before shipment. 3. B. Maintain a supply of dry ice from a local supplier for transporting specimens to CDC. A block should be sawed at the plant into 1" slabs. Then each of these should be sawed lengthwise. A 7"xlO" slab would fit easily into the shipper without having to break the slab. (Large pieces are preferable to small chunks, since they do not volatilize as rapidly.) Telephone the laboratory at CDC the day the shipment is transported (404) 454-4300. Speak with Brenda Lewis. Specimen Shipping List 1. For each shipment, fill out a blank Specimen Shipping List provided by CDC. If the number of specimens in a shipment is too large to fit on one page, please use the continuation sheets provided. Please give the following information on the blank shipping lists. (See attached example of a completed Specimen Shipping List.): Page number -e.g. 1 or 4 Shipment Number - number shipments sequentially starting with I Number frozen shippers - total number of shippers (containing frozen serum specimens) which are in this shipment Type of Specimen - serum Number of Specimens - number of each type of specimen shipped Name, title, signature, and phone number of person sending shipment or initials as indicated on the continuation sheets Date shipped Specimen ID for each participant - e.g., 87-0006-0011 For each participant, check ( ) each individual / specimen type/aliquot included in this shipment Date Collected - e.g., 111886 Comments - Specify any deviations from collection, storage, and shipment protocols, and date of occurrence �-5- C. Frozen Specimens 1. Materials needed per shipper - 1 styrofoam shipper (each shipper will hold frozen specimens from approximately 1 participant) 3-4 Ibs. dry ice 4 bubble-pack bags 4"x7" Safety glasses or eye shield Strapping tape - 2. Gloves for handling dry ice and frozen specimens Sheets of bubble-pack packing material CDC "Specimen Shipping List" filled out Zip-lock bag Frozen serum specimens (4 serum bottles per participant) Packing procedure When packing the shippers, use gloves to handle the dry ice to avoid burning the hands. Glasses or an eye shield should also be worn if the dry ice cakes are to be broken into small pieces. Place a frozen serum specimen from each participant in one 4"x7" bubble bag and seal. Pack 1 set of filled bubble bags upright in the bottom of the shipper. If necessary, use sheets of bubble-pack, packing material to ensure the specimens vertical position. Put one layer of sheet bubble-pack material on top of the specimens. Fill the shipper with dry ice: Insert the completed "Specimen Shipping List" in a 12"xl2" zip-lock bag and secure to the top of the polyfoam lid with filament tape. Secure the outer carton lid on the shipper with filament tape. �-6- Shipping Procedure - Cover or remove previous address labels on all shippers. Label each shipper with the following: Preaddressed "FEDERAL EXPRESS" mailing label with the following address: Brenda Lewis Chamblee, Building 32, Room 1502 Centers for Disease Control 4770 Buford Highway Chamblee, GA 30341 HUMAN BLOOD - THIS SIDE UP label DRY ICE label ORM-A written on the box Call the Federal Express office at 1-800-238-5355 to arrange for pick-up. Federal Express requires a one-hour notice before the needed pick-up. Telephone the laboratory at CDC the day the shipment is mailed (404) 454-4300. Speak with Brenda Lewis or Sue Lewis. �RANCHLAND PILOT STUDY 87-0006 SERUM COLLECTION AND PROCESSING 1 600mL BLOOD-PACK UNIT WITHOUT ANTICOAGULANT LET CLOT AT ROOM TEMPERATURE AT LEAST THREE HOURS SPIN AT 4000 RPM AT 4°C FOR TEN MINUTES TRANSFER SERUM TO A TRANSFER PACK SPIN AT 4000 RPM AT 4°C FOR TEN MINUTES ALIQUOT INTO DESIGNATED BOTTLES r SI (4 07.. BOTTLE) "" • • " •'I S2 (4 ox. BOTTLE) S3 (6mL WHEATON) i ADD lOOmL • ADD lOOmL i a 1 FREEZE IMMEDIATELY AT -70° C AND STORE AT SAME TEMPERATURE . UNTIL SHIPMENT TO CDC ON DRY ICE ADD 5mL 3 S4 (lOmL M1EATON) BOTTLE) I ADD lOmL , �1 ):; -in ;-j.-n j • '-SOOO-/R? -COOO-/.8 XX-XX-XX ...... .-in :-nyc HNV • r"in:in.in.-id nan X X X X ~~ ~~ " vs cs zs X is XXXX-3000-iB ai jn : AH sn ni ["I'M." Nn-< i.vi'i 'INI-H.-IIH.? 10'Ud. .-rA" NO"! I .•jo X �UNIT NO. 272 , Gal. 1 AC8M16M AC870013Z V069 1015 870530 High-Resolution Gas Chromatographic/High-Resolution Mass Spectrometric Analysis of Human Serum on a Whole-Weight and Lipid Basis for 2,3,7,8-Tetrachlorodibenzo-p-dioxin Donald G. Patterson, Jr.,* Larry Hampton, Chester R. Lapeza, Jr., William T. Belser, Vaughn Green, Louis Alexander, and Larry L. Needham t Division of Environmental Health Laboratory Sciences, Center for Environmental Health, Centers for Disease Control, Public Health Service, U.S. Department of Health and Human Services, Atlanta, Georgia 30333 We describe! an analytical method to measure 2,3,7,8-lelrachlorodlbenzo-p-dloxln (TCDD) and other TCDD Isomers In human serum; the method uses a highly specific cleanup procedure and high-resolution gas chromalography/hlgh-resolullon mass spectromelry. The 2,3,7,8-TCDD Is quantified by the Isotope dilution technique with [™C,2]-2,3,7,8-JCDD as the Internal standard. Other TCDD Isomers are estimated by using published, relative response factors. The 1.25 partper-quadrllllon (ppq) limit of detection for 200-g samples Is more than adequate for determining 2,3,7,8-TCDD concentrations In humarj serum specimens. The method Is modified for analyzing 50-g and 10-g serum samples. Analytical accuracy Is demonstrated by the results obtained In analyzing spiked samples. The method Is shown to be unaffected by a number of potentially Interfering compounds. A series of quality control material Is used to verify system performance. For 200-g samples containing 25.8 ppq of native 2,3,7,8TCDD, a coefficient of variation (CV) of 13.0% Is observed (n - 20). (For 10-g samples from a pool fortified with 2,3,7,8-TCDD (1.9 parts per trillion, n =' 22), a CV of 15.5% Is observed.1 Intense public health interest continues to focus on the polychlorinated dibenzo-p-dioxins and related compounds. Humans are exposed to many of these compounds from such sources as municipal incinerators (1) and automobile exhausts (2); other sources, such as the manufacture and use of compounds for which 2,4,5-trichlorophenol is a synthetic intermediate, givp rise primarily to 2,3,7,8-tetrachlorodibenzo-pdioxin (2,3,7i8-TCDD). The 2,3,7,8-TCDD congener, one of 22 tetra isomers, reportedly is the most toxic of these compounds. Studies have documented its toxicological properties, such as acute oral LDM (3), teratogenicity (4), carcinogenicity (5), and fetofoxicity (6) in selected animal species. However, human toxicity associated with exposure to 2,3,7,8-TCDD has not been as |vell documented. Findings of a recent study of the residents of a mobile home park in Missouri suggested that long-term exposure to 2,3,7,8-TCDD ia associated with depressed cejl-mediated immunity, although the effects did not result in 'an excess of clinical illness (7). However, in this study of health effects and in another (8), exposure was derived from self-rerjorted histories and not from body burden measurements. Such measurements are needed in these healthrelated studies. '' Polychlorinated dibenzo-p-dioxins are lipophilic and thus are found in body stores that are high in lipid content. Body burden measurements for 2,3,7,8-TCDD in humans have been determined in blood plasma (9), in human milk (10,11), and in adipose tissue (12-15). The primary disadvantage of the breast milk matrix in health-related studies is that the cohort is restricted to females within a limited age range. The primary disadvantage of adipose tissue is that the sample must be obtained surgically. Therefore, a biological specimen, such as blood or its components, that can be obtained with a less invasive procedure than adipose and that is available from all participants, is highly desirable. Other lipophilic xenobiotics, such as the chlorinated hydrocarbon pesticides and polychlorinated biphenyls, have been determined in both human adipose tissue and serum for years. Because the fat content of serum is much less than that in adipose tissue, these compounds are in higher concentrations in the adipose tissue. Consequently, a large volume of serum �.Gal. _ [0. 273 2 AC8M16M AC870013Z V069 1016 870630 's normally used when these compounds are determined in jumans. Because 2,3,7,8-TCDD is present at the picogramper-gram or parts-per-trillion (pptr) level in adipose tissue, any method for determining it in whole blood, plasma, or erum would have to be particularly sensitive as well as se—sctive. These criteria require methods based on gas chromatography/mass spectrometry (16). We report here a high-resolution gas chromatographic/high-resolution mass :pectrometric method for determining 2,3,7,8-TCDD in human *gerum; this method is an adaptation of our method for determining this xenobiotic in human adipose tissue (17,18). EXPERIMENTAL SECTION Safety. Chemists undertaking this work with 2,3,7,8-TCDD and other such toxic compounds must understand the potential 'lealth effects of such compounds (19) and prudent laboratory )ractices for handling toxic chemicals (20). Specific precautions *fcave been described (21,22). More recent Environmental Protection Agency (EPA) draft methods have emphasized specific ispects of protective equipment, training, personal hygiene, isolation of the work area, disposal of waste, laboratory cleanup, driaundry, wipe testing, problems in inhalation, and accidents. We have described safety precautions in the operation of our Chemical Toxicant Laboratory (23), and other laboratories have also decribed their'procedures (24). Materials! In addition to the materials already described (17, 18), we used ethanol (anhydrous reagent, J. T. Baker, Phillipsburg, "W), ammonium sulfate (certified primary standard, Fisher Scientific Co.', Fair Lawn, NJ), and sulfuric acid (Reagent ACS, Wisher Scientific, Fair Lawn, NJ). "'• _ Sample Preparation. Two hundred grams of serum is yeighed into a 600-mL Teflon bottle (Nalge Co., Rochester, NY). «Vn internal standard solution consisting of 240 pg of l3C-labeled 2,3,7,8-TCDD is added to the sample. The standard (maintained •\t room temperature) is accurately measured by using an electronic ligital pipet ,(Rainin Instrument Co. Inc., Woburn, MA) with •disposable microliter pipet tips. The disposable pipet tip is primed by dipping the tip 2-3 mm below the surface of the standard and operating the pipet for pickup and dispensing back into the tandard. A repeat operation is done for pickup and dispensing ^into the side, of the bottle containing the 200 g of serum. The sample is capped tightly and shaken vigorously with a wrist action shaker Model 75 (Bunnell Corp., Pittsburgh, PA) for 30 min. To he sample is then added 100 mL of aqueous saturated ammonium ^ulfate solution (50 mL to a 10- to 50-g sample), 100 mL of absolute ethanol (50 mL to a 10- to 50-g sample), and 100 mL of hexane (50 mL to a 10- to 50-g sample). The flask is then capped tightly md shaken vigorously for 30 min with the wrist action shaker.. J'he emulsion formed after shaking is centrifuged for 10 min at 1600 rpm. The top hexane layer is transferred to a 500-mL Teflon separatory funnel. To the bottom aqueous layer is added another 100 mL of heiane, followed by vigorous shaking, centrifuging, and combining of the two hexane extracts. The combined hexane extracts (200'mL) are then extracted with concentrated sulfuric acid with a 500-mL separatory funnel and a total of 200-mL of ixmcentrated bulfuric acid (70 mL for 10- to 50-g samples) in 20-mL aliquots. The first three extractions are not shaken vigorously Ho prevent the formation of an emulsion. The acid-washed hexane is then extracted with a total of 75 mL of deionized water in 25-mL idiquots. Thd hexane is then transferred to a 250-mL Erlenmeyer [lask, followed by the addition of 10 g of sodium sulfate and Evaporation under a nitrogen stream to ~76 mL. The sample Is then loaded onto the first chromatography column for part I ?f a two-part sample cleanup procedure (17,18), which is capable >f processing five samples unattended overnight. The sample from part I in toluene is then subjected to rotary evaporation at 65 °C under ~0.1-0.2 atm vacuum after 60 fil of dodecane (99%, Aldrich Chemical^o^Jnc^MilwauJtee^WIHs added. The toluene solutioitfcafefully taken to about 1 mLancf then blown to dry ness under a gentle streain of nitrogen. After the sample is reconstituted in hexane, it is ready for part II of the procedure (17). Before evaporation of the final extract to dryness, 1 /iL of dodecane is added to the conical sample vial. This sample extract is reconstituted to 6 nL with toluene just before analysis by high-resolution gas chromatography/high- 1 resolution mass spectrometry (17). Instrument Analysis. Our analytical instrument system consists of a VG ZAB-2F high-resolution mass spectrometer with a VG 2260 data system and a Hewlett-Packard 5840 gas chromatograph. Our analyses are conducted in an iaomer-specific mode, with a 60 M SP2330 capillary column. The injection is splitless with a 30-s purge. The injector temperature is 240 °C. The initial column temperature of 100 °C is held for 2 min, programmed to 250 °C at 15 "C/min, and held for 14 min. The average linear velocity of helium is 23 cm/s or about 2.9 mL/min flow rate. The mass spectrometer is operated in the high-resolution (static RP = 10000 at 10% valley) selected ion recording mode, with perfluorotributylamine used to provide a lock mass at m/z 314. Peak top jumping is accomplished by stepping the accelerating voltage after any necessary correction during the scan of the lock mass. Ions m/z 320 and 322 provide a measure of the native TCDD, and ions m/z 332 and 334 are monitored for the elution of the Jabeled internal standard. Five analytical standards that correspond to 1.25-25 ppq of 2,3,7,8-TCDD in a 200-g serum sample have been used to establish a linear calibration curve. The data for the standard curve are tabulated in Table I. The internal standard is the ["Cizl^.S^.S-TCDD at a concentration corresponding to 1.2 pptr in the original 200-g samples. The other TCDD isomers can be quantitated by using our published (25) response factors relative to 2,3,7,8-TCDD. The best precision in quantitation ;is obtained by using chromatographic peak areas and by using the sum of the two ions for the native TCDD and two ions for the internal standard. On a regular basis, isomer-specific chromatography la demonstrated by analyzing a standard containing the 22-TCDDs. Our serum Quality Control (QC) ppolsL and H contain, among other dioxins and furans, the 1,2,3$TCDD isomerthaTTa¥T)TuW to establish isomer specificity for 2,3,7,8-TCDD in analytical runs containing a sample from these QC pools (see Figure 1). The calibration curve is verified by analyzing an analytical standard during an 8-h, shift. Instrument resolution at 10000 RP, tuning, and other parameters are checked on a regular basis to ensure optimum sensitivity and specificity. Criteria for a positive TCDD determination are as follows: (1) signal/noise greater than 3/1 for both signals on ions 320 and 322; (2) signal/noise greater than 10/1 for both signals on ions 332 and 334 from the internal standard; (3) observed retention times within ±1 scan of each other on ions 320 and 322 and the relative retention time (RUT) (to lI3C,j]-2l3,7,8-TCDp) must be within 2 part-per-thousand of the RRT of the analytical standard; (4) the ratio of the intensities of the ion 320 to 322 and 332 to 334 is within the 95% confidence intervals established for these ratios (see Table II). �Spiked and nonspiked human serum y<J material has been prepared and characterized. Incorporating these materials in the analytical run sets control limits and provides a means for demonstrating that the analytical system is in cotitrol_RecQverY_data_ are calculated on the basis of the absolute^tmSjtfiounTs for m/T332 + 334 in thejsample vs. the standards. ^""^^ Serum Total Llplds. Cholesterol esters, triglycerides, and high-density jlipoprotein cholesterol (HDL) are determined in duplicate by'standard methods (26). Total phospholipids are determined in duplicate by a modification (27) of the Folch procedure (28). Free cholesterol is determined in duplicate by an enzymatic method (29). The summation method (30) estimates total lipids in serum. The agreement is excellent between this summation value and the corresponding estimate obtained through extraction and gravimetric analysis (30). QUALITY ASSURANCE (QA) PROGRAM Quality Control (QC) Materials. The main feature of the QA program is the use of matrix-based materials that are well characterized for TCDD concentration to ensure that the analytical system is in control. Human serum has been dispensed into various sized aliquots. Two of the pools have been spiked with various levels of dioxiris and furans, whereas the other pool has not been spiked. Three pools of material are available to be inserted into the analytical run. The spiked pools contain the following dioxins and furans in addition to those already present in human serum: 2,3,7,8-TCDD; 1,2,3,4-TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxinV (PnCDD); 1,2,4,7,8-PnCDD; 1,2,4,6,7,9-hexachlorodibenzo-pdioxin (HxCDD); 1,2,3,6,7,9-HxCDD; 1,2,3,6,7,8-HxCDD; 1,2,3,7,8,9-HxCDD; 1,2,3,4,7,8-HxCDD; 1,2,3,4,6,7,9-heptachlorodibenzo-p-dioxin (HpCDD); 1,2,3,4,6,7,8-HpCDD; oc-. tachlorodibenzo-p-dioxin (OCDD); 2,3,7,8-tetrnchlorodibenzofuran (TCDF); octachlorodibenzofuran (OCDF). QC Charts. QC Charts graphically document the analytical performance of the system. Figure 2 shows 4M* the QC chart for pool L, which was established during the development of this method; the statistical data are shown in Table II. Details of the Analytical Run. The status of the specimens being analyzed is unknown to the laboratory analysts. Samples are received and arranged in analytical runs of five (three serum samples, a method blank, and one QC sample from pool I or L). In every fourth analytical run, a QC sample from a different pool is substituted for the pool I or L QC sample. In addition, a serum sample selected at random from one of the four analytical runs will be analyzed in duplicate, providing that sufficient serum is available. The samples are then submitted for cleanup by a manual method (17) or an automated procedure (18) and then submitted to the mass spectrometery (MS) laboratory for analysis. The MS personnel are also unaware of the nature of the extract. To minimize the possibility for carryover or cross-contamination of samples and analytical standards, analysts use separate syringes for samples and for each analytical standard. The sample syringe is discarded periodically or when a serum sample that contains more than 75 ppq of 2,3,7,8-TCDD is analyzed. Between injections of a standard or a sample, the syringe is inserted through a Teflon-coated septum into a 16-mL vial containing 12 mL of toluene, and the barrel is filled and emptied 10 times. This process is repeated twice more with different 15-mL vials containing toluene. A final wash of the syringe is done by filling and emptying the barrel 10 times with aj fourth toluene wash solution. These wash solutions are discarded at the end of each working day. The final 5 nL of:toluene for reconstituting samples is then taken from a fifth Verified blank toluene source. The step-by-step procedure leading to an analytical result, the accompanying documentation, and the criteria for identifying TCDD and for reporting results have been reported previously (17). EVALUATION AND VALIDATION STUDIES i Interferences. We have previously described (IT) our studies to verify the elimination, by the cleanup process, of compounds that could interfere in the analysis for TCDDs. The results of these analyses indicated that these potentially interfering compounds, which are present at 103- to 10'-fold excess, are effectively removed during the multicolumn cleanup of the sample. Validation of 2,3,7,8-TCDD Analytical Standards. In a previous analysis of a series of 2,3,7,8-TCDD standards received from various laboratories and chemical suppliers, we found that the stocks varied from -65% to +35% of the stated concentration (17). Because.of these findings, we validated our stock solution against 2,3,7,8-TCDD that we had synthesized and characterized in our laboratory. At the time of the previous report, the National Bureau of Standards (NBS) had plans lo issue a Certified Reference Material for 2,3,7,8-TCDp, which is now available. Therefore, we have validated our stock standard solution that we used for our quantitative'measurements against CDC synthetic material and EPA and NBS analytical standards. The results of the measurements are given in Table HI. The agreement among these standards is very good and well within the stated uncertainity. j Recovery of 2,3,7,8-TCDD. Human serum samples (200 g, 50 g, 10 g) were spiked with 240 pg of |l3C,s]-2,3,7,8-TCDD and processed through the entire cleanup procedure described above and the entire five-column cleanup described previously (17, 18). These samples were analyzed by using {"CIJ2,3,7,8-TCDD as the external standard to give average recoveries of 69%, 54%, and 68%, respectively (Table IV). Recovery of the 22 TCDDs. A standard that contained the 22-TCDDs that had been processed through the fivecolumn cleanup procedure was compared with a standorjL analyzed directly by GC/ftS. TUe results, whTcrTTonged" from 95% to 124% recovery (17), were adequate for quantitating the 22 TCDDs. �Withln-Vlal Variability. Periodically, we need to rerun the mass spectral analysis of a sample because of a number of possible hardware or software problems such as electrical failure in the laboratory, poor signal-to-noise ratio, incorrect isotope ratios, high-voltage shut down, or data system crash. In addition, highly concentrated samples may sometimes saturate the detector and require dilution before a second analysis. We have examined the variability involved in a reanalysis from a sample vial (2 ^L of 3 nL) that was analyzed (2 pL of 5 jiL) the same day, one day earlier, and up to 27 days earlier (Table V). The data in Table V indicate that the samples may)be reanalyzed up to a month later with less than a 10% bias ^eing introduced. Method Performance. All 200-g serum samples examined • thus far have produced sufficiently strong signals (signal-tonoise ratio :> 3/1) to permit quantification. With regular routine maintenance, a limit of quantification of 5 ppq for a 200-g sample'may be readily achieved for routine samples from epidemiologlcal studies. We have previously defined our criteria (17) for reporting samples such as Q (quantifiable), NQ (nonquantifiable), and ND (nondetect). The accuracy of the method is demonstrated in part by the spiked recovery experiments; (Table IV). In these tests, three different calibrated aliquots of 2,3,7,8-TCDD were spiked into separate 200-g samples of pool I. This experiment was performed twice by two different analysts. The values obtained on analysis ' are in good agreement with the expected values. We have also conducted a series of experiments in which we combined vials of QC pool L to provide ~20-, 30-, and 40-g samples that were spiked' with 240 pg of 13C12-2378-TCDD and carried through the Analytical procedure. The expected and observed values (Table VI) are in good agreement. Another measure of system performance is the precision associated with characterizing the QC materials (see Table II). For spiked 10-g serum samples at the 1.9 pptr level, a coefficient of variation (CV) of 16% was observed. For 200-g unspiked serum samples at the 25.8-ppq level, a CV of 13% was observed. ! i Stabilityiof 2,3,7,8-TCDD in Human Serum. Samples of QC pools! and L were stored at -40 °C and analyzed at various times during the method development phase of this study. We have observed no apparent degradation of the 2,3,7,8-TCDp in these materials over a period of 1 year. RESULTS AND DISCUSSION Human erum Results. During and after the method developmen : phase of this study, we have successfully analyzed, for 2,3/7,8-TCDD, various individual samples of human serum, plasma, and whole blood, as well as pooled samples collected fnjm local and regional centers. These results, jumniarized' in Table VII, are the first reported levels of 2,3,7,8-l^pp in human serum taken from individuals in the general population with no known exposure to 2,3,7,8-TCDD. The arithmetic mean of the individual serum samples is 47.9 ppq (range of 13.6-211 ppq, n ** 22) on a.whole-weight basis and 7.66 pplr (range of 1.87-26.0 pptr, n = 21) on a lipidweight basis; These results in serum on a lipid-weight basis are in good agreement with results that we have published previously (14,15,17} relating to human adipose tissue, as well as with results in adipose tissue from other laboratories (12,13, 31-3$) as shown in Table VIII. Future Method Development. A key to substituting serum for the more difficult to obtain adipose specimen is to experimentally calculate the partitioning coefficient of 2,3,7,8-TCDD in these two matrices. We have begun a study of the distribution of 2,3,7,8-TCDD in paired serum and adipose tissue samples collected from the same individuals. The analysis of each blood sample for total and free cholesterol, triglycerides, HDL, and phospholipids will allow us to examine the distribution of 2,3,7,8-TCDD in the various lipid compartments of blood. ACKNOWLEDGMENT i he authors thank Quinis Long and Eileen S. Morgan for typing this manuscript. We also thank Thomas Bemert, Omar Henderson, and Wayman Turner for performing the Hpid analyses and James Pirkle for technical support. We also thank Brenda Lewis and Carolyn Newman for providing the materials and logistics for encoding, handling, and sample receiving. i LITERATURE CITED (1) Karasek,.F. W.; HuUlngor, O. Anal. Chem. 1986. SB, 633A-642A. (2) Ballschmjter, K.; Buchert, H.; Nlemczyk, R.; Munder, A.; Swerev. M. ChamosQhero, In press. ' I (3) Henck, I. M.; Now, M. A.; Koclba, R. J.\ Rao, K. 8. Toxlcol. Appl. Pharmacpl. 1981, S9, 405. ! (4) Tuchmanb-Duplossls In Accidental Exposure to Dloxlns, Human Health Aspects •' Collision, F.. Ed.; Academic: New York, 1983; p 201. (5) Wassomj J. S.; Huff. J. E.; Loprleno, N. Mutat. Res. 1977/1978, 47, 141. i (6) Poland, A.; Knutson, J. Annu. Rev. Pharmacol. Toxlcol. 1982, 22, 617. (7) Hoffman, R. E.; Stehr-Greon, P. A.; Webb, K. A.; et al.mp*. J*. Am Mod. Assoc. 1986, 255, 2031-2038. /N t • (8) Slehr, P.!A.; G. Stein; H. Fatk; et al. Arch. Environ. Health 1996, 41, 16-22. (9) Rappe. p.; Nygren, M.j Quslafson, Q. Chlorinated Dloxlns end Furam In the Total Environment; Choudhary, Q.; Kollh, L.. Rappe, C., Eds; Butterworth: MA; Stoneham, 1983; pp 355-365. i (10) Hoath, R. Q.; Harless, R. L.; Gross. M. L.; el al. Anal. Chem. 1986, 68, 463-,468. i (11) Rappe, C.; Bergovlst, P. A.; Hansson, M.; K|eller, L. O.: Llndstrom, Q.; Marklund, S.; Nygren, M. Banbury Report ,8: Biological Mechanisms of Dloxln: Action 1984, pp 17-25. Jfc_ . (12) Schecter. A.; Ryan, J. J.; Qltlltz, Q. In Chlorinated Dloxlns and Dibenzofurans In Perspective; Choudhary, Q.; Keith. L. H., Rappe. C., Eds.; John Lewis: Chelsea, MI, 1988; Chapter 4 pp 51-65. i (13) Gross, M. L.; Lay. J. O., Jr.; Lyon. P. A.; et al. Environ. Res. 1984, 33, 261- 268. (14) Pattersoi , D. G.. Jr.; Hoffman, R. E.; Neodham. L. L.; .;«lt\.JhUA,j. Am. Mod. Assoc. 1986, 256, 2683-2686. �(15) Patterson. D. Q., Jr.; Holler. J. S.; Smith, S. J.; et al. Chemosphere 1966, 15, 2055-2060, MASS RETENTION TIME HEIGHT AREA 319.90 OHRS23MINS58SECS 25.9438 16B.BB3B 321.89 OURS 23 WINS 67 SECS 32.4174 217.9545 (16) Albro, P.|w.; Crummett. W. B.; Dupuy. A. E. Jr.; et al. Anal. Chem. 1885. 57,. 2717-2725. :| - (17) Patterson, D. 0., Jr.: Holler. J. 8.; Lapeza, C. R. , Jr.; et al. Anal. Chem. 1886, SB. 705-713. (16) Lapeta, C. R., Jr.; Patterson, D. Q., Jr.; Uddle, J. A. Anal. Chem. 1986, 54, 713-716. i (19) Halogenated Blphenyls, Terphenyls, Naphthalenes, Dlbenzodloxlns and Related Products; Klmbrough, R. D., Ed.; Elsevler/North-Holland Blomedlcal Press: New York, 1980. T (20) National Research Council Prudent Practices for Handling Hazardous Chemicals In Laboratories; National Academy Press: Washington, DC, 1981. 331.94 0 MRS 23 MINS 66 SECS T 683.8873 3873.7650 848.0622 6352.4980 (21) EPA Method 813 Fed. fteglst. 1979. 4^(233). 69326-69330. (22) Harloss, R, L.; Oswald. E. 0.; Wilkinson. M. K.; Dupuy, A. E.; McDan-' lei, D. D.; Tat, Han AnaL Chem. 1980, 52, 1239-1245. 333.93 ftHRS'23 MINS 66 SECS (23) Alexander, L. R.; Patterson, D. Q.; Myers, Q. L.; Holler, J. S. Environ. Scl. Technot. 1986, 20, 725-730. (24) Safe Handling of Chemical Carcinogens, Mutagens, Teratoggna and Highly Toxic Substances; Walters. D. B., Ed.; Ann Arbor Science Publishers: Ann Arbor, Ml, 1980. (25) Patterson, D. Q., Jr.; Alexander. L. R.; Qelbaum, L. T.; et al. Chemosphere 1986, 15, 1601-1604. Figure 1. Mass chromatograms trom a 10-g sample ol pool L (1.8 pptr) showing separation between 2,3,7,8- and 1,2,3,4-TCDD. \ (27) Beverldge. J.; Johnson, 8. Can. J. Res., Sect. B. 1949, 27. 159-163. (28) M ! Sloan Stanl ' - «y. Q- H. J. Blot. Chem. 1957. 226. (29) Cooper. Q. R.; Duncan. P. H.; Hazlehurst. J. 8.; et al. Selected Moth1.0 (30) - Oh. Chem. (Winston -Salem, NC.) 1969. i (31) Graham. M.; Hlleman F. D.; Wendllng J.; et al. Chtorocarbons hi AdlSn'rwi8?".9! JTni" ?' ^S8!"18"18t •"« 6lh Inlernatlonal Symposium y si I °17 1985 "* Compound8' BaV'e^' West Ger- (32) Ryan J. J.; Williams D. J.. Abstracts of Papers, 186th National Meeting hi « T-l'^UuCh«mlcal Soctety- Washington DC; American Cherril btry Soc ety: Washington DC. 1983; Environmental Chemistry Sec• Uon, Abstract 55, p 157. ' ' I ' "V, (33) Graham M; Hlleman F. D.; Wendllng J.; et al. Background Human Exposure to 2,3,7,8-TCDD. Presented at the 4th International Symposium on ChlorinatedI Dlpxlns and Related Compounds, Ottawa, Canada, uciooer 16-18, 1984; RECEIVED foil review January 6,1987. Accepted April 27,1987. Use of trade, names is for identification only and does not constitute endorsement by the Public Health Service or the U.S. Department of Health and Human Services. 10 tS 20 Run Number Figure 2. Quality control chart (or spiked human serum pool L (10-g samples). • �Table I. Estimated Concentration (Parts per Trillion in a 10 g Sample) and Linear Regression Parameter Estimates from Mail Spectrometry Calibration 95% control limits lower upper 0.0139 008 .34 0.0793 0.2438 0.4676 bias, % std dev coeff of variation, % 0.0243 0.0490 -3 -2 •0.0900 . 0.2687 0.4912 -10 7 -2 0.0053 0.0053 0.0054 0.0127 0.0121 22 11 6 6 2 calibrator concn 0.025 0.050 0.100 0.250 0.500 0.0346 0.0595 0.1012 0.2935 0.5148 obsd mean concn Intercept slope coeff of determinations 0.000816705 0.0241131 0.9941 INITIAL TABLE WIDTH IS DOUBLE COLUMN Table II. Statistical Data for the Human Serum QC Pools . . H, pptr* concn of 2,3,7,8rTCDD N (sample size, g) std dev (a) coeff of variation 99% control linns, upper 99% control limits, lower 95% control limits, upper 95% control limits, lower m/t 320/322 ratio N (sample size, g) std dev (a) \ coeff of variation 99% control limits, upper 99% control limits, lower 96% control limits, upper 95% control limits, lower m/z 332/334 ratio N (sample size, g) std dev (a) coeff of variation 99% control limits, upper 99% control limits, lower 95% control limits, upper 95% control limits, lower 6.83 8 (10) 0.64 9.4 8.48 5.18 8.08 6.57 86.7 8 (10) 2.6 2.9 93.3 80.1 91.7 81.7 77.6 8(10) 6.2 8.0 93.7 61.6 89.8 65.4 I, ppq' L, pptr« 25.8 1.93 20 (200) 22 (10) 3.4 0.30 13.0 16.5 34.4 2.70 17.1 1.16 32.3 ' 2.61 19.2 1.35 79.3 80.4 20 (200) 22 (10) 9.45 6.28 11.9 • 7.8 - ^ 103.7 96.6 " 64.9 64.2 97.9 92.7 60.8 68.1 77^1 76.0 20(200) 22(10) 5.12 4.04 6.6 6.4 90.3 85.4 63.9 64.6 87.1 82.9 67.0 67.1 •These pools spiked with dioxins and furans described in text. 'This pool unspiked composite serum from 67 individuals. INITIAL TABLE WIDTH IS SINGLE COLUMN Table HI. Validation of CDC Quantitation Stock Solution Against EPA and NDS Material for 2,3,7,8-TCDU reported concn* NBS' SRM 1614 EPA,- 7.87 ± CDC-A* CDC-B' CDC-C* 11 CDC-D11 CDC-E mean' 67.8 ± 2.3 78.7 ± 7.9 3.77 6.02 25.1 60.2 125.6 69.4 79.6 3.34 4.46 24.9 49.4 123.4 , CAS: *M«6-01-6 ! found 6 using CDC standard curve std^dev coeff of variation N 3.0 2.7 0.22 0.23 1.51 4.23 7.47 4.3 3.4 6.8 6.2 6.1 8.6 6.1 4 4 4 4 4 4 2 % bias +2.4 +1.1 -11 -11 -0.8 -1.6 -1.7 * Concentration in pg/pL. 'Each standard was made in duplicate and each vial was analyzed on two different days. 2400-pg of |I3C,,J2,3,7,8-TCDD was added to each vial as internal standard. After evaporation to dryness, the vials were reconstituted to 50 pL with toluene prior to mass spectral analysis of 2 tiL aliquots. 'A 25-fiL aliquot of this standard was added to ench vial. 'These standards were diluted 1:100 before 2->L aliquots were taken. 'These standards were prepared by an additional 1:10 dilution of the slock solution used to make CDC-C, D, and E. The increased bias for these two standards may reflect the extra 1:10 dilution of the stock solution required to prepare these two standards. INITIAL TABLE WIDTH IS DOUBLE COLUMN �Table IV. Recoveries of Internal Standard and Native 2,3,7,8-TCDD "Spiked" Human Serum found (200-g samples) aliquot added target* A B C 49.8 ± 6.1 72.2 ± 3.5 96.5 ± 6.9 ~ ~ 42.0 78.6» 75.6 2 39.0 65.6 73.6 32.0 74.0 90.0 mean obsd 3 1 64.2 80.9 112.5 bias, % 44.3 ± 12.0 74.7 ± 6.9 87.9 ± 15.6 -11.0 +3.5 -8.0 ["C,,1-2,3,718-TCDD (% recovery) i 200-g samples of human serum spiked with 240 pg of [l3Cia]-TCDD 60-g samples of human serum spiked with 240 pg of [13C,2]-TCDD 10-g samples of human serum spiked with 240 pg of iI3Cl2j-TCDD 66, 60, 84, 93, 48, 63, 81. 80, 66, 69, 76 68, 68, 63, 61, 64, 32 66, 68, 61, 64, 60, 100, 77 •The targe value was calculated by adding calibrated aliquots to the pool I (x = 25.8 ± 3.4 ppq). Aliquot A = 24.0 ± 3.8 ppq (N = 6); B " 46.4 ± 0.6 i ipq (N ** 3); C « 69.7 sk 6.0 ppq (N a 6). 'Undetermined amount of sample spilled. The internal standard ion counts were low. INITIAL TA&LE WIDTH IS DOUBLE COLUMN j Table V. Within-Vial Variability sample dayl I pg (pptr) day 1 pg J9.7 Jl.87) 19.8 (1.87) JU.7 (73.6)o 1 4.3 (21.6)a dayl eo.1 (6.77) 67.q (6.49) 71.9, (3.46) 48.0 (1.63) 78.0 (1.85) 18.9 21.0 13.6 4.4 (1.79) (1.98) (67.6)o (22.0)« day 2 PB 69.7 56.4 75.6 47.6 82.6 (6.62) (5.40) (3.62) (1.61) (1.96) maximum % bias 4.2 6.1 8.9 . 2.3 average % bias 6.4 maximum " • average % bias % bias 14.7 1.6 6.1 1.1 6.8 6.7. dayl 10 11 12 13 14 16 day 5 to 18 pg (pptr) maximum % bias average % bias 12.8 (64.2)" 6.6 (33.4)' 6.2 (26,2V 6.4 (27.0)« 39.6 (182)" 36.4 (6190)0 11.7 (68.7)o 6.4 (32.4)o 6.1 (25.7)o 4.6 (23.2)o 40.4 (186)o 41.8 (6960)o 9.4 3.0 1.9 16.4 2.0 14.8 7.9 dayl Pg 16 17 18 19 20 1 day 27 Pg maximum % bias average % bias 18.6 (1.76) 18.J6 (1.77) . 38.19 (1.85) 63.J9 (1.71) 76.3 (1.79) 18.7 (1.76) 13.7 (1.30) 41.8 (1.98) 61.6 (1.64) 76.7 (1.82) 0.6 36 7.0 4.3 1.7 9.9 Parts-per-'quadrillion. INITIAL TApLE WIDTH IS SINGLE COLUMN �J _ Table VI. Quantitatlon of Combined Aliquot* of QC Pool L ' 11 eipt expected* X ± aid dev Pg(PPt) level, g 20.6 (1.93 ± 0.29) 10.6 20.3 (1.93 ± 0.29) 10.53 21.06 40.6 (1.93) 60.7 (1.93) 31.45 42.fr 81.3 (1.93) 21.116 ' 40.8 (1.93) 61.4 (1.93) 31.795 81.8 (1.93) 42.369 20.3 (1.93 ± 0.29) 10.525 20.984 40.5 (1.93) 31.587 61.0 (1.93) 81.4 (1.93) 42.162 obsd Pg (PPt) 18.6 (1.76) 18.6(1.77) 38.9 (1.85) 63.9 (1.71) 75.3 (1.79) 44.4 (2.1) 69.5 (1.87) 105.2 (2.48) 21.1 39.1 69.1 88.5 (2.0) (1.86) (2.19) (2.1) % bias -9.1 -8.6 -4.3 -11.2 -7.4 +8.9 -3.0 +28.6 +3.9 -3.4 +13.3 +8.8 •See Table II for QC pool L data. INITIAL TABLE WIDTH IS SINGLE COLUMN Table VII. Concentration of 2,3,7,8-TCDD in lluman Plasma, Whole Blood, and Serum Samples pooled serum, no. of persons concentration sex race age whole weight" 10 11 8 3 ! j [ 42.0 29.0 9.5 21.0 12.2 22.2 25.8 29.6 19.8 d d d d 'f \ I f I I f f f f f M F M F M M M F M M F M F F M M M M F F F F F M F F F W W W W B W W B W W B W B W W .W W. w w w w •w w w w w w 28 69 27 30 61 68.2 26.8 18.9 49.9 23.9 40.9 23.1 33.6 68.6 68.0 69.5 35.4 70.0 37.0 48.6 43.2 63.6 37.4 45.2 48.1 40.5 31.3 c c c c 14.0 64.5 48.0 61.0 26.6 67 78 107 c 19.6 31.9 10.9 12.8 3 e e e lipid weight 6 c c c c c 37.6 63.5 18.8 63.0 13.5 34.6 21.7 39.1 45.4 83.1 28.8 24.2 211 142 30.0 17.2 68.8 45.8 22.0 24.1 24.5 16.0 - c c c c c 4.2 c c c 10.2 2.77 8.7 1.87 4.88 3.04 5.74 7.08 12.0 4.91 3.07 26.0 21.9 4.10 4.93 9.43 11.94 4.44 4.22 4.72 2.88 •Concentration In ppq. 'Concentration in pptr. 'Percent lipid not determined. Plasma sample from 4 different individuals. 'Whole ' blood sample1 (lysed cells) from 5 different individuals. 'Serum sample from 22 different individuals. INITIAL TABLE WIDTH IS DOUBLE COLUMN �Table VIII. Concentration of 2,3,7,8-TCDD in Human Serum and Adipose Tissue from Individuals with No Known TCDD Exposure N mean, pptr 21 7.6 present study: human serum on lipid-weight basis S 7.4 human adipose, Patterson et al. (14) 57 35 7.1° human adipose, Patterson et al. (15) 7.2" ' . '.;.•; rjuman adipose, Graham et al. (31) 35 7.5 . • • • ' . ( > '-\' • human adipose 61' 6.4 25 .:' .'•' > '• .'•••! if M11"080 ^ipoae, Schecter et al. (12) 7.2 8 '^''•''^'j^l^'-^V-^'''''-:^^'^'^ ' •"'•' |46c '• •Geometrlo mean. * Combination of results from 13, 32, and 33. Three results from persons known to have chlorophenol [were excluded. 'ND, not detected. ^ INITIAL TApLE WIDTH IS DOUBLE COLUMN The number, of words in this manuscript is 4034. ••' • • • ' '-• !i • ' -. . The manuscript type is A. . Aulhor Index Entries Patterson, Jr., D. Q. Hampton, L. Lapeza, Jr.-, C. R. Belser, W. T. Green, V. UNIT NO. 283 .Gal. 12 AC8M16M AC870013Z V059 1015 Alexander, L. Needham, L. L. Public Domain Indicator Pr»*«nl Text Page Size Estimate =• Graphic Pa'ge Size Estimate = 3.5 Pages 2.6 Pages i Total Page.Size Estimate = 6.1 Pages 870630 range, pptr 1.9-26.0 1.4-20.2 2.7-19 1-15 ND,' 2.0-13 1.4-17.7 hod exposure to 2,4,5-tri- � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 069 Folder The folder containing the original item. 1851 Series The series number of the original item. Series III Subseries III Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource McKinlay, Sonja M. Description An account of the resource <strong>Corporate Author: </strong>New England Research Institute, Inc., Watertown, Massachusetts Title A name given to the resource Women's Vietnam Veterans Health Study Protocol Development, Study Design and Protocol, Appendices, Deliverable D Subject The topic of the resource Women Vietnam Veterans Health Study PTSD congenital birth defects VA ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/3d65f5f778163ad86ac725d0cfa113b9.pdf 6defcc309622f23b4d558c2074923644 PDF Text Text Item ID Number 0185 Author McKinlay, Sonja M. Corporate Author ^ew England Research Institute, Inc., Watertown, Mass RBDOrt/ArOClO TltlO ° Women s ' Vietnam Veterans Health Study Protocol Development, Study Design and Protocol, Deliverable D Journal/Book Title Year 000 ° Month/Day Color n Number of Images 98 DeSCrlptOfl Notes Contract No. V101(93)P-1138; includes handwritten margin notes. Wednesday, July 11, 2001 Page 1851 of 1870 �WOMEN VIETNAM VETERANS HEALTH STUDY PROTOCOL DEVELOPMENT CONTRACT NO. V101(93)P-1138 STUDY DESIGN AND PROTOCOL DELIVERABLE D SUBMITTED BY NEW ENGLAND.RESEARCH INSTITUTE PRINCIPAL INVESTIGATOR SONJA M. MCKINLAY, PH.D NEW ENGLAND RESEARCH INSTITUTE, INC! 42 Pleasant Street Watertown, Massachusetts 02172 (617)923-7747 �TABLE OF CONTENTS INTRODUCTION 1 SECTION 1: BACKGROUND 2 SECTION 2 : STUDY APPROACH 3 2.1 3 2.1.1 Historical Cohort Study 3 2.1.2 Case/Control Study of Reproductive Outcomes 8 2.1.3 Sub-Study of Post Traumatic Stress Disorder 11 2.1.4 Validation Sub-Studies 2 .2 DESCRIPTION OF THE STUDY DESIGN 12 RATIONALE FOR THE PROPOSED DESIGN 17 2.2.1 Historical Cohort Design 17 2.2.2 Case/Control Study of Reproductive Outcomes 18 2.2.3 Case/Control Study of Cancers 18 2.2.4 Sub-Study of PTSD 19 2.2.5 Cell-Mediated Immune Function Sub-Study 19 2.2.6 Validation Sub-Studies 20 SECTION 3: VARIABLES 21 3 .1 EXPOSURE VARIABLES 21 3 .2 OUTCOME VARIABLES 24 3. 3 CONFOUNDING VARIABLES 26 SECTION 4 : HYPOTHESES 28 SECTION 5: ELIGIBLE POPULATION AND SAMPLING FRAMES 31 5.1 POPULATION DEFINITION 31 5. 2 SAMPLING FRAMES 32 �SECTION 6: SAMPLES SIZES 40 6.1 ASSUMPTIONS 40 6.2 RESPONSE RATES 40 6. 3 OUTCOME RATES 43 6.4 SUB-STUDY SAMPLE SIZES 44 6.4.1 Reproductive Outcome Study 44 6.4.2 PTSD Sub-Study 46 6.4.3 Nurses Sub-Study 49 6.4.4 Validation Sub-Studies 50 SAMPLE SIZE ADEQUACY 52 6.5 SECTION 7: DATA COLLECTION 7 .1 53 53 7.1.1 Full Cohort Study 53 7.1.2 Reproductive Outcome Study 56 7.1.3 PTSD Sub-Study 57 7.1.4 Validation Studies 58 7.1.5 Rationale for Individual In-Person Measurement 60 7.1.6 Special Issues in Data Collection 7.2 STRATEGIES 60 QUALITY CONTROL AND DATA MANAGEMENT 61 SECTION 8: ANALYSIS 64 8.1 FULL COHORT STUDY OF VE EXPOSURE 64 8.2 REPRODUCTIVE OUTCOME CASE/CONTROL STUDY 65 8.3 PTSD SUB-STUDY 66 8.4 NURSES SUB-STUDY 68 8. 5 VALIDATION SUB-STUDIES 70 8. 6 COMPARISON WITH OTHER DATA SETS 70 �SECTION 9: HUMAN SUBJECTS 9 .1 72 INFORMED CONSENT 72 9.1.1 Verbal Consent 73 9.1.2 Access to Medical Records 73 9.1.3 Consent to In-Person Measurement 74 9.1.4 Consent for Offspring Examination 76 9. 2 CONFIDENTIALITY 76 9. 3 REPORTS TO RESPONDENTS 77 SECTION 10: SCHEDULE AND WORK LOAD 79 10.1 TASKS 79 10.2 SCHEDULE 82 10. 3 WORKLOAD 84 10. 4 ORGANIZATION 84 SECTION 11: UNRESOLVED ISSUES 88 BIBLIOGRAPHY 92 �TABLES AND FIGURES TABLE 1 •TABLE 2 SUMMARY OF SPECIFIC HYPOTHESES 30 ELIGIBILITY FOR VIETNAM SERVICE RIBBON 33 TABLE 3 CONTROL SAMPLE NUMBERS FOR THE VA MORTALITY STUDY.. 36 TABLE 4 ESTIMATED RATES FOR SELECTED HEALTH AND REPRODUCTIVE OUTCOMES 41 EXPECTED SAMPLE SIZES FOR THE ENTIRE STUDY AND NURSES SUB-STUDY (ARMY NURSES ONLY) 45 COEFFICIENTS OF VARIATION FOR SELECTED VALUES OF cx' AND [3 , ASSUMING A TWO-SIDED TEST 47 SMALLEST DETECTABLE RELATIVE RISK (GREATER THAN 1) FOR c< = .05 (TWO-SIDED), VARYING SAMPLE SIZE, AND 51 TABLE 8 DATA COLLECTION WORKLOAD 85 FIGURE 1 OVERLAP OF MORTALITY STUDY AND PROPOSED STUDY SAMPLES 38 SCHEDULE OF TASKS 83 TABLE 5 TABLE 6 TABLE 7 FIGURE 2 �INTRODUCTION This document describes and justifies a proposed design and protocol for the study of women Vietnam veterans. Following a brief overview of the background to this study (Section 1), the general approach is outlined and justified (Section 2). Section 3 then presents the major variables for exposure, outcome and confounding effects, including a discussion of measurement approaches. The hypotheses relating these variables are specified in Section 4, while Section 5 describes and justifies the populations and sample sizes selected for the study. Section 6 then documents the adequacy of the proposed sample sizes to detect and estimate the smallest Relative Risks corresponding to each hypothesis. Section 7 outlines the proposed data collection strategy, including quality control and data management requirements. Section 8 outlines the analytic approaches required to address the hypotheses specified in Section 4, while Section 9 presents human subjects protection requirements, in terms of informed consent and confidentiality. Section 10 proposes a schedule for implementing the study, including set up of data management systems, staff recruitment and training, data collection, processing and analysis as well as estimated effort and project organization. A final Section 11 outlines some unresolved issues as of June, 1987 which may affect aspects of this design and protocol. �1. BACKGROUND A comprehensive literature review, conducted in preparation for this study, has indicated clearly that there is a need for this congressionally mandated investigation of the impact of the Vietnam Experience (VE) for women in the military. Women have served in other wars this century, primarily as nurses. In this role they have been wounded and killed by enemy fire, lived under similar conditions to combat troops and have been held as prisoners of war. Yet no study of the impact of this experience on these women has yet been conducted. The Vietnam Experience was similar to prior war experiences for nurses with respect to: risk of injury or death; exposure to tropical diseases and the prophylactics or preventatives to combat them (drugs, repellent sprays, insecticides); difficult, primitive living and working conditions; and the lack of public acceptance of the valid contribution of such women to the war effort. The Vietnam Experience was (at least potentially) different from prior war situations in: the use of phenoxy herbicides as defoliants; lack of a definable front-line and constant presence of the Viet Cong in or near U.S. installations; lack of a clearly articulated rationale for the presence of U.S. troops in Vietnam and the concommitant lack of public support in the U.S.; and the fact that this largely guerilla action fought over several years, was never officially declared a war, which was won or lost. Exposure to any of these aspects of the Vietnam conflict (singly or in combination) constitutes a unique "Vietnam Experience," the effects of which, in terms of subsequent physical and mental health are to be assessed in this study. �2. STUDY APPROACH 2.1 DESCRIPTION OF THE STUDY DESIGN Four components are proposed for the study design. They are: Historical Cohort Study; Case/Control Study of Reproductive Outcomes; Sub-study of Post Traumatic Stress Disorder (PTSD); and Validation Sub-studies. Each of these is described in the following subsections. 2.1.1 Historical Cohort Study The proposed study has a basic historical cohort design with two cohorts, one exposed to the Vietnam Experience (Cohort A) and one not exposed (Cohort B). This design is similar to a prospective observational study, in that comparison groups are defined on exposure, but both exposure and outcome occur before the point of data collection. For each cohort, several outcomes will be included, in the areas of general health, reproductive function (normal cyclic function in the absence of conception) and reproductive outcomes. The exact variables proposed (exposure, outcome �and potential confounding factors) are described in detail in the following section. Included in Cohort A will be all women in the Armed Services (Army, Air Force, Navy and Marines) who served in Vietnam (See Section 5 below for a definition). This group consisted primarily of nurses (approximately 85%), other line officers and some enlisted personnel (about 15%, combined). An equivalent sample of women in the Armed Services who did not serve in Vietnam, frequency matched on service, and occupation with Cohort A will constitute Cohort B. These Vietnam-era veterans were eligible for Vietnam service but did not actually serve in Vietnam. Variations to this basic cohort study are also proposed, defined by the inclusion or exclusion of selected cohort members. These variations will produce four primary data sets for analysis as described below. Data Set 1 (Entire Cohort). This will comprise all eligible members of Cohorts A and B, including those who died subsequent to the exposure period of service on which eligibility is defined. Deceased participants (approximately 100 expected in each cohort) are included in this data set for analyses of outcomes which could result in death (e.g., heart disease, selected cancers, attempted suicide, alcohol consumption). Because key exposure and confounding information may not be obtainable from proxy interviews for deceased participants, it is recognized that this data set will be used for a limited range of analyses. �Data Set 2 (Entire Live Cohort) This data set is equivalent to Data Set 1, but excludes deceased members. Because information is expected to be complete for this set, this is the data set on which the majority of analyses addressing the overall impact of VE on military women will be based. Data Set 3 (Nurses Sub-Study) Although this is a study assessing the effects of VE in women veterans the cohorts are very skewed in terms of VE exposure, both by service and by occupation. Approximately 80% of all women in Cohort A served in the Army and about 85% of these were nurses of officer rank. In other words, 0Ut 70% Of all WOmen l-fJuTIMl VP^*"*8"*8 Maya a-rwy Other line officers and enlisted personnel, in all the Services, were few in number and primarily in support occupations in or near Ho Chi Minh City (formerly Saigon). Their exposure to the various elements of VE was, therefore different from nurses in field hospitals. Nurses in the Air Force and Navy were distinct from Army nurses in at least the following major respects: • These nurses were more likely to be career military and therefore older and more likely to remain in active service for several years after the war; 1 Unlike Army nurses, these women had to serve a full tour of duty (one year) before overseas assignment; Navy nurses worked in stable teams and were not exposed to phenoxy herbicides or combat, except at �the on-shore base at Da Nang, relatively late in the period; Air Force nurses were minimally exposed to phenoxy herbicides and to the trauma of dealing with major wounds, as they were on evacuation flights, but worked essentially alone with considerable responsibility. Army nurses were assigned individually to hospital units on an as needed basis, were typically within one year of graduation from nursing school (except for the relatively few senior officers, mostly veterans of World War II or the Korean Conflict), were least likely to remain in a military career, and were most exposed to "in country" combat areas and other related trauma. This is, therefore, a relatively homogeneous group with respect to age, education and VE exposure and comprises the majority of Cohort A. The equivalent group in Cohort B was variably exposed to the trauma of nursing wounded veterans, who were evacuated from Vietnam, usually within a few days. In contrast to their Vietnam veteran counterparts, they were exposed to the extraordinary nursing demands of major sepsis of all wounds and to the emotional problems of readjustment experienced by the wounded veterans. It is important to note that this unique nursing exposure was also experienced by many Vietnam veteran nurses from Cohort A, either before or after their Vietnam tour of duty and is therefore not unique to Cohort B members. Because of the varying degrees of exposure to nursing of the wounded veterans experienced by nurses in Cohort B, it is therefore proposed to include a third cohort of nurses not exposed to either VE fiE the nursing of recovering �wounded veterans. The cohort proposed is the subset of Air Force nurses included in Cohort B, who did not nurse wounded veterans and were not Flight nurses. This sub-group will include almost all Air Force nurses in the cohort as comparatively few Air Force personnel were wounded and returned to CONUS Air Force hospitals. Moreover, any wounded Air Force veterans were nursed separately in Casualty Staging Units, primarily by corpsraen. Nurses had little contact with these patients in the Air Force CONUS hospitals until they were relatively recovered. This data set will therefore consist of three comparison cohorts (including subsequently deceased members) : V, *P Vietnam veteran Army Nurses only from Cohort A (5>. Vietnam-era Army Nurses from Cohort B Vietnam-era Air Force Nurses (excluding those who nursed wounded veterans) , from Cohort B. Some age and/or nursing service adjustments in either sampling for the third cohort oj: analysis will be required to reduce any age and nursing service differences between Army and Air Force personnel. Data Set 4 (Live Nurses Sub-Study) This data set is equivalent to Data Set 3 but excludes those nurses who died after the exposure period (as in Data Set 2). This data set will be the basis for most of the analyses addressing the effects of combat-related stress. �The Air Force nurses will serve as a control group, subject to the routine stresses of a military nurse. The Cohort B Army nurses will serve as an intermediate group variably exposed to additional stresses of caring for wounded veterans during recovery. The Cohort A Army nurses were all exposed to VE and variably to the caring of wounded veterans during recovery. 2.1.2 Case/Control Study of Reproductive Outcomes An increased rate of adverse reproductive outcomes (including congenital abnormality and spontaneous abortion) has been associated with exposure to the dioxin TCDD in animals, and with exposure to phenoxy herbicides and/or to TCDD (the highly toxic contaminant in the production of the phenoxy herbicide 2,4,5-T and hexachlorophene) in humans (see Literature Review). Less than one percent of live births in a general population will produce a major diagnosed congenital abnormality, while multiple spontaneous abortions are likely to occur in less than 3% of fertile women given a 15% rate for a single conception (Kline et al, 1981). Spontaneous abortion is defined here as loss in less than 20 weeks gestation. These reproductive outcomes are, therefore, relatively rare. This sub-study will investigate the set of hypotheses relating TCDD exposure to subsequent adverse reproductive outcomes: that rates of major congenital malformation and multiple spontaneous abortion will be higher in the exposed cohort (HPF, HpL in Table 1, Section 4, below). Cases will be defined as all women (from Cohort A) who are alive at the time of study and either report at least one pregnancy resulting in a congenital abnormality; or. �report two or more spontaneous abortions not clearly attributable to an identified cause. Excluded causes are: • Unequivocal karyotypic abnormality; • Uterine abnormality (fibroid tumors; other intrauterine pathology; congenital, Mullerian anomalies). All remaining causes of repeat spontaneous abortion will be included as cases. Possible causes included in this group are: Lupus anticoagulant, immunologic abnormalities, luteal phase insufficiency, hypothyroid abnormality, DES exposure, maternal diabetes, and recurrent infection. Controls also from Cohort A, will be pair-matched on the following variables: • maternal age at birth for the index pregnancy resulting in abnormality (or for the first such pregnancy in the case of multiple abnormalities) or maternal age at first spontaneous abortion; and • order of the index birth/pregnancy (first or subsequent); For example, if a participant in her second child, born when she matched control will have at least the second child born when she was has a major abnormality was 28, then an ideally two live children, with also 28. In practice, an age match within five year age ranges will be adequate for women aged < 35 years at the time of the index birth or fetal loss. For women aged > 35 at the event, matches will be sought within 2 year ranges to accommodate the rapidly escalating risk of a fetal �abnormality beyond this age (NCHS, 1978). Age ranges within which a match will be defined are: 15 20 25 30 35 37 3 9 41 43 - 19 years at last birthday - 24 - 29 - 34 - 36 - 38 - 4 0 - 42 - 44 etc. Birth order is included as the other variable known to affect the rate of abnormality (NCHS, 1978). The major difference in rates is between first and subsequent live births. Matching will be on first or subsequent birth with exact matching on birth order only if the pool of potential matches is sufficient. There will be no additional matching for cases of spontaneous abortion. Matching on parity, gravidity or any other potential confounder, such as paternal exposure to TCOD is not considered, to avoid over-matching and the problems of unmatchables (McKinlay, 1974; Schlesselman, 1982). Measurements will include blood (serum) TCDD determinations on all cases and controls. Currently, the half life of TCDD in human tissue is being investigated on the Ranch Hand II Study. Depending on the results of this investigation, it may be possible to extrapolate from current TCDD body burdens to the TCDD level at the date of the index pregnancy to provide an estimate of TCDD exposure at the time of conception. 10 �2.1.3 Sub-Study of Post Traumatic Stress Disorder The extent to which PTSD may be related to other neurobehavioral problems and/or phenoxy herbicide exposure is not clear from research to date, although PTSD has been related to war stress among male veterans of the Vietnam conflict as well as of prior wars, albeit under other labels (see Literature Review) . A sub-study is therefore proposed, within Data Set 4, of live Army nurses, to investigate these relationships. Equal samples of Army nurses will be randomly selected from the following five groups: 1. Cohort A, classified with acute PTSD from the quesionnaire; 2. Cohort A, classified with delayed PTSD from the questionnaire ; 3. Cohort A, classified with chronic PTSD from the questionnaire ; 4. Cohort A, with no evidence of PTSD from the questionnaire; and 5. Cohort B, with no evidence of PTSD from the questionnaire ; Each will be eligible for an extensive battery of memory and related neurobehavioral tests as well as determinations . Army nurses are proposed as subjects from Cohorts A and B because of their uniformly high level of educational attainment (required for several tests) as well as for their relative homogeneity of socio-economic background. This group is also, a priori, more likely to be exposed to phenoxy herbicides, hexachlorophene and/or war-related stressors than other women veterans. 11 �2.1.4 Validation Sub-Studies Because the majority of the data collected will be by interview (or self-administered questionnaire), and therefore self-reported, several key items will require independent validation. This is particularly true of items relating to the index service period (up to 24 years earlier, assuming data collection in 1988-89). The following validation studies are proposed, based on currently available knowledge. One or more may be deleted or replaced, depending on the results of on-going research. Six such studies are briefly described below. (a) Reproductive Outcomes Both reported congenital abnormalities and reported multiple spontaneous abortions will be verified, wherever possible, by independent (blind) abstraction of medical records and pathology reports. Participants will be asked to identify hospital or physician records most likely to document the abnormality, diagnosis or spontaneous abortion, and written releases will be obtained for future acquisition of the record. This will be attempted for all cases in the case/control study of reproductive outcomes. It is recognized that access may be refused by some participants, while others may not remember where records exist. For still other cases, the records may no longer be available (a hospital may have closed or may no longer retain records; a physician may have died, moved or destroyed old records). Additionally, for all live, accessible offspring, a pediatric examination is proposed, following the protocol used on the Ranch Hand Study, for both cases and controls in the case/control study of reproductive outcomes (see 12 �Appendix). This examination will be performed by a single pediatric neurologist or physician qualified in an equivalent specialty and trained to perform the examination blind to the participant's self-reported status. This is considered feasible, given the relatively small number of families involved, over a two year period. If there is 90% agreement or better between the participant's self-report and the examination or medical record documentation (where available), then all cases will be included based on self-report. If the agreement is less than 90%, then only those cases verified by at least one independent data source will be included as cases. (b) Validation of Selected Disease Diagnoses The following diagnoses will be verified by independent (blind) abstraction of appropriate medical records: • soft-tissue sarcomas (STS). liver cancers, nonHodqkin's lymphoma. Hodgkin's Disease and any other cancer of an internal organ likely to be misclassified when it is actually STS (Percy et al, 1981). For each of these cancers, copies of the hospital record, pathology report and the slides themselves will be requested for validation, following protocols already developed (See Appendix). Only verified cases will be included. • myocardial infarction, sudden death, cerebrovascular accident. For these outcomes, medical records will be requested, including EC6 tracings, CK (and CK-MB) enzyme determinations. In the case of sudden death (which generally occurs out of hospital) an interview with next-of-kin may be required. Protocols for this validation have already been well 13 �developed by projects funded by the National Heart, Lung, and Blood Institute (see Appendix). Only verified cases will be included. • randomly-selected sample of reported cases of breast cancer, benign breast tumors or cysts, cervical or endometrial uterine cancer, endometriosis, fibroids or ovarian tumor (benign, malignant gy other cyst). Agreement between self-report and medical record in this sample of 90% or better will result in acceptance of all self-reported cases. If a lower rate of agreement is obtained, then the possibility will be considered, funds permitting, of verifying all cases and including only verified cases in analysis. Surgical notes will also be used to verify endometriosis, where available. • randomly selected sample of reported cases of depression or related psychiatric diagnoses (including PTSD). For a sample of these selfreported cases, records will be obtained from a hospital, physician or psychologist making the diagnosis. As above, if agreement is 90% or better, all self-reports will be included. If less than 90%, all cases may require validation for inclusion in analysis. Even for those diagnoses to be sampled for verification, it is proposed that written release (and possibly a copy of the record itself) be obtained for all reported diagnoses, in anticipation of possible further study. Also, where regular hospital records may no longer be available, key laboratory reports (pathology, ECG, enzymes, etc.) may be accessible in the original, which is usually independently filed by the department or laboratory responsible, and retained over longer periods. 14 �(c) Validation of Other Health Events Apart from key diagnoses, certain events and surgical procedures will also require validation. • jtysterectomy/Oopherectomy; medical records and (where available) pathology reports will be reviewed for a sample of surgeries reported to involve removal of the uterus, with or without removal of at least one ovary. As above, the 90% agreement criterion will be used to determine inclusion of cases. • Prolonged amenorrhea (12 consecutive months) with no obvious cause (e.g., pregnancy and/or lactation) in women under 40 years will result in a check of hormone levels for all cases, especially gonadotropins from two venous blood samples of at least 5 ml of whole blood each, drawn 20-30 minutes apart, using a standardized kit, and obtained between 7:00 am and 10:00 am. Elevation of FSH in particular (> 30 mlU) is an indicator of permanent ovarian failure (as in natural menopause). • Attempted Suicide will be verified from hospital records, where available. • Tropical Diseases will be verified for a sample of nurses in Cohort A by comparing with the Chief Nurse's Monthly Report (where available). The 90% criterion for inclusion of all self-reports will be used. 15 �(d) Validation of Phenoxv Herbicide Exposure Based on the pending results of the CDC validation studies, an index of exposure may be constructed on the basis of the "Service Herbs" tapes for all Vietnam veterans in Cohort A. Minimally exposed groups include Navy and Air Force Nurses as well as line officers and enlisted personnel who were based primarily in or near Ho Chi Minn City. Most vulnerable to exposure were Army nurses. If an index is constructed for potential analysis, then the subgroups on which TCDD body burden is determined will provide validation of that index. The criterion for determining validity (magnitude of correlation) will be determined using CDC results. Validation of VA Lists for Cohorts A and B (Data Set 1 The completeness of these lists to be used as the sample list for the proposed study (see Section 5 below), will be determined by asking each participant to name one other woman serving with them: • For Cohort A, during their (longest) Vietnam tour; and • For Cohort B, during a sampled tour of duty in the exposure period. This name will then be checked against the Cohort A list (for Cohort A) or against the appropriate morning report (for the Army), computerized personnel files (Air Force, Navy and Marines), and/or the Cohort B listing (for Cohort B). 16 �This approach is a simple capture-recapture experiment, with the list of names reported by participants as the initial "marked" sample, and the lists within which these names should appear as the second "mixed" sample. List completeness will be estimated directly as the proportion of the "marked" names successfully matched (see, for example, Seber, 1973). The success of this estimation method will of course depend on the memories of participants, completeness of existing lists (such as morning reports) and the availability of sufficient information on each "marked" sample name to ensure an accurate match. Only one name will be solicited to reduce the impact of recall bias among subjects on the probability of name selection. This important validation study is proposed as a substitute for the originally specified Pilot Study in the Planning Contract No. V101(93)P-1138. This task was deleted from the initial contract because of problems of feasibility and overlap with activities in the concurrent mortality study being conducted by the VA. 2.2 RATIONALE FOR THE PROPOSED DESIGN This section reviews the issues considered in selecting the four components of the study design described above. 2.2.1 Historical Cohort Design This design has already been used in CDC's major VE exposure study which is on-going (CDC, 1987). It is the most appropriate design for a study of women veterans as VE (the primary exposure) is clearly defined but the important 17 �outcomes are uncertain. It is this uncertainty of several health and reproductive outcomes in women which has been a major motivation for the study. An alternative case/control design would only be appropriate if a single, salient outcome had been identified for specific study. 2.2.2 Case/Control Study of Reproductive Outcomes This small case/control study is included because the potential impact of phenoxy herbicide/dioxin exposure on women has not yet been investigated using reliable methodologies (as documented in the Literature Review). At the same time/ there is suggestive evidence that increased incidence of these major outcomes may be related to such exposure in women (See Table 3, p.60 of the Literature Review). The expected number of cases (see Section 6 below) is sufficiently small and the exposure measurement (TCDD blood sample determination) sufficiently expensive to obtain, that such a case/control study is clearly the design of choice for this limited set of hypotheses. 2.2.3 Case/Control Study of Cancers An equivalent case/control study of selected cancers was also considered and rejected for at least the following reasons: • the number of cases of clearly relevant cancers (STS, Hodgkin's Disease, Non-Hodgkin's Lymphoma) would be marginally sufficient for sttiayr"as less than two cases of STS are expected/across both cohorts and less than 30 cases of HD or NHL are expected, based on SEER registry rates (NCI, 1987) see Table 4 below; 18 �there is no clear rationale for including other cancers as potential outcomes of VE exposure; even if sufficient numbers of cases were available, several may be deceased or too ill for further study; exposure to chemotherapy and/or radiation therapy in many cases will have compromised the immune system; and cancer treatment and/or the disease itself may have resulted in such a depletion of adipose tissue in some cases that TCDD determinations will not be feasible (even if the subject was well enough for the sampling of a unit of blood). 2.2.4 Sub-Study of PTSD This is proposed for a sub-group of women in Cohort A (and B) who are not included in the case/control study of reproductive outcomes. The motivation for this study is to investigate whether or not PTSD (as diagnosed from interview) is related to neuro-behavioral function and/or to phenoxy herbicide/dioxin exposure. 2.2.5 Cell-Mediated Immune Function Sub-Study Following the suggestive findings of Hoffman et al., (1986) on residents of a trailer park on TCDD contaminated ground, and animal study results, (see Literature Review) inclusion of immune function tests in the cancer case/control study was proposed. The hypothesis was that cell-mediated immune function would be compromised in those 19 �highly exposed to TCDD and would increase the risk of subsequent cancer development. With deletion of the cancer case/control study, this hypothesis could no longer be tested in the proposed study design. However, if the TCDD values obtained in the two proposed sub-studies of reproductive outcomes and PTSD are sufficiently varied to indicate a relatively wide range of exposures, the possibility of performing appropriate immune function tests on these women may be considered later in the study, time and funds permitting. There is insufficient evidence of a strong association to justify a costly substudy of immune function at this point. 2.2.6 Validation Sub-Studies As a general principle in any study, given heavy reliance on self-report, validation sub-studies should always be included. Such studies are particularly important for the proposed investigation because: • recall is required over the entire period of adult life and in particular the period since Vietnam exposure (up to 24 years); • the political climate in which this study will be conducted makes it particularly vulnerable to reporting bias (subjects will over- or underemphasize certain symptoms, behaviors, events); and • the fact that this is the first such study of women veterans, and the cohorts will consist of entire populations of certain groups or relatively large samples of others, implies a need to complete as comprehensive and thorough a study as possible at this time. 20 �3. VARIABLES This section describes the major (groups of) variables to be included in study hypotheses. The two primary groups of variables are: exposure and outcome. A third group of potential confounding variables will also be considered briefly. 3.1 EXPOSURE VARIABLES As specified in the original RFP for the current planning and development contract, the primary exposure of interest in this study is: exposure to the "Vietnam Experience" This general exposure includes variable exposure to any of the following elements for women veterans; • phenoxy herbicides; • insecticides; • prophylactic drugs, repellents etc. to combat tropical diseases; • combat (confrontation with the enemy); • pervasively vulnerable and primitive living conditions associated with serving in Vietnam; and • difficult demobilization in an (increasingly) hostile political climate in which this action was fought. 21 �Clearly, not all women military serving in Vietnam will have been exposed to all of the above elements. At the same time, some of these elements will have been different enough from prior or subsequent experience to qualify as "unique". Apart from considering this total experience as a single, invariant exposure, some limited measurement of individual elements of this exposure are proposed. (a) Phenoxy Herbicide Exposure Based on the on-going Agent Orange study being conducted by CDC, an index of probable exposure could be constructed, using information on assignments and movements of women from such sources, as morning reports, Chief Nurses' Monthly Reports and self-reported recall in combination with, primarily, Service Herbs tapes of perimeter and other ground spraying operations. Because of wide-spread, incomplete or missing data, primarily in reports of perimeter sprayings (Report of the Agent Orange Working Group Science Subpanel on Exposure Assessment, 6/3/86), construction of such an index is not proposed for this study, at this time. Alternatively, as a validation of exposure, TCDD body burdens will be measured on sub-samples of Vietnam veterans, as this is a contaminant of concern in the production of the phenoxy acid 2,4,5-T, the most widely used phenoxy herbicide in Vietnam. These measurements will be made in the two substudies proposed (of reproductive outcomes and PTSD). 22 �(b) Insecticides Although the exposure to insecticide spraying is insufficiently documented for reliable inclusion in this study, participants will be asked to recall the use of skin repellents during their Vietnam tour. Details on type of repellent or frequency of use will not be obtained as recall of this information is unreliable up to 25 years later. (c) Tropical Diseases Illness due to such diseases among nurses was documented in the Chief Nurses' Monthly Reports which will provide a validation of participant recall for nurses. (d) Prophylactic Drugs Anti-malarials (Chloraquine-Primaquine and Dapsone) were routinely prescribed but not generally taken because of the frequently severe side effects of gastric upset (stomach cramps, diarrhea). Self-report of use will be the measurement included. (e) Combat/Contact with the Enemy This measure will include care of Viet Cong and North Vietnamese casualties, exposure to direct rocket/mortar fire or other enemy attack and service before/after the TET offensive. To the extent available, the first two exposures will be validated from the Chief Nurses' Monthly Report, which is likely to include such information. This exposure applies primarily to nurses. 23 �(f) Workload (nurses onlvl The volume of casualties per day, divided by the number of nursing staff (including corpsmen) per shift will be used to construct an index of (potentially stressful) workload for veteran nurses. Such data are provided in the Chief Nurses' Monthly Report, which will be used directly with Data Sets 3 and 4 (described above) for Vietnam veterans. Reports from CONUS hospitals will be used for nurses in Cohort B. 3.2 OUTCOME VARIABLES The original RFP specified the following categories of health outcomes: • general physical health; • general mental health; • reproductive function;and • specific reproductive outcomes. \ Each of these categories is addressed below. (a) General Physical Health will be assessed primarily by considering all major disease diagnoses including cancers and hospitalizations or other institutionalizations (e.g., rehabilitation facility) for physical complaints in the study period. Excluded here are elective hospitalizations for procedures such as elective abortions, tubal ligation or 24 �tooth removal which are not the direct result of an acute health problem. Selected diagnoses and other events will be validated as described in Section 2 above. Women with births resulting in congenital abnormality may be more likely to have tubal ligation and likely to have it earlier than other women. However, as an elective procedure for contraceptive purposes, this surgery, as well as elective abortions, would not be included as a major health outcome. Additionally, current health and prescription drug use will be assessed. (b) General Mental Health is similarly defined as all major psychiatric diagnoses, (including PTSD) hospitalizations and institutionalizations for mental health problems-in the study period. Aspects of status to be assessed from the questionnaire will include presence of (delayed/chronic) post-traumatic stress disorder (PTSD), history of acute/delayed PTSD, depression and general mood state. Neurobehavioral assessments of mental functioning will be conducted in the PTSD sub-study. Indirect measures of mental health (adjustment) will also be assessed from the questionnaire, including: alcohol and other drug consumption; arrests for driving under the influence of alcohol; family problems; job history; and marital history. (c) Reproductive Functioning includes menstrual history (menarche, menopause, regularity, flow, fertility, and prolonged amenorrhea). These aspects of health will be assessed from the onset of menarche. 25 �(d) Reproductive Outcomes will be assessed from a complete pregnancy history, including all recognized fetal loss (spontaneous and induced), still births, reasons for fetal loss or still births (including fetal abnormality), and live births. For all live births, major congenital abnormalities will be documented. It is important here to distinguish between aspects of health related to reproductive function (reproductive health) and outcomes of reproduction which are, by definition, outcomes of conception (pregnancies). Reproductive outcomes may have an impact on maternal health, but are themselves not health outcomes. 3.3 CONFOUNDING VARIABLES In planning an observational study, all known risk factors for specific outcomes should be considered potential confounders, with actual confounding status to be determined in the analysis. The potential confounders included here are not an exhaustive list of candidate variables, but rather indicate the types of variables to be considered. For example, personal lifestyle characteristics will include such key variables as: smoking, alcohol use, other recreational drug use (including marijuana, cocaine), and other drugs not for specificmedical indication (including oral contraceptives in particular). This category could also include such dietary supplements as vitamins. Environmental characteristics will include residential or occupational toxic exposures, other occupational exposure (to stress, for example) and (for reproductive outcomes) 26 �paternal toxic exposures. This category will also include exposure to the medical care system (in terms of the .rpi«anr«Y r»f iit-jlization of medical services) . This last variable is of particular importance in interview studies relying heavily on self -reported data for aspects of health. Those who use the medical care system more frequently are more likely to have conditions diagnosed and treated (McKinlay and McKinlay, 1986; Roos, 1983). Moreover, it is plausible that utilization rates will vary by exposure to service in Vietnam (especially given the increasing public interest in the health consequences of this experience) . For nurses, this category will also include important chemical exposures, particularly hexachlorophene which was widely used until the late 1970 's and anesthetic gas exposure. The third important set of potential confounding variables are socio-demographic. For example, date of birth, which is probably associated with exposure severity (in terms of pre- or post- TET offensive service), also determines risks to certain outcomes (such as number of pregnancies, or certain cancers). Similarly race, educational attainment and related socio-economic indicators may be associated with differing exposure and/or outcome. Because some of these factors pre-date military service, they may not be confounders as defined above. Rather they may be external variables which determine (are causally related to) exposure variables and thence to outcomes, but have no direct association with outcomes. It is appropriate to include these variables as potential confounders in the proposed study design. 27 �4. HYPOTHESES The following can be stated as the basic hypothesis of the proposed study (in the null form): General Hypothesis (H0): That exposure to the Vietnam Experience (VE) has no subsequent effect on physical or mental health, reproductive function or reproductive outcomes in women veterans, followed for up to 24 years after exposure. Specific hypotheses can then be considered in two groups: • those hypotheses relating VE to specific outcomes; and • those hypotheses relating elements of VE to specific outcomes - to be considered in sub-studies only. These hypotheses are summarized in Table 1. Each column of this table represents an exposure element, with the first column representing the total VE exposure. Each row then corresponds to a specific set of outcomes. Each cell entry corresponds to the hypothesis so formed with the exposure subscript listed first. For example Hy^ can be specified as: That exposure to VE has not resulted in an increased rate of menstrual disorders. 28 �It is anticipated that the proposed study design will allow testing of all hypotheses relating to the general VE exposure (all with subscript V). The power to detect small relative risks of certain outcomes (e.g., specific cancers) may not be adequate. This is discussed further in Section 6 below. The hypotheses relating to Phenoxy Herbicide exposure (P) will only be tested in the Case/Control Study of Reproductive Outcomes (HpF and Hpl\ and in the sub-study of PTSD (HpN and Hps). Finally, hypotheses relating exposure to the wounded veterans (W) to health outcomes will only be considered for Data Sets 3 and 4. Moreover, it should be noted that Army nurses in Cohort B were also exposed to this element to varying degrees. Therefore, a third comparison group of no exposure, consisting of comparable Air Force nurses in Cohort B is included. Hypotheses in this column will compare all three groups in two stages as follows: Stage 1; Army nurses exposed to wounded veterans, regardless of Vietnam service, will be no different in outcome from Air Force nurses not exposed to war wounded. Stage 2; Among Army nurses exposed to wounded veterans, differences in outcome are related (if at all) to degree of exposure, ipdependentlv of Vietnam service. 29 �TABLE 1 SUMMARY OF SPECIFIC HYPOTHESES EXPOSURES OUTCOMES VIETNAM EXPERIENCE (V) PHENOXY<b) HERBICIDES/TCDD (P) EXPOSURE T WAR WOUNDED (W) GENERAL HEALTH • Cancers (C) Hvc H1WC • Cardio-vascular Disease (H) H1VH HWH • PTSD (acute/chronic/ delayed) (S) HVS HPS • Neuro-behavioral function (N) HPN • Accident/Suicide (attempted) (A) H•WS HVA H, WA • Infertility (I) » VI H, WI • Menstrual Disorder (M) H-VM H, WM REPRODUCTIVE FUNCTION REPRODUCTIVE OUTCOME • Fetal Loss (F) HVF HPF 1 H,WF • Congenital Abnormality in Live Born (L) HVL HPL H, WL (a) Assigned subscripts are indicated in parentheses for each variable. (b) This set of hypotheses will be addressed only for the subsamples measured for TCDD body burden depending on the pending CDC results. (c) This set of hypotheses will be addressed in Data Sets 3 and 4 (Nurses only, three comparison groups in Nurses Sub -study). (d) Measured in sub-study of PTSD only. 30 �5. ELIGIBLE POPULATION AND SAMPLING FRAMES 5.1 POPULATION DEFINITION This study involves the comparison of two basic groups of women military personnel: • the Exposed Group - those who served in Vietnam (Vietnam Veterans); and • the Non-Exposed Group - those who were eligible to serve in Vietnam at the same time but who did not (Vietnam-era veterans). Because service in Vietnam was acknowledged by the Armed Forces through the award of a special y^y--h-n«Tn ^jbbon. and eligibility for this award is specified on all military records (whether or not the ribbon was actually requested by the veteran), this award is used to define Vietnam veterans unambiguously. All those who served in Vietnam, its water, airspace, or in neighboring Thailand, Laos or Cambodia between July 3, 1965 and March 28, 1973 were eligible for this award. •.•. ... Apart from service "in country" in Vietnam, on evacuation flights, or on hospital ships (the u.s.S. Sanctuary and U.S.S. Repose1, the only other women military eligible for the award were a small number of primarily Air Force support personnel stationed in Thailand (estimated at approximately 100). This small group would be included in Data Sets 1 and 2 only. Another group, inclusion of which is also questionable, includes all women military personnel stationed in Guam, the Philippines and Japan. These women, as Vietnam-era veterans, 31 �are eligible for inclusion in the non-exposed group but were exposed to tropical diseases in these South West Pacific islands. The nurses in these stations were exposed to war wounded in first-line evacuation hospitals. After discussion, it was decided to include these women in the study as, apart from the tropical living conditions, their experience is not different from nurses in other hospitals on the evacuation routes from Vietnam and their living and working conditions were comparable to state-side assignments. Even if excluded for analysis from Data Sets 1 and 2, they certainly should be included in Data Sets 3 and 4. Finally, the few women military "advisors" - primarily nurses- serving in Vietnam before July 3, 1965 are excluded from the study. Their numbers were very small (estimated at less than 100 - see Holm, 1982), they were much less likely to be exposed to herbicide spraying or risks of rocket or mortar fire, and they were not exposed to the nursing work conditions experienced once the fighting began. Eligibility for service in Vietnam generally required that basic training and an initial tour of duty in the United States had been completed, although there were exceptions. Those who had not completed this in time to complete a minimum tour of duty in Vietnam to qualify for the Vietnam service award before March 28, 1973, are not eligible for the study. Table 2 summarizes these criteria. 5.2 SAMPLING FRAMES The obvious sampling frame for the population defined above would be a list of all women on active duty in the Armed Forces and eligible to serve in Vietnam in the period 32 �TABLE 2. ELIGIBILITY FOR VIETNAM SERVICE RIBBON Personnel Basic Training Length Enlisted 12 weeks Medical Officer Branch 5 weeks Latest Service Entry Date for Eligibility Various centers depending upon MOS 1/2/73 Fort Sam Houston Academy of Health Services 2/20/73 Fort Benjamin Harrison, Ind. 12/5/72 6 weeks Lackland A.F.B. 2/13/72 3 weeks Sheppard A.F.B. Wichita Falls Texas 3/6/72 Officer Candidate School 12 weeks Lackland A.F.B. 1/2/72 Enlisted 8 weeks Orlando, FL. 1/30/72 Medical Officer Army 4 weeks Newport , R.I. 3/13/72 16 weeks Newport, R.I. 12/5/71 Officer Candidate School u> Location * Air Force Enlisted Medical Officer * U.S. Navy Officer Candidate School 16 weeks * Dates reflect necessity to do one year CONUS tour of duty before overseas assignment by Air Force and Navy. �7/3/65 - 3/28/73. Such lists, however, only exist in accessible, computerized form for the Air Force, Navy and Marines, which together comprise a relatively small proportion (less than one third) of all women military personnel (Holm, 1982). No readily available listing of women serving in the Army is available. Rather, morning reports of the various units on active duty during the appropriate period must be screened for women assigned to them, and personnel records abstracted at the National Personnel Records Center in St. Louis, Missouri. Even then, current name, address and vital status (as of January 1987, say) will not be available from these sources. Alternative listings considered include: available lists of those completing training at the few training centers for women; and lists of those claiming a variety of veteran's benefits (educational, medical, pension) and current Reserve lists. The first type of list has the following major disadvantages: • these lists do not exist sufficiently far back in time to include all women seeing their first war-time service in the period 1965-1972; • they do not include women who were on the Reserve lists from World War II and Korea; • they do not include current (or recent) name and address; and • they are not computerized. The second type of lists will not include those still on active duty as of the start of the study (projected for 1988 - 1989). This proportion may be as high as 15%, although it 34 �is almost certainly decreasing rapidly up to 24 years after Vietnam-era service, as career military personnel reach retirement. Some advantages of these lists are: • computerization; • recent or current name and address; and • vital status. The primary disadvantage, however, which outweighs these advantages, is their lack of completeness (not all discharged veterans will have claimed educational or medical benefits). Finally, current reserve lists, although complete, may not be up-to-date with respect to vital status, current name and address. The labor required to obtain complete listings with current name, address and vital status is such that constructing a complete sampling frame is not feasible. Currently, the VA is conducting a mortality study of women Vietnam veterans for which they have nearly completed construction of a list of the approximately 5000 women Vietnam veterans, with current name, address and vital status, at least as of January 1, 1986. Work is just beginning on the sampling of computerized personnel lists and Army morning reports to construct an equivalent sample of Vietnam-era veterans. Given the costs of producing these lists, it is reasonable to use them to provide the basis for the proposed study sample. Because nurses were disproportionately assigned to Vietnam service, the sampling of Vietnam-era veterans is being frequency matched by service and personnel category to corresponding numbers of Vietnam veterans. Sampling fractions are therefore being adjusted to provide a Vietnam-era sample as similar to the Vietnam cohort as possible in terms of occupation and 35 �TABLE 3; CONTROL SAMPLE NUMBERS FOR THE VA MORTALITY STUDY ESTIMATED JUNE. 1986 BRANCH OF SERVICE TARGET SAMPLE OF ELIGIBLE CONTROLS ARMY Nurses Other Officers Enlisted Personnel AIR FORCE Nurses Other Officers Enlisted Personnel NAVY Nurses Other Officers INITIAL SAMPLE OF POTENTIAL CONTROLS 3800 4940 210 750 273 975 450 (500) 585 (1,000) 250 100 325 130 450 585 20 26 25 20 33 26 MARINES Officers (no nurses) Enlisted Personnel TOTAL 6,075 (6,575) 36 7,898 (8,898) �service distribution. In particular, almost all Vietnam-era Army Nurses will be sampled for the Mortality Study Comparison group and, therefore, for Cohort B of the proposed study. Estimates of eligible women required, in each service, as of June, 1986, are provided in Table 3, based on then available estimates of Vietnam veterans. Currently (June, 1987) the number of Vietnam veterans is approximately 5000, after removal of ineligibles (by year, gender) and duplicates (by name or from different branches of the service). The large initial sample of potential controls is inflated to compensate for losses from ineligibility, duplicates and untracables. Two points should be made concerning the sampling of the control group for the Mortality study. • The sampling period is 1964-1972 inclusive for the initial sample, with application of the dates 7/4/65 - 3/28/73 for period of service to define final eligibility. Personnel joining after 12/31/72 will not be eligible for inclusion. * Women who separated from the Air Force before July 1, 1969 were not sampled as their social security numbers were not available in the record. This item was required for tracing purposes. Approximately 34% of officer and 53% of enlisted records were not sampled for the three years 1966-1968 as a result. This will introduce a bias towards longer service in those sampled in years 1966-1968, as they had to be on active service as of July 1, 1969. Figure 1 diagrammatically represents overlap between those included in the Mortality Study and those eligible for 37 �FIGURE 1. CALITY STUDY AND PROPOSED STUDY SAMPLES (VIETNAM AND VIETNAM-ERA) MORTALITY STUDY INCLUDED Women not eligible according to Table 2, but on active duty through 12/31/72. PROPOSED STUDY Women eligible according to dates in Table 2, with Social Security, numbers and on active duty through 12/31/72 Supplementary sample of Air Force Nurses CONUS only* oo EXCLUDED Untraceables Air Force Personnel separating before 716 / / 9 and eligihles joining after 12/31/72 Duplicates and other ineligibles �the proposed study. Given the dates in Table 2, it is clear that all those eligible for the proposed study will be included in the Mortality Study sample, with the exception of the supplementary sample of Air Force Nurses for the third comparison group in the Nurses Sub-Study and a very few Army enlisted and nursing officer personnel. Not depicted in Figure 1 is the potential identification of women in the Mortality Study control group who are eligible as Vietnam veterans according to the proposed criteria even though they did not serve a full tour of duty in Vietnam. Crossover between Mortality study cohorts is expected for a few subjects, in defining cohorts for the proposed study. Current estimates of eligible women in each service, for the Vietnam and Vietnam-era groups in the Mortality Study are provided in Table 3. The sample of Vietnam-era Air Force nurses will be augmented by the number in parentheses for the proposed study (Cohort B), although they are not required for the Mortality study. Figure 1 provides a diagrammatic representation of how the defined Cohorts A and B for the proposed study overlap with the Mortality Study lists. 39 �6. SAMPLE SIZES 6.1. ASSUMPTIONS In calculating expected sample sizes and assessing their adequacy to detect relative risks and/or differences, the following assumptions are made: 1. The expected total number of Vietnam veterans (Cohort A) eligible for study is 5000. 2. The expected total number of Vietnam veteran Army nurses (Cohort A) eligible for study is 5000 x .7 = 3,500. 3. The expected numbers of Vietnam-era veterans (Cohort B) eligible for study is as in Table 3 above. 4. Response rate to initial telephone survey for all subjects (or proxies) is 85%. 5. Response rates to any in-person protocol is 90% of those responding to the initial interview. The numbers expected for the overall study and the Nurses Sub-Study (Army nurses only) are provided in Table 5, based on the above assumptions. 6.2 RESPONSE RATES Two response rates must be considered: (a) Response to the initial telephone interview; and 40 �TABLE 4. ESTIMATED RATES FOR SELECTED HEALTH AND REPRODUCTIVE OUTCOMES OUTCOME YEAR BASE POPULATION RATE (per 100) A. GENERAL HEALTH • Malignant Neoplasm Incidence'3' (white women, age adj.) 1983 • Malignant Neoplasm Mortality^' (white women, 35-54 yrs, age adj.) 1984 " 0.14 • Incidence of Hodgkin's Disease'a' and Non-Hodgkin's Lymphema (white women, age adj.) 1984 " 0.013 • Incidence of Soft tissue Sarcomas(a' (incl. Head)(all women, age adj.) 1980-84 " 0.002 • Heart Disease Prevalence^0) (all women,< 45 yrs) 1985 " 3.71 • Heart Disease Mortality^) (white women, 35-54 yrs, age adj.) 1984 " 0.08 • Cerebrovascular Disease Prevalence^0) (all women,< 45 yrs) 1985 " 0.14 • Cerebrovascular Disease Mortality'**) (white women, 35-54 yrs, age adj.) 1984 " 0.02 • PTSD (chronic and/or delayed)(d) 1980+ Civilian pop., U.S. U.S. Veteran pop. 0.31 3.0+ B. REPRODUCTIVE FUNCTION • Infertility Rate<d) (30-39 yrs) 1982 41 Currently married women, U.S. 10.0 �TABLE 4. Continued YEAR OUTCOME BASE POPULATION RATE (per 100) C. REPRODUCTIVE OUTCOME • Major Congenital Malformation'*) 1973-74 • Multiple Spontaneous Abortion^) (< 20 wks gestation) 1980 Pregnancies (approx) 3.00 • Fetal Mortality^) (>20 wks gestation) 1984 Live births to fetal deaths, U.S. 0.81 • Infant Mortality^) ( <• I yr) 1984 Live births, U.S. 1.10 Sources: Live births, U.S. 0.82 (a) NCI: 1986 Annual Cancer Statistics Review. NIH Pub. No. 87-2789. (b) NCHS: Health, United States, 1986. DHHS Pub. No. (PHS) 87-1232, PHS, Washington, D.C., U.S. Govt. Printing Office, Dec. 1986. (c) NCHS: Current Estimates Survey, U.S. 1985 No. 160 DHHS Pub. D.C., U.S. Govt. form the National Health Interview Vital & Health Statistics Series 10. No. (PHS) 86-1588, PHS Washington, Printing Office, Sept. 1986. (d) Literature Review, VA Contract V107 (93) P-1138, 1987. (e) Mosher, W.D. Reproductive Impairments in the U.S., 1965-82, Demography (1985) 22:415-430. (f) NCHS: Congenital Anomalies and Birth Injuries among Live Births: U.S., 1973-74 Vital & Health Statistics Series 21. No.31 DHHS Pub. No. 79-1909, PHS, Washington, D.C., U.S. Govt. Printing Office, Nov. 1978. (g) This is estimated using a basic rate of 15% spontaneous abortion/pregnancy quoted by Kline et al., 1981. �(b) Response to in-person measurement. The response to the initial interview, given interest in the study and prior experience with similar studies (including CDC's VE study), is expected to be 85% of eligible subjects. Maintenance of this response rate will depend on attention to some of the special issues mentioned below (Section 7.1.6). Response to in-person protocols, conditional on response to the telephone interview, is expected to be at least 90%, provided the participant burden is minimized and protocols are completed locally, at the participant's convenience (wherever possible in the participant's home). This projection is based on the contractor's own experience with other on-going research. Because the response rates are expected to be relatively high, no major bias from non-response is anticipated. Some data from service records will be available on non-respondents, from the Mortality Study, with which to check evidence of potential bias. These data include: date of birth, length of service, veteran status (Vietnam or Vietnam-era), highest rank attained, branch of service and occupation. 6.3. OUTCOME RATES Table 4 presents rates for key study outcomes for female populations. These rates are used to approximate outcome rates for Cohort B subjects (control population). Wherever possible, rates are presented for the most recent year for which data are available. It is clear from this table that, except for some death rates and cancer 43 �incidence rates, outcome rates are generally near or greater than 0.1%. Moreover, for congenital malformation rates, calculated on a base of live births, conservatively twice the number of births are expected in the cohort for the number of women (NCHS, 1986), effectively doubling the available sample size. Age ranges approximating that of the cohort were used for rates where large age differences are observed. Assuming the minimum age at potential VE exposure was 20 years in 1973 and the maximum age in 1965 was 40, the age range of the cohort in 1989 will be approximatley 35-64 years, with the majority in the range 35-49 years. 6.4 SUB-STUDY SAMPLE SIZES This section provides estimates of expected numbers for the sub-studies. 6.4.1 Reproductive Outcome Study As noted in Section 2 above and Table 4, the rate of major congenital abnormalities is approximately 1/100 live births, while the rate of two or more spontaneous abortions per woman is estimated at no more than 3%. An average of two live births per woman is assumed, using live births, by age of mother (NCHS, 1986), averaged and deflated slightly to yield a rate of 2.0 live births/woman. This lower rate is used on the assumption that veterans were less likely to marry (or marry early) than other women of the same age. (This trend was suggested from pre-testing and focus group experience during the planning of this study. No data are presently available to confirm it.) Certainly, use of a conservative rate of live births will result in a conservative lower bound for expected sample size. The rate of congenital abnormality (assuming two live births/woman) is therefore: �TABLE 5. EXPECTED SAMPLE SIZES FOR THE ENTIRE STUDY AND NURSES SUB-STUDY (ARMY NURSES ONLY) COMPONENT STUDY COHORT A Entire Study 4,250 5,164 4,165 5,062 2,975 3,230 COHORT B Entire Study (Alive Only <b)) Army Nurses Sub-Study (a) Total eligible x 0.85 (b) Assuming a death rate of .02 in both cohorts (based on 100/5000 deaths identified in Cohort A for the Mortality Study), 100 deaths in Cohort A and 120 expected deaths in Cohort B are deducted from eligible numbers before multiplication by Response Rate (0.85). 45 �.07 X 4,165 X 2 - 83, using live Cohort A subjects only (Table 5). Assuming a 3% rate of repeat spontaneous abortions/woman and that 50% (conservatively) have no obvious cause (Dr. A. Haney, personal communication), the number of women with unexplained habitual abortion is estimated as: .03 X .5 X 4,165 = 62. Provided no woman reports both adverse reproductive outcomes, the expected number of cases in Cohort A is: 83 + 62 = 145. An equal number of controls will be selected from the remaining 4020 subjects in Cohort A (a ratio of 28:1 of available: required matches). With a 90% in-person response rate, approximately 260 subjects (and offspring) will be available for this study. 6.4.2 PTSD Sub-Study The numbers required for this sub-study involved additional assumptions. From Lezak (1983) (see Appendix) it appears that the outcomes of the neurobehavioral tests are either scores (which can be considered continuous) or consist of proportions (numbers) of successes/failures. For the tests producing scores, the ratio of S.D. to mean, 46 �TABLE 6, Coefficients of variation (CV) for selected values of oC and 0 , assuming a two-sided test 0.05 0.01 0.001 0.30 0.40 0.32 0.26 0.20 0.36 0.29 0.24 0.10 0.31 0.26 0.22 47 �S.D./mean < 0.25, in all cases. Assuming a meanjbi, in the control group, a minimum meaningful difference in scores A = 0. lju, and population S.D. =<r, the required sample size (n), assuming equal sample sizes, is: n - 2<r 2 /[*Ol| /L 2 x CV-2(D)], - 2(.252)/[.01 X CV2(D)], where CV(D) « S.E.(D)/£. and is pre-specified. Table 6 demonstrates the relationship between CV(D) and the power for detecting pre-specified differences, which indicates that CV(D) < .30 is sufficient to provide adequate power. Solving for n with CV(D) «= .3 yields a minimum sample size of 139. Assuming a 90% in-person response rate for the neurobehavioral tests, an initial sample of 155 subjects, identified from the telephone interview, will be required for each of five groups (a total of 775 subjects) to yield 698 completed responses. An alternative sample selection design which will retain equivalent power for combined comparisons but use fewer subjects is as follows: Acute PTSD 52 Delayed PTSD 52 Chronic PTSD 52 PTSD Combined = 156 Control (Cohort A) « 78 Controls Combined =156 Control (Cohort B) - 78 Total Sample t 312 �This alternative uses 45% of the subjects (312/698) and reduces cost accordingly. Comparisons between sub-groups of PTSD and controls will have reduced power in this design. However, it should be noted that, for many of the tests, OXu. < .15. For these tests, n < 50 is sufficient to maintain CV(D) < .30. The alternative design (total sample selected «= 312) is therefore proposed. 6.4.3 Nurses Sub-Study All available Army nurses will be included in this substudy (Table 5). It remains to determine the number of Air Force nurses from Cohort B for the third comparison group. From available available Study and Table 3, 450 eligible Air Force nurses will be for use in Cohort B. This subgroup will be as the third comparison group in the Nurses Subis restricted to Air Force nurses who are: • not on flight status at any time during the entire exposure period; and • not exposed to any measurable extent to care of wounded Vietnam veterans during the entire exposure period. Assuming an 85% response rate, 382 will be available, of whom an estimated 75% will meet the above criteria (this is a conservative guess, as statistics are not readily available for these factors). In other words, only 287 (estimated) will be available for the third comparison �group. This small number is further compromised by the bias towards longer service in the early years of the exposure period. In order to increase this number by 500 (to approximately 790), an additional 500 f 0.75 ~ 0.85 = 785 eligible Air Force nurses will be required. As in the Mortality Study, this is increased by 30% to ensure enough potential subjects in the initial sampling. In other words, approximately an additional 1000 Air Force nurses will need to be selected from the computerized Air Force listings for this study (over and above those selected for the Mortality Study). 6.4.4 Validation Sub-Studies The criterion for acceptance of self-reports, based on verification of a sample, is 10% discrepancy or less. Reliable estimation of the proportion (p) of discrepant reports is defined by (Cochran, 1977): CV(p) = (l-p)/np. Assuming a maximum CV(p) of .3, as above, and solving for n, n - 100 In other words, random samples of 100 self-reported cases should be sufficient to provide precise estimates of the proportion validated. 50 �FORC* = .05 (TWO-SIDED). VARYING SAMPLE SIZE^ j (* AND p SAMPLE SIZE 5000 3000 780 0.001 3.72 4.95 12.79 0.01 1.65 1.87 3.03 8.56 0.05 1.28 1.36 1.78 3.38 0.10 1.20 1.26 1.54 2.60 0.001 4.35 5.93 16.26 81. 14 0.01 1.77 2. 04 3.48 10. 67 0.05 1.32 1.43 1.92 3.93 0.10 1.23 1. 30 1.64 2.94 d. 130 0.20 68.37 p - o.io (a) Sample size is the size of the control sample (see Schlesselman, 1982) (b) p is the outcome rate in the control population 51 �6.5 SAMPLE SIZE ADEQUACY Table 7 presents the smallest detectable Relative Risks for various pertinent sample sizes, outcome rates and two values of (i (0.10, 0.20). The significance level ( ( is o) assumed constant at 0.05, for two-tailed tests. The entire sample will detect relative risks less than 4.0 with 80% power, for outcome proportions as small as 0.001. These numbers are clearly adequate to detect meaningful risks for major health outcomes except rare cancers (STS in particular - see Table 4). The Nurses Sub-Study will detect risks of less than 3.0 with adequate power for proportions of .01 or higher, assuming that the Air Force control group contains at least 780 subjects. For comparisons involving Army nurses only, the minimum detectable risks are less than 2.0, for p > .01. For the Reproductive Outcome Case/Control Study, oddsratios (relative risks) of 3.5 or less will be detectable for exposure rates of .05 or higher (assuming TCDD exposure can be meaningfully dichotomized). 52 �7- DATA COLLECTION This section outlines the major data collection strategies proposed, with rationale, and a discussion of special issues (7.1), followed by quality control and data management requirements (7.2). 7.1 STRATEGIES The various data collection strategies are described here for each study component. 7.1.1. Full Cohort Study This study involves collection of data by telephone interview with each subject (or with a next-of-kin for deceased subjects). (a) Telephone Interview Because participants will be scattered throughout the U.S. and other countries, the primary mode of data collection must be feasible, cost efficient and produce data of acceptable quality. Telephone interviews were chosen over mailed selfadministered questionnaires (SAQ's) for the following primary reasons: • Respondent Burden (SAQ's take longer to complete.) • Data Quality (Even short, simple SAQ's result in skipped questions and/or missing or ambiguous items which are not random but are related to educational level and,-independently, to health status.) 53 �• Bias (Respondents have less opportunity in a telephone interview to discuss the questions and their responses with others, compared to a SAQ which can be shared with colleagues, family or friends, before or after completion.) • Response Rate (The considerably lower perceived burden and direct interaction with an interviewer will increase response rates - especially among those with less education.) • Accurate Completion (Assurance is obtained that the correct person provides the information, without prompting or consultation.) Given the complexity of the interview, which includes occupational, contraceptive and reproductive histories and requires 1.75 - ?.Q hours to computer-assisted telephone interviewing (CATI) was not considered feasible. Once a respondent's memory is activated in one area, responses may be corrected in another area, many pages and skip patterns earlier. Moreover, CATI discourages interviewer comments which will be most valuable in this unique study. It is expected, on the basis of pre-test experience, that the majority of interviews will be completed in one call. Interrupted interviews (because of family or other intrusions into respondents' time) must be completed as soon as possible (generally within 24 hours) . Given the nature of the study and the sensitivity of the topics, the use of professional interviewers with considerable experience is required. Data from the openended questions will be post-coded to standardized 54 �categories, thus eliminating the potential for interviewer error and delay, when presented with the long answer lists required for certain close-ended questions. Much of the coding of medical data will require professionals trained in the use of ICD-9 codes and surgical procedures. In-person interviews for those without telephones or with unlisted numbers will be conducted - estimated at 10% of the sample. (b) Proxy Interview For already identified deceased subjects, the next-ofkin listed on the death certificate will be contacted in order to identify the best person(s) with whom to complete a proxy interview. For subects dying after list compilation, the informant providing this information will be the initial contact. The best proxy will meet the following criteria: (a) knew subject immediately prior to the death; and (b) of those meeting criterion (a), knew her the longest. It is expected that in most cases the informant will be a parent, sibling, offspring or spouse in that order, unless living with the spouse for at least 10 years. For the veterans under study, lower rates of marriage and/or less stable marriages than average may require heavy reliance on parents or siblings for proxy interviews. As for subjects, in-person interviews with proxies will be conducted in the absence of an accessible telephone. 55 �7.1.2 Reproductive Outcome Study This study will involve in-person measurement of the subject (blood sampling for TCDD determination) and of the approximately 170 offspring of women reporting a major congenital abnormality. Hospital record review will be required to validate the 60+ habitual abortion histories. Each of these strategies is discussed below. (a) Blood Sampling for TCDD Determinations Because a unit (450 mis) of whole blood is required (see Appendix), to be obtained under strictly sterile, controlled conditions, it is proposed that this collection be completed by regional Red Cross offices under subcontract. Individual collection kits which are free of chemical contaminants will be required. These will be delivered to the designated Red Cross office, and Red Cross staff will be trained in their use by project staff. The assays must be completed in a laboratory with the capacity already established as the assay is highly complex to set up successfully (Patterson et al, 1987 - see Appendix). Currently only CDC has this capability in the U.S. For this sub-study, a maximum of 260 assays will be required. This number may be reduced if a subject is too sick or has an unacceptably low hematocrit for sampling of a unit of blood (see Section 9). Data regarding deferrals for low hematocrits are not consistently tabulated by the Red Cross. However, the national office estimates that approximately 4% of women donors are deferred for hematocrit 56 �levels less than 38 (personal communication, Red Cross, Blood Operations Support, 1987). (b) Pediatric Examination It is proposed to follow closely the protocol developed for the Ranch Hand Study, with all examinations to be completed by a single, trained physician. This should be feasible as approximately 80 families will be eligible (170 children) to be examined over 24 months. This is equivalent to 7 examinations ( 3 - 4 families) per month. The protocol for this examination, following closely that used on the Ranch Hand Study being conducted by the Air Force, is in the Appendix. (c) Medical Record Verification In those cases for which a pediatric examination is not possible (the offspring is deceased, ill or living in another country), the physician performing the examinations will review available hospital and medical records to verify the abnormality. All repeat abortions will have records reviewed to rule out the excluding causes listed above. A panel of three physicians specializing in reproductive medicine will independently review these records and determine eligibility for inclusion. A majority (2/3) determination will be sufficient for a decision. 7.1.3 PTSD Sub-Studv (a) Neuro-behavioral Testing All 312 women consenting to participate in this substudy will complete a battery of tests as presented in the 57 �Appendix, following closely the test protocol used on the CDC VE study. This battery will be completed by one of a small number of trained project staff with appropriate backgrounds in psychological testing. Depending on the availability of a quiet room, without interruption in the participant's home, the testing will be completed either in the subject's home or in an appropriate room (for example hotel conference room) rented nearby. TCDD Determination All 312 subjects will also be eligible for blood sampling for TCDD determinations. These will be collected as proposed in Section 7.1.2 above. 7.1.4 Validation Studies Apart from the validation of cases described in Section 7.1.2 above, three types of validation are proposed: • medical record review; • review of pathology slides; and • blood testing. Each is described briefly below, (a) Medical Record Review For each case (including fatal and non-fatal diagnoses) a panel of three physicians, including at least one internist and at least one specialist in the appropriate area, will independently review each case and determine the 58 �diagnosis. A majority (2/3) will be sufficient for a decision. The major exception to this procedure will be suspected cases of myocardial infarction, sudden death and stroke, for which an established diagnostic algorithm is available (Gillum et al, 1984) and a protocol developed and tested (see Appendix). (b) Pathology Slide Review To verify oopherectomy, slides will be independently reviewed by a panel of three gynecologists (reproductive specialists). A majority (2/3) will be sufficient to confirm the surgery. To verify cancer type, a panel of three oncologists/pathologists including specialists in Kodgkins Disease and Non-Hodgkins Lymphoma will independently review pathology slides (if available) or records. In the case of STS, suspected cases will be reviewed using the WHO criteria (Enzinger et al, 1969) (see Appendix). (c) Hormone Blood Testing To confirm premature menopause (12 months of consecutive amenorrhea without obvious cause in a woman under age 40), FSH and LH levels will be checked using two venous blood samples, of at least 5 ml whole blood each, drawn 20-30 minutes apart, between 7:00-10:00am. Blood specimens will be collected in the subject's home. Samples will be centrifuged and serum shipped to a well-established 59 �endocrine laboratory for analysis, standardized "kits" are available for these assays. 7.1.5 Rationale for Individual In-Person Measurement It is proposed to collect all blood samples and complete all in-person measurement individually, either in the subject's home or at a locally convenient site, rather than at a nationally central site (as in the CDC VE study) for the following primary reasons: respondents are likely to have family responsibilities making travel to a pre-determined location difficult; requiring travel of a respondent increases perceived burden, increases broken appointments, and decreases response; and it is more cost-efficient to complete protocols in the home, in terms of project staff time and required travel costs especially given the relatively small number (less than 600 subjects) involved. 7.1.6 Special Issues in Data Collection The following concerns will require special consideration in the conduct of the study: • the impact of publicity external to and prior to the study; • the most effective publicity (especially sponsorship) to enhance response rates on the study; 60 �the maintenance of interviewer/examiner blindness to veteran status (Vietnam veteran or Vietnam-era veteran); and participant networking which may increasingly affect response rate and/or response bias among subjects interviewed later during the study. These and related issues must be addressed in data collection and/or analysis. 7.2 QUALITY CONTROL AND DATA MANAGEMENT To the extent possible, as few project staff as possible should be involved in data collection. This is a particular concern for in-person protocols, for which direct supervision may not be possible. The following sub-sections address minimum quality control requirements for telephone interviewing and in-person measurement as well as minimum requirements for a data management system. (a) Telephone Interviewing Quality Control Telephone interviewing quality control should consist of at least the following: • regular monitoring of interviews by a supervisor; • call-back and edit checks, by a supervisor, of 10% of all final dispositions (including ineligibles, refusals, and completed interviews); and 61 �• regular review of refusal and production rates of all interviewers. (b) In-Person Protocol Qualtiy Control Because specialists and subcontractors will be employed for most of the in-person protocols, random visits by the Project Director (or other senior project staff) during scheduled data collection should be completed (on at least 5% of all scheduled appointments). Another 10% of subjects/ subcontractors should be called after the scheduled data collection to ensure timely accurate completion of protocols. (c) Data Management Requirements A responsive, automated data management system is required to complete the following tasks: • produce regular (weekly) production reports; • provide for immediate entry, verification and editing of all data within 2 weeks of acquisition; • assist in efficient scheduling of project staff/subcontractors and subjects for in-person protocols; • provide range and logic checks for data entry/editing; • monitor protocol completion (including integration of laboratory results, multiple physician diagnoses, etc. into the data base); 62 �produce automated form letters and record release requests; produce automated reports on in-person measurements for subjects and (optionally) for their physicians; and produce periodic summary reports of aspects of data collection, including production statistics and quality control check statistics. 63 �8. ANALYSIS The analytical approach for this study will vary depending on the hypotheses and sub-study of interest. The recommended analytic strategies are outlined in this section for each of the component studies and with reference to the hypotheses presented in Section 4 above. 8.1 FULL COHORT STUDY OF VE EXPOSURE The overall investigation of the effect of VE on various health related outcomes will be completed on Data Sets 1 and 2 of the two cohorts (A and B) . Hypotheses addressed include all those in the far left-hand column of Table 1 above. As is clear from Section 3 and Table 4, all of the major health or reproductive outcomes can be considered as dichotomies (present/absent) . It will therefore be possible to derive, directly, estimates of relative risks of these outcomes by exposure from the historical cohort design. The primary issue in deriving these estimates will be effective adjustment for potential confounding variables (age, length of service, smoking, alcohol consumption, etc.). It is recommended that a logistic approach be employed to estimate the contribution of potential confounding variables and that the final estimates of relative risk be adjusted for those effects which contribute significantly and consistently. In other words, for an outcome proportion p^, log[pi/(l-Pi)] - logit(pi) -ofi + Zfj 64 �where x^j is the jth covariate (potential confounding variable) associated with the ith outcome. Given the estimation of multiple equations from the data set, the following restrictions on the analysis are recommended: • the significance level for inclusion of a variable in the logistic model should be set, strictly, at 0.01; • interaction terms should only be considered if all lower order terms involving these variables are included in the model; • consistency of models with biological mechanisms and findings from other relevant studies (on veterans, nurses, etc.) should be checked; and • the stability of models should be investigated by some form of jack-knifing (using, say, several random samples of 50% of each cohort for repeat estimation). References for this type of analysis include Bishop et al (1974) and Kleinbaum and Kupper (1978). 8.2 REPRODUCTIVE OUTCOME CASE/CONTROL STUDY Because the outcome variable (TCDD body burden) is essentially continuous, mean differences may be considered. Assuming that pair-matching is effective, differences in TCDD levels between pairs will be observed and the mean of these differences calculated. 65 �The effectiveness of the pair-matching should be checked by comparing the variance of the mean of paired differences (<%2) with the variance of the difference of two means calculated from the observations as if from independent samples (on2 - X ). If these two variances are _ x, equivalent and produce the same test statistic, then pairmatching was ineffective. 4 Mean differences can be adjusted for continuous covariates using analysis of covariance (Snedecor and Cochran, 1972). For dichotomous or other categorical confounders, post-stratified estimates of mean paired differences can be estimated. Such adjustment methods are described further by Schlesselmann (1982). 8.3 PTSD SUB-STUDY This study will be relating TCDD levels and results of neuro-behavioral tests to PTSD, diagnosed from a version of the Diagnostic Interview Schedule (DIS - see Appendix). The hypotheses addressed are those specifically relating PTSD and neuro-behavioral functioning to TCDD exposure (see Table 1). As is clear from the Appendix, most of the neurobehavioral tests have scores, which can be treated as essentially continuous data. The remaining tests use number or percent of "successes" or "failures" as the primary outcome (approximating Poisson-distributed "count" variables). As noted above, TCDD is also measured continuously in parts per quadrillion. For continuous outcomes, therefore, using the initial PTSD groupings as blocks or strata, analysis of variance 66 �(covariance) techniques can be employed to investigate differences in test results, adjusting for TCDD levels. See Snedecor and Cochran (1972) for further discussion of covariance adjustment. For "count" data, a square root transformation can be used (see, for example, Tukey, 1977) and analysis of covariance performed on the transformed data. For dichotomized results of neuro-behavioral tests, the equivalent approach is logistic regression, comparing PTSD groups pair-wise. If this approach is used, the following set of comparisons should be made: PTSD Groups; 1. Acute PTSD 2. Delayed PTSD 3. Chronic PTSD 4. Cohort A control 5. Cohort B control Comparisons: (a) 1 + 2 + 3 V. (b) 1 v. 4+5 (PTSD v. no PTSD) 2+3 (c) 1 + 2 v. 3 (Acute v. delayed or chronic PTSD) (Acute or delayed v. chronic PTSD) (d) 4 v. 5 (Cohort A v. Cohort B controls or VE v. no VE exposure) 67 �Finally, using experience from the CDC VE study, principal components analysis or other equivalent multivariate techniques may be used to construct one or more composite indices from the neuro-behavioral tests (Cureton and D'Agostino, 1983). These indices may then be used in place of individual test scores in analyses of variance. 8.4 NURSES SUB-STUDY The analytic approach to this sub-study will be similar to that for the entire cohort and will address hypotheses in the right-hand column of Table 1. Two distinct features of this study are: 1. An index of exposure to wounded veterans can be constructed based on nursing workload, proportion of veterans treated, and department or ward assigned. 2. Three comparison groups are available representing a continuum of exposure to nursing of wounded veterans. With respect to the first feature, an index of exposure must first be constructed. The variables from each tour of duty to be included in the index are: • workload (average hours worked per day x average number of patients/average number of nurses); • average proportion of patients who were Vietnam veterans; and • ward, department or type of hospital unit assigned for all or most of the tour. 68 �Index values will then be summed across all tours of nursing duty during the exposure period. Clearly the Air Force control group from Cohort B will have uniformly low values, based primarily on a regular workload and no nursing care of Vietnam veterans, while Army nurses serving at least one full tour in Vietnam and additional tours in CONUS hospitals will have the highest scores. Logistic models will then be constructed for health outcomes, using this index and other covariates (including age and length of service prior to exposure) and ignoring comparison group designation. Apart from this comprehensive analysis, the following group comparisons should be investigated: Comparison Group; 1. Army nurse, Cohort A 2. Army nurse, Cohort B 3. Air Force nurse, Cohort B Comparisons; (a) 1 + 2 v. 3 (b) 1 v. 2 69 �8.5 VALIDATION SUB-STUDIES This distinct set of studies involves relatively straight forward estimation of the proportion of selfreports not verified by other independent information sources. The proportion will be estimated and a one-sided test of significance used as follows: H0: p < 0.10 H^: p > 0.10 The significance level, because of multiple testing, will be set at 0.01 (one-sided), so that the test criterion will be 2.33 standard errors above 0.10. An estimate (p) above the test criterion will result in rejection of unvalidated selfreported outcomes for inclusion in analysis. 8.6 COMPARISON WITH OTHER DATA SETS Sections of the questionnaire (see Deliverable C) to be administered in the telephone interview have been deliberately designed for equivalence with data from the following national surveys: • National Health Interview Survey (NCHS: on-going); • National Health and Nutrition Examination Survey III (NCHS: Scheduled to begin the first 3-yr. sample, October, 1988); • National Survey of Family Growth (NCHS: Cycle IV, 1987). 70 �To the extent that data from these surveys will be available, comparisons on important health outcomes and major confounding variables will be feasible with national, civilian samples of women, surveyed approximately concurrently with this study. 71 �9. HUMAN SUBJECTS This section reviews requirements for informed consent (9.1) and confidentiality (9.2) in the proposed study, as well as reports to respondents (9.3). 9.1 INFORMED CONSENT Four types of informed consent will be required from the subject (or next of kin). They are: • verbal consent to a telephone interview; • written consent to access medical records; • written consent to in-person measurement; and • written consent for examination of offspring. The basic procedures to be followed in obtaining all of these consents include: • providing full and accurate information, verbally and in writing; • answering all subjects' questions; and • providing subjects with sufficient written material and appropriate contact names and telephone numbers, so that remaining concerns can be adequately addressed even after informed consent is obtained. 72 �Each of the types of consent is discussed below and consent forms are provided in the Appendix. 9.1.1 Verbal Consent Subjects (proxies) should be mailed, immediately before telephone contact (wherever possible), a letter describing the study, its purpose and sponsorship, inviting participation and alerting the subject to a subsequent telephone call. The letter should contain local and/or tollfree telephone numbers which the subjects can call to verify the legitimacy of the study, as well as the telephone number for the contractor completing the study. At initial telephone contact, the interviewer will describe, clearly, the following: • the length of the interview (1.75-2.0 hours); • the fact that refusal to participate or to answer specific questions will not jeopardize their status with respect to the VA or related services; and • the complete confidentiality of the information given (even the VA will only have data by ID number, with no way to identify actual individuals by name). Completion of part or all of the telephone interview will constitute implicit consent. 9.1.2 Access to Medical Records A written consent form will be mailed, with an accompanying letter, to all subjects (proxies) volunteering the name and address of hospitals or physicians to verify 73 �procedures or diagnoses. A consent form, specifying the name of the hospital/physician source, the name of the subject and the date (as accurately as possible) for the record will be sent to the subject for each procedure/diagnosis. The subject will check the accuracy of the form, sign and date it, and return each form to the contractor. The accompanying letter, to be retained by the subject (proxy), will list all requests made and describe how these requests will be used. Copies of these written consents will then be sent by the contractor to the hospitals or physicians with covering letters requesting copies of the named record. Follow-up telephone calls to these sources may be required, as well as fees for pulling and copying records. 9.1.3 Consent to In-Person Measurement For sub-studies requiring in-person measurement, the subject will be asked to read and sign an informed consent form which will be witnessed by a project staff member or subcontractor. The staff member will be trained to answer all questions concerning the procedure, including risks and benefits, before obtaining the subject's signature. Such consent will be required as follows: (a) TCDD Blood Sampling The subject will be informed of her eligibility for this measurement by project staff (by telephone, confirmed by mail). Signed consent will be obtained and witnessed by a Red Cross staff person, who will be trained by the contractor for this study. The original of this consent will be sent to the contractor, a copy being retained by the Red Cross Regional Office. 74 �The risks of giving a unit of blood will be fully explained. The benefits of the TCDD determination will be indirect, involving increased knowledge of the potential effects of this exposure. Blood will not be drawn from subjects with a low hematrocrit who are taking anticoagulants, who have a blood clotting disorder, who are too ill or have a chronic condition (e.g., diabetes) which increases risk of adverse effects from drawing this amount of blood. (b) Hormone Blood Sampling For the few women with suspected early natural menopause, a project staff member (or subcontractor) will, in the subject's home, draw two venous blood samples (5 mis each), 20-30 minutes apart, between 7:00am and 10:00am. The purpose, risks and benefits will be explained, first on the telephone when the appointment is scheduled, and more fully in-person before informed consent is obtained and witnessed. Exclusions from this blood sampling are as in (a) above, except for hematocrit level and chronic condition. (c) Neuro-Behavioral Testing As in (a) and (b) above, initial telephone contact will be made by project staff to explain the procedure and schedule an appointment. This will be confirmed in a followup letter. The tester will provide, in-person, more detailed explanation and will obtain and witness informed consent. There are no real risks from these tests (except some fatigue) and only indirect benefits in terms of knowledge accumulation. 75 �9.1.4 Consent for Offspring Examination For offspring who are legally minors (under 18 years of age), written consent must be obtained from a legal guardian (usually a parent). For children who are over 12 years of age, or who request it, direct written consent will also be obtained from them, if feasible. For offspring who are legally adults and able to give informed consent, written consent will be obtained directly. If an adult offspring is unable to give informed consent, it will be obtained from the legal guardian. These procedures and the purpose of the examination will be explained to the subject (mother) by telephone and an appointment confirmed by mail, including the examining physician's name and contact telephone number. At the appointment, the physician will provide a more detailed explanation, answer questions, and obtain and witness informed consent. In cases in which the subject (mother) is not the legal guardian, efforts will be made to obtain consent of the guardian by mail before the appointment is scheduled. 9.2 CONFIDENTIALITY Minimum requirements for maintaining confidentiality of all data collected, include the following: • clear separation of all personal identifiers from data collected: and • strict file security with restricted access to master files which link personal identifiers with ID numbers. 76 �All forms, including telephone contact records and informed consent forms, which include ID numbers and personal identifiers must be separately filed in a securely locked file, with access restricted to designated project staff. Similarly all such computerized files must be maintained under a secure password system. If contact information is obtained for future follow-up of subjects, this information must be maintained independently and not made available for possible merging with the resulting data sets until such time as a contract is awarded for follow-up data collection. 9.3 REPORTS TO RESPONDENTS The promise of a final report of findings has been found to be an important motivator to participate in such a study and effective in maintaining high response rates. If a follow-up of participants beyond this study is planned, such a report would have to be carefully prepared to avoid contaminating subsequent data collection. But further data collection should not be a sufficient reason not to send a report. Finally, participants consenting to any test or measurement should have the option of receiving results of these tests and/or having them sent to a physician. While some tests may be difficult to interpret, most participants will value receiving results. A report should, therefore, at least describe what tests are completed, provide interpretable results wherever possible, and interpret them for the participant. If abnormal values indicate possible underlying pathology, this should be indicated with a recommendation to have a physician check these results. 77 �In particular, two rare events require special attention. First, women with abnormally high TCDD levels, indicating high prior exposure, should be informed of this in a telephone call by project staff, followed by the report itself. The project staff should be prepared to answer respondent questions concerning this result and make appropriate referrals, gecond, if an abnormality, not [previously diagnosed, is identified in an offspring in the course of a pediatric examination, this information should |be conveyed to the respondent by the examining physician rerbally, before a report is sent. The examining physician should also be prepared to talk to the offspring's own physician concerning this diagnosis. 78 �10. SCHEDULE AND WORKLOAD This section outlines the schedule, tasks and workload for completing the proposed study, as well as required project organization. 10.1 TASKS The following tasks and sub-tasks are identified: • preparation (recruitment, training, printing of forms, set up of data-management and quality control procedures); • sampling and tracing of 1000 additional Air Force nurse records; • abstraction of Chief Nurse reports; • data collection on cohorts (telephone interviews, in-person measurement, record abstraction, quality control); • data entry, editing and analysis; and • final report. 10.1.1 Preparation This should not be a lengthy task, but provides time to recruit and train staff, set up any subcontracts, set up the data management system and quality control procedures and have all required forms printed. 79 �Although instruments are already developed and tested, they will require formatting and printing by the contractor, in accordance with formatting conventions used by the contractor. Staff will require training in protocols and some staff may require recruitment. 10.1.2 Acquisition of Air Force Nurse Supplementary Sample This task involves working closely with the VA and the Environmental Support Group (ES6) to sample 1000 records of non-Vietnam veteran Air Force nurses. The most recent name and address for each will then be traced using available record systems including the VA benefits records, active duty records, pension records and reserve listings. 10.1.3 Abstraction of Chief Nurse Reports These are non-computerized paper reports which are archived in or near Washington D.C. They will require manual abstraction of information at the archive site for subsequent computerization. The maximum number of relevant reports for the exposure period is estimated at 92 months x 100 hospital units/facilities = 9200 reports. The actual number will be less, as not all hospital units operated for the entire 92 months (especially in Vietnam). 10.1.4 Data Collection on Cohorts This includes obtaining final dispositions on approximately 11,700 names and addresses (including the Air Force supplement), resulting in approximately 9,900 completed interviews. It is estimated that 1000 interviews will be completed in-person, because of no telephones or unlisted numbers and the remainder will be completed by telephone. A 10% sample will be recontacted and dispositions reviewed for quality control. 80 �Apart from the basic telephone interview, the following activities must also be completed: • abstraction and diagnosis verification of approximately 1000 medical records, including review by three physicians of each of 700 of these records; • pediatric examination to verify congenital anomalies in approximately 80 families (160 examinations); • administration of a battery of neuro-behavioral tests to 312 subjects; • sampling and processing of a unit of blood for TCDD determinations on approximately (260 + 312) x 0.95 «= 540 subjects, assuming about 5% will not be eligible to have this amount of blood drawn. • sampling and processing of blood samples for no more than 50 subjects requiring FSH/LH levels (approximately 1% of an estimated 3000 subjects under 40 years of age). 10.1.5 Data Entry Editing and Analysis This task will overlap with data collection and involves construction of clean, edited and documented data sets for analysis. The following data sets will be constructed for analysis: • data sets 1, 2, 3 and 4 as described in Section 2 above for the main study and nurses sub-study; • data sets for the Reproductive Outcome and PTSD substudies ; 81 �• validation data sets for all major outcome groupings as defined in Section 2 above, including selfreported data and equivalent data from all independent sources accessed, for each validated record; • data set of Chief Nurses' Reports, to be linked by hospital code and dates to individual service records of subjects (data sets 1-4). 10.1.6 Final Report It is assumed that a draft Final Report will be submitted for comment in time to allow reanalysis and other revisions before submission of a Final Report. 10.2 SCHEDULE Assuming a three year study period, the schedule of tasks described in 10.1 above is summarized in Figure 2. Only three months is provided for preparatory tasks as described above. Sampling and tracing of the Air Force Nurse Supplement should be completed in one year, beginning in the first month, so that sufficient time is available (15 months) for data collection on this supplementary sample. Abstraction and computerization of the Chief Nurse Reports can occur in parallel with data collection as it is an independent activity. Twelve months is allowed for this task so that the data set is available for pre-testing of linkages with a preliminary data set from telephone interviews with subjects. 82 �FIGURE 2. SCHEDULE OF TASKS PROJECT YEAR TASK 1. Preparation 2. Air Force Nurse Supplement 3. Chief Nurse Reports Acquisition 00 4. Data Collection on Cohorts 5. Data Entry, Editing and Analysis 6. Final Reports �All data collection is to be completed in 24 months. Collection activities will, of course, be staggered, with in-person measurement and record abstraction occurring up to three months after interview completion. Data entry, editing and analysis is planned to occur in parallel with data collection. For the Reproductive Outcome, PTSD and validation substudies, data from the telephone interview must be computerized before eligibility is determined. This design constraint requires timely editing and computerization of all telephone interviews as they are completed. 10.3 WORKLOAD Table 8 summarizes the volume of work required for all data collection tasks and indicates the level of effort required in full-time equivalents (FTE's) per month, based on 20 work days per month and the indicated completion rate per FTE per day. The completion rates include time for paperwork and travel as well as vacation and sick leave allowances. The rates are estimated from other, similar data collection tasks completed by the contractor. 10.4 ORGANIZATION The project director or principal investigator should be an epidemiologist (Ph.D. or M.D.) with an appropriate background in reproductive, chronic disease and/or occupational epidemiology. Other senior project staff should provide complementary epidemiologic expertise. Project leadership will require at least 0.5 FTE (comprising one or more individuals). 84 �TABLE 8. DATA COLLECTION WORKLOAD Data Collection Task; Volume Completion/ FTE/day No. FTE's per month 1« Interviewing 4 5.5 1.5 1.5 (a) Acquisition/Abstraction 1,000 2 1.0 (b) Diagnosis verification 8 260 consultant physician days 1 (family) 0.5 (physician) (a) Telephone 10,530 (b) In person 1,170 2. Record Abstraction(a) 700 3. Pediatric Examination 80 4. Neuro-Behavioral Testing 312 1.0 5. TCDD Blood Sampling(b) 545 1.5 plus Red Cross 6. Chief Nurses* Reports 9,600 (max) 16 7. Air Force Nurses Supplement 1,000 2.5 2.0 continued next page 85 �Table 8. continued (a). Records will be abstracted as follows: Habitual Abortion Selected Cancer Diagnoses 62 60 (30 cases STS, HD, NHC X2) Heart Disease and Stroke Other Cancer (sample) Depression, PTSD (sample) Hysterectomy and oopherectomy Death certificates TOTAL 380* 100 100 100 200 1002 * Approximately 300 of these will not require physician review. Application of a standard algorithm will be sufficient. (b). The total number required is calculated as follows: Reproductive Outcome Sub-Study 260 PTSD Sub-Study 314 TOTAL 574 5% eliminated 29 545 86 (130 each cases and controls) �Apart from project direction, the following supervision and technical effort is required: • Interviewing; Supervision of 7 FTE interviewers; • In-Person Measurement; Supervision of 4 FTE's for record abstraction, pediatric examination (physician), neuro-behavioral testing and training for TCDD blood sampling, as well as liaison with Red Cross Regional Offices and laboratories; • Data Set Acquisition; Supervision of the acquisition of the Air Force Nurses Supplementary Sample and Chief Nurses' Reports; • Data Management; Supervision of programmers and data entry personnel to ensure adequate support to the data collection effort and timely completion of data files for analysis; • Data Analysis; Senior statistical expertise to direct statistical programmers in the analysis. • Physician Panel; A panel of internists, oncologists, cardiologists, pathologists and reproductive specialists is to be retained for record review; • Other Technical Consultants; Additional resources to be available to the project should include (but are not limited to) consultants on military and veteran issues, the Vietnam conflict, occupational risks in nursing, and phenoxy herbicide/TCDD effects. 87 �11. UNRESOLVED ISSUES As of June 30, 1987, some key issues remain unresolved, related to on-going research which may have an impact on study design, data collection and/or analysis. For most of these issues, data will be available later in 1987 or early in 1988, in time to inform the approach before data collection begins. (a) Diagnostic and Statistical Manual Revision A new version, with revised criteria for PTSD is currently being finalized. This will have a direct impact on the Diagnostic Interview Schedule (proposed to measure PTSD), which is also under revision to reflect these changes. The questionnaire should include questions to allow coding by either DSM-III or by the revised version in order to permit comparisons with other already completed studies which used the current version (DSM-III). (b) Neuro-Behavioral Testing A full-day, comprehensive battery of tests has been included in the VE study currently being conducted by CDC and is proposed for this study (see Appendix). The analysis of results on these tests should identify an optimal subset, which can be administered in a home setting to women veterans. Currently there are no appropriate data sets available on which to base such a determination. If possible, based on CDC VE study results, the battery of tests should be shortened to a subset which can be completed in 3 hours or less. 88 �(c) Agent Orange Exposure Determination The index constructed for use in CDC's current Agent Orange Pilot Study relied very heavily on the "Service Herbs" tapes documenting perimeter and other ground sprayings/contamination. Unfortunately, this data set is very incomplete as documented in the Report of the Agent Orange Working Group Science Subpanel on Exposure Assessment (June, 1986). Even though the movements of female personnel were much more restricted than combat troops and, therefore, more reliably documented, a preliminary review of available data indicates that the highly variable quality of spraying data makes construction of a valid, reliable index problematic. It is, therefore, proposed that inclusion of an index of exposure to phenoxy herbicides/TCDD be contingent on the results of CDC's Agent Orange pilot study which validates the index against TCDD body burden. A report of these results is due July 31, 1987. The results of the pilot study may also modify the approach to analyzing TCDD data proposed for this study. (d) Obtaining Medical Records The contractors are unaware of any prior study which has successfully obtained medical (particularly hospital) records up to 25 years prior to contact with a respondent. Extensive follow-up of Framingham Study respondents over 20 years or more, to obtain hospital records, is currently underway. Preliminary results from this effort should be available early in 1988, with which to inform the feasibility of this proposed activity to validate health events and diagnoses. 89 �Depending on the Framingham Study experience, validation studies proposed here, may require modification. (e) PTSD Diagnosis Dr. Lee Robins of University of Washington, St. Louis, Missouri, has recently developed a shorter version of the DIS used for diagnosing PTSD as well as other disorders. This instrument will be available by early fall, 1987, after thorough pre-testing and validation and is specifically designed for telephone administration. It is proposed that this instrument be considered to replace sections of the current questionnaire for the following reasons: • it is relatively short (no more than 30 minutes); • has been thoroughly tested and validated; and • permits discrimination of acute, delayed and chronic PTSD. (f) Future Follow-Up of Participants It is proposed that comprehensive contact information be obtained from all study participants to facilitate possible further follow-up for both mortality as well as selected morbidity (including selected cancers and heart disease.) Given the cost of the NHANES I Follow-Up Study (NCHS), in which participants were traced at great expense after 10 years with no contact information available, it is strongly recommended that the same error not be made in this important study. The proposed study includes a follow-up since exposure of, at most, 24 years. The majority are still premenopausal, and have not reached the age at which cardiovascular events increase. Important cancers (STS, in particular) may have long latency periods of 30 years or 90 �more. Funding for further follow-up is therefore recommended, and the collection of contact information is proposed with that in view. 91 �BIBLIOGRAPHY Bishop, Y.M., Fienberg, S., and Holland, P. Discrete Multivariate Analysis; Theory and Practice (1974) MIT Press, Boston, HA. Cureton, E.E. and D'Agostino, R.B. Factor Analysis. An Applied Approach (1983) Erlbaum Assoc., Hillsdale, N.J. Center for Disease Control, "Postservice mortality among Vietnam veterans," JAMA (1987) 257:790-795. Gillum, R.F., Fortmann, S.P., Prineas, R.J., et al. "International diagnostic criteria for acute myocardial infarction and acute stroke," Am Heart J (1984) 108:150158. Hoffman, R.E., StehrGreen P.A., Webb Evans G., et al. "Health effects of long term exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin," JAMA (1986) 255:2031-2038. Holm, J. Women in the Military. (1982) Presidio Press, Ca. Kleinbaum, D.G. and Kupper, L.L. Applied Regression Analysis and Other Multi-variable Methods (1978) Duxbury Press, N. Scituate, MA. Kline, J., Levin, B., Stein, Z. et al. "Epidemiologic detection of low dose effects on the developing fetus," Environmental Health Perspectives (1981) 42:119-126. McKinlay, S.M. "The expected number of matches and its variance for matched-pair designs." Applied Statistics (Nov. 3, 1974) 23:372-383. McKinlay, S.M. and McKinlay, J.B. "Health status and health care utilization by menopausal women." In Aging Reproduction and the Climacteric. L. Mastroianni Jr. and C. Paulsen (eds.), Plenam Publishing Corporation, 1986 and The Climacteric Perspective. M. Notelovitz and P. van Keep (eds.), Lancaster: MTP Press Limited, 1986. National Cancer Institute. 1986 Annual Cancer Statistics Review NIH Pub. No. 87-2789 (1987), US DHHS, PHS, NIH Bethesda, MD. Patterson, D.G., Hampton, L., Lapeza, C.R., et al. Highresolution gas chromatographic/high-resolution mass spectrometric analysis of human serum on a whole-weight and lipid basis for 2,3,7,8 - Tetrachlorodibenzp-pdioxin. (1987 forthcoming). 92 �Percy, C., Stanek, E. and Gloeckler, L. "Accuracy of cancer death certificates and its effect on cancer mortality statistics," Am J Public Health (1981) 71:242-250. Roos, N.P. "Hysterectomies in one Canadian Province: A new look at the risks and benefits," Am J Public Health (1984) 74:1, 39-46. Schlesselmann, J.J., Case-Control Studies; Design. Conduct. Analysis. (1982) Oxford University Press, N.Y. Seber, G.A.F. The Estimation of Animal Abundance and Related Parameters (1973) Charles Griffin & Co., London. Snedecor, G.W. and Cochran, W.G. Statistical Methods (7th ed.) (1980) Iowa State University Press, Ames, Iowa. Tukey, J.W. Exploratory Data Analysis (1977) Addison-Wesley, Reading, MA. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 068 Folder The folder containing the original item. 1850 Series The series number of the original item. Series III Subseries III Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource McKinlay, Sonja M. Description An account of the resource <strong>Corporate Author: </strong>New England Research Institute, Inc., Watertown, Massachusetts Title A name given to the resource Women's Vietnam Veterans Health Study Protocol Development, Study Design and Protocol, Deliverable D Subject The topic of the resource Women Vietnam Veterans Health Study PTSD congenital birth defects VA ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/584708fa5dd2df0381e6bf11d2fb7306.pdf cb5ddd9d56fe48449073f6aad7ee94a8 PDF Text Text Item ID Number °1849 Author McKinlay, Sonja M. Corporate Author ^ew England Research Institute, Inc., Watertown, Mass ROpOrt/ArtldB Title Women's Vietnam Veterans Health Study Protocol Development, Questionnaire, Deliverable C Journal/Book Tltto Year 000 ° Month/Day Color D Number of Images 42 DeSCrlptOfl Notes Contract No. V101(93)P-1138 Wednesday, July 11, 2001 Page 1850 of 1870 �WOMEN'S VIETNAM VETERANS HEALTH STUDY PROTOCOL DEVELOPMENT CONTRACT NO. V101(93)P-1138 QUESTIONNAIRE DELIVERABLE C SUBMITTED BY NEW ENGLAND RESEARCH INSTITUTE, INC. PRINCIPAL INVESTIGATOR SONJA M. MCKINLAY, Ph.D. NEW ENGLAND RESEARCH INSTITUTE, INC.' 42 Pleasant Street Watertown, Massachusetts 02172 (617)923-7747 �QUESTIONNAIRE CONSTRUCTION Several instruments were reviewed for possible inclusion in the Women Veterans Health Study. Whenever possible, questions were taken from other health studies (in particular the National Health Interview Survey) to assure high validity and reliability. This is most evident in the general health section as well as the reproductive history, social support, lifestyle, and demographics sections. Since much of the life history events data is open-ended, a format used successfully in the Framingham Heart Study for hospitalizations and surgical procedures was expanded for use in the civilian employment, military history, and marital history sections. The pertinent hospitalizations and surgeries, as well as the military history, will be validated using hospital and military records respectively. The same format was used to collect employment and military history on the father of each pregnancy and the conception partner sections. These have been pre-tested extensively and have worked very well. Several questions regarding current PTSD have been buried throughout the instrument purposefully as part of the study design. The CESD scale was also included as a reliable means of assessing depression for these women in general. In addition, a short military experience section also gathers information relating to PTSD. The instrument by Dr. Robert Stretch, "Vietnam-Era Nurses Adjustment Survey" provided the basis for this section, and several questions in Stretch's instrument were used here. This instrument is based on the Vietnam-Era Veterans Adjustment Survey (VEVAS), which has been used in research on other veterans, and has established reliability. �In addition, all of the following were reviewed for this section: • The Stress Event Survey; Problem Checklist and Stress Event Test (Pearce, 1985) • The Youthful Liability Scale (Laufer, 1985) • Independent Variable and Demographic Questionnaire (Frye, 1982) • Post-Traumatic Stress Disorder Checklist (Ellen Frank, University of Pittsburgh, School of Medicine, Department of Psychiatry, 1987) • Post-Traumatic Stress Disorder questionnaire from the Diagnostic Interview Schedule (L.N. Robins, J.E. Helzer and J.L. Croughan) • Psychiatric Epidemiology Research Interview (PERI; Laufer, 1985) These instruments listed above (except for the problem checklists which are duplicative of several other instruments), were excluded due to the difficulty of administration (several must be done in an in-person interview and/or require a clinician's assessment) and the length of time required to administer them. Also, given that the primary focus of this study is on female reproductive outcomes, the scope of the study must be limited for feasibility and to meet the time limits of a telephone interview. Several general health studies as well as studies of Vietnam Veterans were reviewed for the instrument design: • • • • • • The Veterans Health Survey Questionnaire for CDC (conducted by RTI, 1985) The Survey of Female Veterans for the VA (conducted by Louis Harris and Associates, 1985) The Vietnam Era Twin Study Survey of Health The Vietnam Veterans History Questionnaire for the VA (Foy, 1986) The Ranch Hand Study for the USAF (1982) The National Health Interview Survey for the U.S. Public Health Service (1984) �The Australian Veterans Health Studies for the Australian Government (Australian Royal Commission, 1985) Thesis by Gregory Paul Korgeski for the University of Minnesota (1987) on "The Psychological, Neurological and Medical- Correlates of Self-Reported and Objective Ratings of Herbicide Exposure among Vietnam Veterans." The Women Vietnam Era Veteran's Social History Form (Butler and Samson) A Guide to Obtaining a Military History from Vietnam Veterans (Scorfield and Blank) In addition to all of those listed above, several other instruments were reviewed specifically for the reproductive history section. These instruments together formed the basis for this section and pertinent topics addressed in these instruments are covered in the protocol. In addition to instruments developed by this project's Principal Investigator on studies of female reproductive functioning and social support networks the following were reviewed: • The Reproductive Health Questionnaire for NCHS • National Survey of Family Growth Cycles III and IV for HHS • Menstrual Distress Questionnaire (Moos, 1968) • Social Support Questionnaire (Norbeck, 1983) For the nursing section, the following were very helpful and formed the basis for questions included in this section: • Protocol from the Vietnam Nurse Veteran Project (Paul and O'Neill, 1984) • The Staff Burnout Scale for Health Professionals by J.W. Jones (Cronin-Stubbs, 1985) • The Nursing Stress Scale by Gray-Toft (CroninStubbs, 1985) • Questionnaire for Rating Stressful factors in the ICU/CCU developed by Dr. L. Huckabay, (Norbeck, 1985) �These instruments were provided directly from the researchers through correspondence. �PRE-TEST REPORT The pre-test was conducted with 37 interviewees in four distinct groups: (1) twenty-seven Red Cross women who served in Vietnam; (2) one non-military nurse who served in Vietnam with AID; (3) seven Vietnam-era veterans (both nurses and non-nurses); and (4) two Vietnam veteran nurses. The majority of the 37 interviews were conducted with former Red Cross volunteers for two major reasons: (1) the similar exposure (i.e., Vietnam experience) and, (2) the fact that this group will not be eligible for the Women Veterans Health Study and therefore would not reduce the sample of interest. In order to pre-test the specific military and nursing sections however, a small number of Vietnam and Vietnam-era veterans were included. These names were made available through consultants on the project who are Vietnam and Vietnam-era veterans themselves. The names came from veterans organizations and the American Nurses' Association. The number of women from these groups was purposely small so that very few would have to be eliminated from the proposed study. The instrument went through several different modifications during the pre-test, and feedback was requested from interviewers and interviewees in an effort to improve the instrument. On the whole, the interview was well-received. Respondents felt that it was thorough, comprehensive and neither offensive nor intrusive. The utilization of professionally-trained interviewers with several years of interviewing experience was certainly an important factor in this assessment. �The interview was always conducted at a convenient time for the respondent and for the majority, a specific appointment time was made due to the length of time required to administer the initial versions of the instrument. The average length of time required to administer the instrument across all four groups was 69.61 minutes. The average was 71.20 for the Red Cross group; 85 minutes for the two Vietnam veteran nurses; 44 minutes for the one AID nurse; and 63 minutes for the seven Vietnam-era veterans (nurses and non-nurses). �INSTRUMENT BIBLIOGRAPHY NOTE: The articles cited in this Bibliography provided the basis for correspondence with the individual researchers. We requested copies of the actual questionnaires or instruments used in their research. The researchers were extremely helpful and provided us with copies of their protocols for our review. �REFERENCES Australian Royal Commission, "Royal Commission on the use and effects of chemical agents on Australian personnel in Vietnam", Australian Govt. Publish. Serv., Canberra, 1985. Cronin-Stubbs, D., Schaffner, J.W., "Professional impairment: Strategies for managing the troubled nurse", NAQ. 1985, 9(3), 44-54. Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides; Baseline Questionnaire, USAF School of Aerospace Medicine (1982). Foy, D.W., Sipprelle, R.C., Rueger, D.B., Carroll, E.M., "Etiology of posttraumatic stress disorder in Vietnam veterans: Analysis of premilitary, military, and combat exposure influences", Jnl. of Consulting & Clinical Psychology. 1984, 52, 79-87. Frye, J.S., Stockton, R.A., "Discriminant analysis of posttraumatic stress disorder among a group of Vietnam veterans", Am. J. Psychiatry, 1982, 139(1), 52-56. Gray-Toft, P., Anderson, J.G., "Stress among hospital nursing staff: Its causes and effects", Soc. Sci. and Med.. 1981, 15A, 639-647. Korgeski, G.P., Leon, G.R., "Correlates of self reported and objectively determined exposure to Agent Orange", American Journal of Psychiatry. 1983, 140(11), 1443-1449. Laufer, R., "War trauma and human development: The Vietnam experience", The Trauma of War: Stress & Rec in V. Vets., Sonnenberg, S.M., Blank, A.S., Talbott, J.A., Am. Psychiatric Press Inc., 1985, 33-55. Moos, Rudolf H., "The Development of a Menstrual Distress Questionnaire", Psychosomatic Medicine. Vol. XXX, No. 6, 1968. Norbeck, J.S., Tilden, V.P., "Life stress, social support, and emotional disequilibrium in complications of pregnancy: A prospective, multivariate study", Jnl. of Health and Social Behavior. 1983, 24, 30-46. Norbeck, J.S., "Perceived job stress, job satisfaction, and psychological symptoms, in critical care nursing", Research in Nursing and Health. 1985, 8, 253-259. Paul, E.A., "Wounded healers: A summary of the Vietnam nurse project", Military Medicine. 1985, 150(11), 571-576. �Pearce, K.A., "A study of posttraumatic stress disorder in Vietnam veterans", J. of Clinical Psychology. 1985, 41(1), 9-14. Robbins, L.N., Helzer, J.E., "Drug use among Vietnam veterans three years later", Med. World News. 1975, Oct. 27, 44-49. Robins, L.N., Helzer, J.E., Davis, D.H., "Narcotic use in Southeast Asia and afterward", Archives of General Psychiatry. 1975, 32, 955-961. Robins, L.N., Helzer, J.E., Croughan, J., Ratcliff, K.S.: "The NIMH Diagnostic Interview Schedule": Archives of General Psychiatry. 1981, 38, 381-389. Stretch, R.H., Vail, J.D., Maloney, J.P., "Posttrauraatic stress disorder among army nurse corps in Vietnam veterans", J. of Consulting & Clinical Psych.. 1985, 53(5), 704-708. �WOMEN'S VETERAN HEAIJIH STODY QUESTIONNAIRE �GENERAL HEALTH SECTION First, I have some general health questions to ask you. 1. Would you say your health in general is: 1. Excellent 2. Very good 3. Good 4. Fair, or 5. 9. 2. Poor DK Overall, how much do you worry about your health: 1. Not at all 2. Very little 3. Some of the time, or 4. Most of the time 9. DK In the past 2 weeks, have you had any illness, accident or injury which has restricted your usual activities? YES 1. NO 2. 9. DK 3.1 How many days altogether were your usual activities restricted by illness, accident or injury in the past 2 weeks? DAYS 3.2 What was the reason (or reasons) for this limitation? �I will read you a list of common problems which affect us from time to time in our daily lives. Thinking back over the past two weeks. have you been bothered by any of the following? EQ IBS £K a. Dizzy spells 1 2 9 b. 1 2 9 c. Diarrhea d. Constipation e. Persistent cough 1 1 1 2 2 2 9 9 9 f. Feeling blue or depressed 1 2 9 g. Backaches or lower back pain 1 2 9 h. Anxiety i. Upset stomach 1 1 2 2 9 9 j . Headaches 1 2 9 k. Night sweats 1. Aches/stiffness in joints 1 1 2 2 9 9 m. 1 2 9 n. Sore throat o. Loss of appetite p. Menstrual problems 1 1 1 2 2 2 9 9 9 q. Fluid (water) retention r. Difficulty in concentrating 1 1 2 2 9 9 s. Nervous tension 1 2 9 t. Urinary tract/bladder infections 1 2 9 u. Trouble with bladder control/frequency 1 2 9 v. Rapid heartbeat 1 2 9 w. Hot flushes/flashes 1 2 9 x. Nightmares 1 2 9 y. Trouble sleeping or insomnia 1 2 9 z. 1 2 9 aa. Depression 1 2 9 bb. Forgetfulness 1 2 9 Lack of energy 'Pins and needles' in hands or feet Irritability IF YES TO ANY ASK: Why do you think you've had these problems lately? �5. Compared with persons of your own age and sex, how would you rate your risk of having a heart attack or stroke within the next ten years? 1. 2. 3. 4. 5. 9. Much lower than average Somewhat lower than average About average Somewhat higher than average, or Much higher than average DK 6. Do you know approximately what your blood pressure is? SYSTOLIC DIASTOLIC DK - 999 DK - 999 7. Do you know approximately what the level of cholesterol in your blood is? mg/dl DK - 999 8. How tall are you in your stocking/bare feet without shoes? round to the nearest inch. FT. IN. DK - 999 Please INCHES 9. How much do you weigh in light indoor clothing without shoes? round to the nearest pound. POUNDS DK - 999 Please �10. Excluding weight gains due to pregnancy, since you were 21, have you ever weighed 20 or more pounds over your current weight? 1. NO 2. YES 10.1 When was that? (PROBE FOR YEAR(S) AND CIRCUMSTANCES) 10.2 What is the most you have ever weighed? POUNDS DK - 999 11. Since you were 21, have you ever weighed 20 or more pounds under your current weight? 1. NO 2. YES 11.1 When was that? (PROBE FOR YEAR(S) AND CIRCUMSTANCES) 11.2 What is the least you have ever weighed? POUNDS DK - 999 �CIVILIAN EMPLOYMENT HISTORY In order to get a complete picture of you as an individual, we need to collect a complete history on several areas of your life. I'd like to start with your civilian employment history. 1. What have you been doing for most of the past 12 months -- were you in the military, working at a non-military job for pay, going to school, or doing something else? 1. SOMETHING ELSE 2. 3. IN THE MILITARY I GOING TO SCHOOL 4. WORKING AT A JOB FOR PAY V 1. What were you doing? 01. RETIRED 02. LAID OFF 03. LOOKING FOR WORK 04. KEEPING HOUSE 05. ILL 06. DISABLED 07. VOLUNTEER WORK 08. OTHER (SPECIFY): 2. Excluding active duty while in the military, have you ever worked at a job for pay? 1. NO 9. DK V SKIP TO NEXT SECTION 2. YES 2.1 Excluding jobs before you were 21 years old and excluding active duty in the military, let's begin with your first job after you reached 21. IF NO PAID JOBS AFTER 21 YEARS OF AGE SKIP TO NEXT SECTION �2.1 FOR EACH JOB ASK: (a) What were the dates of your employment for that job? (b) Was that full-time (35 hours or more per week) or part-time «35 hours per week)? (c) What type of work did you do? What, specifically, were your job duties? FOR NURSES ASK: What was your specialty? What type of ward did you work on? (d) What type of an organization did you work for? (Was it a hospital, company, university, etc.?) And, in what city and state was it located? (e) IF NOT CURRENTLY WORKING AT THAT JOB, ASK: Why did that job end? (b) FT PT (a) DATE S JOB # 1 TO MONTH YEAR MONTH YEAR MONTH YEAR MONTH MONTH YEAR MONTH YEAR MONTH 2 YEAR YEAR MONTH YEAR 1 3 2 1 2 1 2 1 TO 2 1 TO 2 V. 4 TO MONTH YEAR MONTH YEAR MONTH YEAR 5 ' TO TO 6 MONTH YEAR (c) TYPE OF WORK �IF NURSE: SPECIALTY WARDS (d) ORGANIZATION CITY, STATE (e) WHY LEFT �2. (CONT.) FOR EACH JOB ASK: (a) What were the dates of your employment for that job? (b) Was that full-time (35 hours or more per week) or part-time « 35 hours per week)? (c) What type of work did you do? What, specifically, were your job duties? FOR NURSES ASK: What was your specialty? What type of ward did you work on? (d) What type of an organization did you work for? (Was it a hospital, company, university, etc.?) And, in what city and state was it located? (e) IF NOT CURRENTLY WORKING AT THAT JOB, ASK: Why did that job end? 7 (b) FT FT (a) DATE S JOB # 1 MONTH 1 8 YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR 9 1 1 MONTH 2 YEAR 1MONTH YEAR MONTH YEAR MONTH YEAR TO 12 2 YEAR TO 11 2 1 MONTH TO 10 2 YEAR TO MONTH 2 1 MONTH 2 1 TO YEAR TO (c) TYPE OF WORK �(d) IF NURSE: SPECIALTY WARDS 10 11 12 ORGANIZATION CITY, STATE (e) WHY LEFT �2. (CONT.) FOR EACH JOB ASK: (a) What were the dates of your employment for that job? (b) Was that full-time (35 hours or more per week) or part-time «35 hours per week)? (c) What type of work did you do? What, specifically, were your job duties? FOR NURSES ASK: What was your specialty? What type of ward did you work on? (d) What type of an organization did you work for? (Was it a hospital, company, university, etc.?) And, in what city and state was it located? (e) IF NOT CURRENTLY WORKING AT THAT JOB, ASK: Why did that job end? (b) FT PT (a) DATES JOE # 13 TO MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR ] MONTH YEAR MONTH YEAR 14 MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR 1MONTH YEAR MONTH YEAR TO 15 1 1 16 17 18 TO 2 1 TO 2 1 TO 2 1 TO 2 2 (c) TYPE OF WORK �(e) IF NURSE: SPECIALTY WARDS 13 14 15 16 17 18 ORGANIZATION CITY, STATE WHY LEFT �MARITAL HISTORY The next section asks for a complete marital history. 1. Have you ever been legally married? 1. NO 2. YES 1.1 What is your current marital status, are you: 1. Married and living with your spouse 2. Separated 3. Divorced, or 4. Widowed 1.2 How many times have you been legally married in your entire life? ENTER # GO TO MARITAL HISTORY SECTION AND RECORD MARRIAGES UNTIL YOU REACH THE # ENTERED ABOVE. �2. (a) What were the dates of your marriage? (b) IF NOT CURRENTLY IN THAT MARRIAGE, ASK: Did that marriage end in divorce, a legal separation, the death of your spouse, or in some other way? REPEAT FOR ALL MARRIAGES. (b) (a) MARRIAG E # DA REASON FOR END OF MARRIAGE TO (1) MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR TO (2) TO (3) TO () 4 TO (5) TO () 6 �REPRODUCTIVE HISTORY The next set of questions ask for a complete reproductive history. 1. Have you ever taken any form of birth control pills? 1. NO 9. D,K SKIP TO QUESTION # 2 2. YES l.la How old were you when you first began taking birth control pills? (b) What year was that? YEARS (a) 1.2 (b) 19 Are you taking birth control pills now? 1. NO 2. YES 1.2a What brand are you currently using? (BRAND NAME) I SKIP TO QUESTION # 1.4 I 1.3 How long ago did you last take birth control pills? 01.< 1 MONTH 02.> 1 MONTH; <; 1 YEAR AGO 03.> 1 YEAR; <; 5 YEARS AGO 04.> 5 YEARS; < 10 YEARS AGO 05.> 10 YEARS; <^ 20 YEARS AGO 06.> 20 YEARS AGO 1.4 As best as you can remember, I'd like to know all of the specific years or time periods when you used birth control pills, and the brand you used. �2. Have you ever used an IUD? 1. NO 9. DK SKIP TO QUESTION # 3 2. YES 2.la How old were you when you first used an IUD? (b) What year was that? (a) 2.2 YEARS (b) 19 How long ago did you last use an IUD? 01. CURRENTLY USING; < 1 MONTH 02. > 1 MONTH; < 1 YEAR AGO 03. > YEAR; <5 YEARS AGO 04. > 5 YEARS; < 10 YEARS AGO 05. > 10 YEARS; < 20 YEARS AGO 06. > 20 YEARS AGO 2.3 As best as you can remember, I'd like to know all of the specific years or time periods when you used an IUD, and the brand you used. �3. Have you ever tried to conceive a child for a period of 12 months or more and been unable to get pregnant? 1. NO 9. 2. YES DK I I SKIP TO Q # 4.1 I 4. Have you ever been in a relationship where you were having intercourse regularly (on a weekly basis) without using birth control for a period of 12 consecutive months or more without conceiving? 1. NO 2. I 4.1 YES 4 old were you when this first happened? How IF NO TO Q # 3 +4 SKIP TO QUESTION # 8 YEARS 4.2 How long did this continue for? MONTHS 4.3 1. 1. YEARS Did you or your partner ever discuss this with a health professional or have any testing to determine why you did not conceive? NO 2. YES i 4.3a 4.4 OR What types of tests did you and/or your partner have? Were you or your partner ever treated by a health professional for this? NO 2. YES ,1. 4T4a As best as you can remember, I'd like to know what types of treatments were prescribed for you and/or for your partner? 4.4b What was the outcome of the treatments? �CONCEPTION PARTNER SECTION I'd like to ask you a few questions about the man you were in a relationship with when you did not conceive after 12 months. [REPEAT QUESTIONS 1 - 7 FOR EACH MAN WITH WHOM RESPONDENT WAS IN A RELATIONSHIP FOR 12 MONTHS WITHOUT CONCEPTION.] * AT END, ASK: Did you ever try to conceive for 12 months or more with any other man or were you having regular intercourse for 12 consecutive months (on a weekly basis) with any other man without using birth control and without becoming pregnant? (IF YES, REPEAT CONCEPTION PARTNER SECTION.) 1. What is his date of birth? First the month, then the day and year. 9. DAY MONTH DK YEAR 2. Did he ever serve in the military? 1. NO 9. DK \ 2. YES I 2.1 Did he ever serve in Vietnam? 9. I DK SKIP TO QUESTION # 3 Now, I'd like to get his complete military service history while in Vietnam, for each tour of duty, beginning with his first tour in Vietnam. Please tell me where he served and for how long. Please include both temporary and permanent tours of duty. (REPEAT UNTIL COMPLETE MILITARY HISTORY FOR ALL BRANCHES SERVED IN) �2.1 (a) What branch did he serve in? 2.1 (b) Where was he stationed? (COUNTRY AND AREA) 2.1 (c) For how long? 2.1 (d) What was his rank during that time? 2.1 (e) What was his assignment? 2.1 (f) FOR DOCTORS, NURSES AND MEDICS, ASK: What was his military occupational specialty? What hospital was he assigned to? What type of ward did he work on? (a) BRANCH (d) RANK (c) TIME (b) WHERE TO MONTH MONTH YEAR YEAR TO MONTH YEAR MONTH YEAR TO MONTH YEAR MONTH YEAR TO MONTH YEAR MONTH YEAR TO MONTH YEAR MONTH YEAR MONTH YEAR TO MONTH YEAR �(f) FOR DOCTORS/ NURSES AND MEDICS: (e) ASSIGNMENT SPECIALTY HOSPITAL NAME TYPE OF WARD 1 �3. Did he ever work in the manufacture or packaging of chemicals? 1. 9. NC DB 2. SKIP TO QUESTION # 4 YES (a) What were the dates of his employment in that type of occupation? (b) Was that full-time (35 hours or more per week) or part-time « 35 hours per week)? (c) What type of work did he do? What, specifically, were his job duties? (d) What was the name of the company he worked for? (e) What was the address of the company he worked for? I need the street, the city, state, and zip code, if you know it. (a) DATES JOB (b) FT PT TO MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR 1 TO 2 1 TO 2 1 TO 2 1 TO 2 () c TYPE OF WORK �(d) NAME OF COMPANY (e) STREET ADDRESS (CITY, STATE, ZIP) �4. Did he ever work in the field of agriculture? 1. 9. YES Np DK SKIP TO QUESTION # 5 I (a) What were the dates of his employment in that type of occupation? (b) Was that full-time (35 hours or more per week) or part-time « 35 hours per week)? (c) What type of work did he do? What, specifically, were his job duties? (d) What was the name of the company he worked for? (e) What was the address of the company he worked for? I need the street, the city, state, and zip code, if you know it. (a) DATE S JOB (b) FT PT TO MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR 1 1 2 1 2 1 2 YEAR MONTH 2 YEAR MONTH 2 1 MONTH YEAR TO TO TO MONTH YEAR MONTH YEAR TO (c) TYPE OF WORK �(d) (e) NAME OF COMPANY STREET ADDRESS (CITY, STATE, ZIP) �5. Did he ever work In forestry? 1. N,0 9. DK YES SKIP TO INTERVIEWER CHECK AT THE TOP OF QUESTION # 6 I (a) What were the dates of his employment in that type of occupation? (b) Was that full-time (35 hours or more per week) or part-time « 35 hours per week)? (c) What type of work did he do? What, specifically, were his job duties? (d) What was the name of the company he worked for? (e) What was the address of the company he worked for? I need the street, the city, state, and zip code, if you know it. (a) JOB (b) FT PT DATES 1 YEAR MONTH YEAR MONTH YEAR MONTH YEAR 1 MONTH YEAR 1 YEAR MONTH YEAR 2 YEAR MONTH 2 YEAR MONTH 2 YEAR MONTH 2 1 MONTH 2 1 TO MONTH TO TO TO TO (c) TYPE OF WORK �(d) NAME OF COMPANY (e) STREET ADDRESS (CITY, STATE, ZIP) �INTERVIEWER NOTE! ASK ONLY IF CURRENTLY MARRIED TO THIS MAN 6. What Is his most recent occupation? What specifically does he do? 7. What was his usual occupation for most of the past 20 years? specifically did he do for most of that time? What �8. Have you ever been pregnant? 1. NO 9. DK SKIP TO MENSTRUAL HISTORY 2, YES I 8.1 Are you currently pregnant? 1. NO I 9. DK YES * 8.la What month of the pregnancy are you in? 2. WEEKS MONTH 8.2 Altogether, how many times (including this pregnancy) have you ever been pregnant? INTERVIEWER NOTE: TIMESIF CURRENTLY PREGNANT FOR THE FIRST TIME. SKIP TO MENSTRUAL HISTORY SECTION, GO TO PREGNANCY HISTORY AND RECORD PREGNANCIES UNTIL YOU REACH THE # ENTERED ABOVE �PREGNANCY HISTORY I'd now like to ask you a series of questions about your pregnancy. time? 1. In what year did you become pregnant for the 19 YEAR 2. How long did the pregnancy last? WEEKS 3. What was the outcome of this pregnancy? 1. ECTOPIC PREGNANCY 3. STILL BIRTH 4. LIVE BIRTH 5. *SKIP TO.QUESTION # 3 . 1 MISCARRIAGE (SPONTANEOUS ABORTION) 2. [CODE RED] INDUCED ABORTION: *SKIP TO QUESTION # 14 SKIP TO QUESTION # 4 (a) Could you please tell me why you had the abortion, or how you came to the decision to have the abortion? (b) Was there any indication that the fetus was malformed? 1. NO 9. DK SKIP TO QUESTION # 14 2. YES [CODE RED] �(c) Could you please tell me when the abortion took place? 19 MONTH YEAR (d) I'd also like to know the name and address of the hospital and the doctor who treated you. HOSPITAL NAME STREET ADDRESS CITY STATE ZIP STATE ZIP DOCTOR'S NAME STREET ADDRESS CITY SKIP TO QUESTION # 14 �3.1 Were you told by a physician that the miscarriage was caused by: [READ a - b] NO YES DK a . A congenital malformation? 2 9 b . A hydatidiform mole? 3.2 1 1 2 9 I'd also like to know the name and addresses of the hospital and the doctor who treated you. HOSPITAL NAME STREET ADDRESS CITY STATE ZIP DOCTOR'S NAME STREET ADDRESS CITY STATE ZIP �3.3 Were you or your partner given any information by a physician about why you may have had the miscarriage? 1. NO 9. DK 2. YES I 3.3.1 What were you told? 3.4 Did you or your partner ever go for genetic counseling or have any tests to determine why you had the miscarriage? 1. NO 9. DK 2. YES i 3.4.1 What types of tests were done and what was the outcome of the testing? 3.5 Did this miscarriage occur after amniocentesis or other similar test procedures? 1. NO 9. DK 2. YES * 3.5.1 What tests were you given? 1. AMNIOCENTESIS 2. OTHER (SPECIFY: 3.6 Why do you think you had the miscarriage? 9. DK SKIP TO QUESTION # 14 �INTERVIEWER NOTE: FOR MULTIPLE BIRTHS (TWINS, TRIPLETS, ETC.) RECORD FOR EACH CHILD. 4. Was this child male or female? 1. MALE 2. FEMALE 5. How much did the child weigh at birth? POUNDS OUNCES 6. Did this child have any birth defects or abnormalities when s/he was born? 1. NO 2. YES 6.1 Please describe the birth defect or abnormality. (any others?) 6.2 Could I please have the name, address, city, state and zip code of the physician who diagnosed your child's abnormality or handicap, and the hospital at which the diagnosis was made? NAME OF DOCTOR ADDRESS CITY STATE ZIP STATE ZIP NAME OF HOSPITAL ADDRESS CITY �7. Was this a forceps delivery? 1. NO 2. YES 9. DK 8. Did you smoke at all during this pregnancy? 1. NO I 9. DK 2. YES v 8.1 How many cigarettes per day on the average did you smoke during this pregnancy? CIGARETTES PER DAY 9. Did you drink alcoholic beverages at all during this pregnancy? 1. NO 2. YES 9. DK 9.1 About how often did you drink alcoholic beverages on the average during this pregnancy? 1. 2. 3. 4. 5. Less Less 1 or 3 or 5 or than once a month than once a week 2 days a week 4 days a week more days a week 10. Did you have any of the following complications during this pregnancy, as a result of the pregnancy? [READ a-d, FOR EACH YES, ASK: During which month or months of the pregnancy did you have this?] PK N_Q YES a. Toxemia 1 2 9 b. Diabetes 1 2 9 c. High Blood Pressure 1 2 9 d. Spotting (Vaginal bleeding)... 1 2 9 MONTHS �11. Did you have any other complications during this pregnancy? 1. NO I 9. DK 2. YES * 11.1 What complications? INTERVIEWER NOTE: FOR STILLBIRTHS, SKIP TO QUESTION # 14 �QUESTIONS 12 AND 13 FOR LIVE BIRTHS ONLY: 12a. How old is this child now? OR 8. DECEASED YEARS MONTHS v 12.1 How old was your child when s/he died? YEARS MONTHS 13. Did this child ever develop any abnormalities, handicaps or learning disabilities which were diagnosed? 1. NO 2. 9. 13.1 DK I SKIP TO QUESTION # 14 YES I you told that your child had a learning disorder or Were disability of any type? 1. NO 2. YES 9. DK 13.1.1 How old wsis the child wh appeared? * SKIP TO Q # 13.2 OR MONTHS YEARS �13.1.2 What specific type of disability were you told your child had? [CIRCLE ALL THAT APPLY] a. HYPERACTIVITY b. EXCITABILITY c. ATTENTION DEFICIT DISORDER d. DYSLEXIA e. OTHER (SPECIFY): 13.1.3 In what specific area of learning is the disability? 13.1.4 Who diagnosed the problem? [CIRCLE ALL THAT APPLY] 01. SPECIAL EDUCATION TEACHER 02. PEDIATRICIAN 03. PH.D. CLINICAL PSYCHOLOGIST 04. SCHOOL PSYCHOLOGIST (M.A.) 05. NEUROLOGIST 06. CHILD PSYCHIATRIST 07. OTHER (SPECIFY:; �13.1.5 Could I please have the name, address, city, state and zip code of the professional who diagnosed your child's learning abnormality, and the year in which the diagnosis was made? NAME OF DOCTOR ADDRESS CITY ZIP STATE 1 9 YEAR DIAGNOSED 13.1.6 Were you told that your child's disability was neurologically based? 1. NO 2. YES 9. DK 13.1.7 Were you told that your child's disability was emotionally based? 1. NO 2. YES 9. DK 13.1.8 What were you told was the cause of the learning disability? �13.2 Were you told that your child had any abnormalities or handicaps other than learning disabilities? 1. NO 2. YES 9. DK 13.2.1 How old was the child when this first appeared? I 4- 13.2.2 What abnormalities or handicaps did s/he develop? 13.2.3 What were you told was the cause of the abnormality or handicap? 13.2.4 Who diagnosed the problem? [CIRCLE ALL THAT APPLY] 01. PEDIATRICIAN 02. NEUROLOGIST 03. CHILD PSYCHIATRIST 04. OTHER (SPECIFY:) 13.2.5 Could I please have the name, address, city, state and zip code of the professional who diagnosed your child's abnormality or handicap, and the year in which the diagnosis was made? NAME OF DOCTOR ADDRESS CITY STATE 19 ZIP YEAR DIAGNOSED �ASK EVERYONE 14. Were you or your partner using any form of birth control when you became pregnant the time? 1. NO 9. DK 2. YES I 14.1 What type of birth control were you or your partner using at the time? (CIRCLE ALL THAT APPLY) 01. BIRTH CONTROL PILLS 02. IUD 03. DIAPHRAGM 04. SPERMICIDAL JELLY 05. SPERMICIDAL FOAM 06. CONDOMS 07. CERVICAL CAP 08. CERVICAL SPONGE 09. DOUCHING AS A FORM OF BIRTH CONTROL 10. NATURAL FAMILY PLANNING (BASAL TEMPERATURE AND/OR CERVICAL MUCUS TEST) 11. RHYTHM 12. TUBAL LIGATION 13. VASECTOMY 14. OTHER (SPECIFY): GO TO FATHER OF PREGNANCY SECTION �FATHER OF PREGNANCY SECTION I'd like to ask you a few questions about the man who fathered the pregnancy. 1. What is the father's date of birth? First the month, then the day and year. MONTH YEAR DAY INTERVIEWER CHECK: IF SAME MAN AS PREVIOUS PREGNANCY, CHECK BOX AND SKIP TO NEXT PREGNANCY. AT END OF PREGNANCY SECTION, SKIP TO MENSTRUAL HISTORY. 2. Did he ever serve in the military? 1. NO 9. DK I 2. YES ^ 2.1 Did he ever serve in Vietnam? 1. NO 2. YES * \/ 9. DK SKIP TO QUESTION # 3 Now, I'd like to get his complete military service history while in Vietnam, for each tour of duty, beginning with his first tour in Vietnam. Please tell me where he served and for how long. Please include both temporary and permanent tours of duty. (REPEAT UNTIL COMPLETE MILITARY HISTORY FOR ALL BRANCHES SERVED IN) �2.1 (a) What branch did he serve in? 2.1 (b) Where was he stationed? (COUNTRY AND AREA) 2.1 (c) For how long? 2.1 (d) What was his rank during that time? 2.1 (e) What was his assignment? 2.1 (f) FOR DOCTORS, NURSES AND MEDICS, ASK: What was his military occupational specialty? What hospital was he assigned to? What type of ward did he work on? (a) BRANCH (b) (d) (c) TIME WHERE RANK TO MONTH MONTH YEAR MONTH MONTH YEAR YEAR YEAR TO MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR TO TO MONTH YEAR TO MONTH YEAR MONTH YEAR TO �(f) FOR DOCTORS/ NURSES AND MEDICS: (e) ASSIGNMENT | SPECIALTY HOSPITAL NAME TYPE OF WARD �3. Did he ever work in the manufacture or packaging of chemicals? 1. NO 2. YES DK SKIP TO QUESTION # 4 v (a) What were the dates of his employment in that type of occupation? (b) Was that full-time (35 hours or more per week) or part-time « 35 hours per week)? (c) What type of work did he do? What, specifically, were his job duties? (d) What was the name of the company he worked for? (e) What was the address of the company he worked for? I need the street, the city, state, and zip code, if you know it. (a) DATE S JOB (b) FT PT 1 1 1 MONTH MONTH YEAR MONTH YEAR MONTH YEAR YEAR MONTH YEAR 2 YEAR MONTH YEAR 2 YEAR TO MONTH 2 YEAR MONTH 2 1 MONTH YEAR 2 1 TO MONTH TO TO TO (c) TYPE OF WORK �(d) NAME OF COMPANY (e) STREET ADDRESS (CITY, STATE, ZIP) �4. Did he ever work in the field of agriculture? 1. NO 9. 2. YES DK SKIP TO QUESTION # 5 (a) What were the dates of his employment in that type of occupation? (b) Was that full-time (35 hours or more per week) or part-time « 35 hours per week)? (c) What type of work did he do? What, specifically, were his job duties? (d) What was the name of the company he worked for? (e) What was the address of the company he worked for? I need the street, the city, state, and zip code, if you know it. (a) JOB (b) FT FT DATES TO MONTH YEAR MONTH YEAR 1 1 1 MONTH YEAR MONTH YEAR 2 1 TO YEAR 2 2 YEAR TO MONTH 2 YEAR MONTH 2 1 MONTH MONTH YEAR MONTH YEAR MONTH YEAR TO TO (c) TYPE OF WORK �(d) NAME OF COMPANY (e) STREET ADDRESS (CITY, STATE, ZIP) �5. Did he ever work in forestry? 1. NO 9. 2. YES DK v \U SKIP TO INTERVIEWER CHECK AT TOP OF QUESTION # 6 (a) What were the dates of his employment in that type of occupation? (b) Was that full-time (35 hours or more per week) or part-time « 35 hours per week)? (c) What type of work did he do? What, specifically, were his job duties? (d) What was the name of the company he worked for? (e) What was the address of the company he worked for? I need the street, the city, state, and zip code, if you know it. (a) DATES JOB (b) FT PT TO MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR- MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR 1 TO 2 1 TO 2 1 TO 2 1 TO 2 (c) TYPE OF WORK �(d) NAME OF COMPANY (e) STREET ADDRESS (CITY, STATE, ZIP) �INTERVIEWER NOTE! ASK ONLY IF CURRENTLY MARRIED TO THIS MAN 6. What is his most recent occupation? What specifically does he do? 7. What was his usual occupation for most of the past 20 years? specifically did he do for most of that time? What �MENSTRUAL HISTORY I'd now like to get a complete menstrual history from you. l.a. How old were you when your period (or menstrual cycles) started? year was that? YEARS (b) What 19 2.a. When you first began menstruating, did you experience any of the following? [READ a - k] 2.b. Over the course of your menstrual history have you experienced any of the following? 2.c. FOR EACH YES TO 2.b, ASK: When was this most severe? NO (2a) YES DK NO (2b) YES DK a. Severe cramps . 1 2 9 1 2 9 b A heavy flow . 1 2 9 1 2 9 o. Nausea or vomiting. . . . 1 . 2 9 1 2 9 d. A very short period (3 days or less) . 1 2 9 1 2 9 A very lengthy period . 1 (7 or more days) 2 9 1 2 9 e. f. Periods of Amenorrhea (loss of periods not caused by pregnancy)... 1 g. A regular but very short cycle « 28 days) 1 9 h. A regular but very long cycle (>35 days). 1 9 i. j. k. An irregular menstrual cycle anywhere between 26 - 40+ days apart with no pattern 1 2 2 Clotting during your period 2 2 1 Premenstrual symptoms (such as breast tenderness or irritability).. 1 <2c) YEARS �3. Have you had a period in the past 12 months? 1. NO 2. YES V 3.1 About how long ago was your last period? 01. HAVING IT NOW \ 02.< 1 MONTH AGO OR SLIGHTLY LONGER THAN 30 DAYS BUT STILL REGULARLY MENSTRUATING. 03.> 1; < 3 MONTHS AGO 0 . 3; <. 6 MONTHS AGO 4> 05.> 6; <.9 MONTHS AGO 06.> 9; _< 12 MONTHS AGO SKIP TO QUESTION # 6 4. V Have your periods stopped? 1. NO 2. YES 4.1 What caused your periods to stop? 01. PREGNANCY/LACTATION 02. SURGERY 03. NATURAL (NON-SURGICAL) MENOPAUSE 04. RADIATION OR CHEMOTHERAPY 05. OTHER CAUSE (SPECIFY): 99. DK �5. About how old were you when you had your last period? YEARS 6. What was the date your last period started? MONTH DAY YEAR 7. When was the last time you had a Pap Test (Pap Smear)? 1. NEVER 9. MONTH 9. DK YEAR DK 8.1 SKIP TO NEXT SECTION How often do you usually have a Pap Test? 01. AT LEAST ONCE EVERY 6 MONTHS; 02. AT LEAST ONCE A YEAR; 03. AT LEAST ONCE EVERY OTHER YEAR; 04. AT LEAST ONCE EVERY FIVE YEARS; 05. AT LEAST ONCE EVERY TEN YEARS; 06. AT LEAST ONCE EVERY 20 YEARS; 07. OTHER (SPECIFY): �MEDICAL HISTORY I'd now like to get a complete medical history from you. 1. (a) Has a doctor or other health professional ever told you that you had any of the following? [READ a - f f . ] FOR EACH YES, ASK: (b) When was this first diagnosed? (YEAR) (c) Do you still have: ? (d) Have vou been treated for in the tiast 6 months? (a) NO (b) DK YES (c) HAS (d) TREATMENT (YEAR) NO YES DK NO YES DK a. High blood pressure (hypertension) 1 9 2 1 2 9 1 2 9 b. Heart disease (inc., heart attack, heart failure, rapid heart, angina) 1 9 2 1 2 9 1 2 9 c. Diabetes (high blood sugar) 1 9 2 1 2 9 1 2 9 1 2 9 1 2 9 d. Stroke or hemorrhage o f t h e brain e. Convulsions o r seizures 1 9 2 1 9 2 1 2 9 1 2 9 f. A n y disease o f t h e pancreas 1 9 2 1 2 9 1 2 9 g- Arthritis o r rheumatism 1 9 2 1 2 9 1 2 9 h. Non-Hodgkins lymphoma 1 9 2 1 2 9 1 2 9 1 9 2 1 2 9 1 2 9 j . Fibrocystic breast disease 1 9 2 1 2 9 1 2 9 k. A pelvic infection or pelvic inflammatory disease (PID) 1 9 2 1 2 9 1 2 9 1 2 9 1 2 9 i. Cancer (IF YES, SPECIFY) 1. Abnormal P a p Smear 1 9 2 �(a) NO DK YES (YEAR) (d) (c) HAS (b) NO YES TREATMENT DK NO YES DK m. Gonorrhea 1 9 2 1 2 9 1 2 9 n. Syphilis 1 9 2 1 2 9 1 2 9 1 9 2 1 2 9 1 2 9 1 9 2 1 2 9 1 2 9 1 9 2 1 2 9 1 2 9 1 9 2 1 2 9 1 2 9 1 9 2 1 2 9 1 2 9 t. Urinary tract infections 1 9 2 1 2 9 1 2 9 u. Gallstones or any gall bladder problems 1 9 2 1 2 9 1 2 9 Any chronic stomach problems (ulcer, gastrointestinal bleeding, colitis) 1 9 2 1 2 9 1 2 9 1 9 2 1 2 9 1 2 9 1 9 2 1 2 9 1 2 9 1 9 2 1 2 9 1 2 9 z. Skin rashes 1 9 2 1 2 9 1 2 9 aa. Asthma 1 9 2 1 2 9 1 2 9 bb. Acne or chloracne 1 9 2 1 2 9 1 2 9 cc. Alcoholism 1 9 2 1 2 9 1 2 9 0. Genital herpes P- Any other sexually transmitted disease (IF YES, SPECIFY:) q- Trichomoniasis r. Vaginal warts s . Recurrent vaginal infections V. w. Allergies X. y. Any liver problems (SPECIFY) Thyroid problems (SPECIFY) �(a) (d) (c) (b) TREATMENT HAS NO DK YES (YEAR) NO YES DK NO YES DK dd. Drug Addiction 1 9 2 1 2 9 1 2 9 ee. Hepatitis 1 9 2 1 2 9 1 2 9 1 9 2 1 2 9 1 2 9 1 9 2 1 2 9 1 2 9 1 9 2 1 2 9 1 2 9 ff. Any others (SPECIFY) �We also need to know if you have ever used medications. of common medications. I am going to read a list 2. For each one, please tell me if you have ever taken it. If you have taken it, I'd like to know when you took it and for how long. (From when to when?) [READ a - z] NEVER WHEN YES, TAKEN MONTH (a) Medicine for your heart or heartbeat YEAR MONTH 2 TO 1 2 TO (c) Medicine for your blood pressure... 1 2 TO (b) Medicine for cholesterol or fats in your blood (d) Diuretic or water pills 1 TO (e) Aspirin, Tylenol or a similar non-prescription pain reliever 1 TO (f) Medication prescribed for migraine headaches 1 TO (g) Any other pain reliever needing a prescription 1 TO (h) Sleeping pills 1 TO (i) Diet pills 1 TO ( ) Pills to relax you which required a j a prescription (valium, librium)... 1 (SPECIFY:) TO (k) Medication for depression (SPECIFY:) TO 1 (1) Hormone pills for menopause or aging symptoms (premarin, DES, estrace, estrogen, etc. ) 1 (SPECIFY:) (m) Hormone treatments for any other problems (SPECIFY PROBLEM AND TREATMENT:) 1 TO TO YEAR �NEVER YES, TAKEN WHEN MONTH (n) Any antimalarial medication 1 (o) Medicine for menstrual problems.... 1 (p) Insulin 1 (q) Calcium/Turns 1 (r) Vitamins, iron supplements or other minerals 1 (s) Thyroid pills 1 (t) Medicine for an upset stomach 1 (u) Herbs or teas for medicinal purposes 1 (v) Medicine for allergies (including injections) 1 (w) Prescription medication for arthritis or rheumatism 1 (x) Prescription medication for other muscle/joint problems 1 (y) Laxatives 1 (z) Antibiotics 1 (aa.) Any others? (SPECIFY): 1 YEAR MONTH YEAR �3. Have you ever had any surgery as an in-patient or on an outpatient basis since 1960? 1. NO 2. YES 9. DK FOR EACH SURGERY, ASK: 3.1 GO TO CHECKLIST AT END OF THIS SECTION QUESTION # 4 SURGERY # [CODE RED] (a) When did you have the surgery? (b) What was the diagnosis (or for what reason were you operated on)? (c) Please give me the name and address of both the hospital where you were operated on and the surgeon who performed the operation. [RECORD EACH SURGERY, THEN GO TO CHECKLIST] (a) DATE () 1 MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR (2) (3) (5) (b) DIAGNOSIS �(c) HOSPITAL NAME ADDRESS CITY, STATE, ZIP SURGEON'S NAME ADDRESS CITY, STATE, ZIP �(SURGERIES CONTINUED) FOR EACH SURGERY, ASK: 3.1 (a) When did you have the surgery? (b) What was the diagnosis (or for what reason were you operated on)? (c) Please give me the name and address of both the hospital where you were operated on and the surgeon who performed the operation. [RECORD EACH SURGERY, THEN GO TO CHECKLIST] (a) SURGERY # DATE (6) MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR () 7 () 8 (9) (10) (b) DIAGNOSIS �(c) HOSPITAL NAME ADDRESS CITY, STATE, ZIP SURGEON'S NAME ADDRESS CITY, STATE, ZIP �(SURGERIES CONTINUED) FOR EACH SURGERY, ASK: 3.1 (a) When did you have the surgery? (b) What was the diagnosis (or for what reason were you operated on)? (c) Please give me the name and address of both the hospital where you were operated on and the surgeon who performed the operation. [RECORD EACH SURGERY, THEN GO TO CHECKLIST] (a) SURGERY # DATE (11) MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR (12) (13) (4 1) (15) (b) DIAGNOSIS �(c) HOSPITAL NAME ADDRESS CITY, STATE, ZIP SURGEON'S NAME ADDRESS CITY, STATE, ZIP �SURGERY CHECKLIST INTERVIEWER: AFTER RESPONDENT LISTS ALL HER SURGERIES PROBE ONLY FOR THOSE NOT MENTIONED ABOVE IN SURGERY SECTION. 4. Have you ever had any of the following operations or procedures? [READ a - i] m YES NOT SURE (a) Removal of the uterus 1 2 9 (b) Removal of left ovary only 1 2 9 (c) Removal of right ovary only 1 2 9 (d) Removal of both ovaries 1 2 9 (e) Tubal ligation (having your tubes tied) 1 2 9 (f) Dilation and curettage (a D&C, scraping of the uterus) 1 2 9 (g) Breast surgery for cysts or benign tumors 1 2 9 ( h ) Breast surgery f o r cancer (i) Any pelvic surgery 1 1 (IF YES, SPECIFY REASON: FOR EACH YES THAT HAS NOT BEEN RECORDED IN SURGERY SECTION, GO BACK AND COMPLETE QUESTIONS 3.1 a - c 2 2 9 9 �5. Have you ever been treated for any type of cancer or leukemia with either radiation or chemotherapy? 1. NO 9. DK 2. YES [CODE RED] V [FOR EACH SET OF TREATMENTS, ASK:] 5.1 SKIP TO QUESTION #6 (a) When were you treated? (b) What was the diagnosis (or type of cancer)? (c) Please give me the name and address of the hospital and the doctor who treated you. (b) DIAGNOSIS (a) DATE CANCER # TO (1) MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR TO (2) TO (3) TO () 4 TO (5) �(c) HOSPITAL NAME ADDRESS CITY, STATE, ZIP DOCTOR'S NAME ADDRESS CITY, STATE, ZIP �6. Have you ever been hospitalized on an in-patient or an out-patient basis for any reason (besides what we've just discussed)? Please include any hospitalization for emotional or psychiatric problems as well. 1. NO 9. 2. YES DK [CODE RED] [FOR EACH HOSPITALIZATION, ASK:] 6.1 SKIP TO QUESTION # 7 (a) When were you hospitalized? (b) What was the diagnosis (or for what reason were you hospitalized)? (c) Please give me the name and address of the hospital and the doctor who treated you. (a) DATE HOSPITAL # (b) DIAGNOSIS TO (1) MONTH MONTH MONTH MONTH YEAR YEAR MONTH YEAR YEAR MONTH YEAR YEAR MONTH YEAR MONTH MONTH YEAR YEAR MONTH YEAR TO (2) TO (3) TO TO (5) �(c) HOSPITAL NAME ADDRESS CITY, STATE, ZIP DOCTOR'S NAME ADDRESS CITY, STATE, ZIP �(HOSPITALIZATION CONTINUED) [FOR EACH HOSPITALIZATION, ASK:] 6.1 (a) When were you hospitalized? (b) What was the diagnosis (or for what reason were you hospitalized)? (c) (b) DIAGNOSIS (a) DATE HOSPITAL # TO (6) MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR TO (7) MONTH YEAR MONTH YEAR (8) (9) Please give me the name and address of the hospital and the doctor who treated you. TO L MONTH TO YEAR MONTH . YEAR TO (10) MONTH YEAR MONTH YEAR �(c) HOSPITAL NAME ADDRESS CITY, STATE, ZIP DOCTOR'S NAME ADDRESS CITY, STATE, ZIP �7. Have you ever seen a counselor or mental health professional for any reason? 1. NO I 2. 9. 7.1 SKIP TO QUESTION # 8 YES i [FOR EACH, ASK:] (a) When was that? (b) What was the reason you went? [PROBE: Any other times?] (a) DATE (b) REASON TO ( D MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR (2) MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR TO TO (3) TO TO (5) �8. Have you ever been part of a support group or therapy group led by a licensed therapist or a certified counselor, such as a licensed social worker, a psychologist or a psychiatrist? 1. NO 9. DK 2. YES * [FOR EACH GROUP, ASK:] 8.1 (a) When was that? (b) What was the reason you went? SKIP TO NEXT SECTION [PROBE: Any other groups?] (b) REASON (a) DATE TO (1) MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR TO (2) TO (3) TO () 4 TO () 5 �SOCIAL SUPPORT NETWORK The next questions concern contact with other people. 1. Are there any groups or organizations that you attend regularly, such as church groups, political groups, unions, clubs, veterans groups, exercise or sports groups, neighborhood or school associations, etc.? 1. N(o 9. 2. YES DK SKIP TO Q # 2 1.1 What is the first group that comes to mind? 1.2 How frequently do you attend it? (RECORD RESPONSES TO BOTH QUESTIONS ON THE FIRST LINE BELOW, THEN PROBE: Is there another group? How frequently do you attend it? RECORD RESPONSE ON THE SECOND LINE BELOW. REPEAT PROBE UNTIL ALL LINES ARE FILLED OR THE RESPONDENT CANNOT THINK OF ANYMORE GROUPS.) NAME OR TYPE OF GROUP AT LEAST AT LEAST AT LEAST ONCE A ONCE A ONCE EVERY 3 MONTHS WEEK AT LEAST ONCE EVERY LESS THAN ONCE EVERY 6 MONTHS 6 MONTHS 1 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2. 2 2 3 4 5 Now I have some questions about people who may be close to you. Do you have anyone who you can go to with problems or from whom you can get advice, help or emotional support? You may include your spouse, partner or other members of your immediate family, other relatives, friends, neighbors, or people with whom you work. 1. 9. NO DK SKIP TO NEXT SECTION 2. YES �2.1 Who is the first person that comes to mind? (PROBE 2 TIMES: Is there anyone else?) PERSON 1 PERSON 2 PERSON 3 IF THREE PEOPLE ARE LISTED, ASK: How many others? SIZE OF NETWORK (GRAND TOTAL): # ABOVE + Now I would like to ask you a few questions about each of the people you just mentioned. 2.2 Is (USE NAME/RELATIONSHIP GIVEN BY RESPONDENT) 1. Male 2. Female 2.3 Approximately how old is (RECORD ANSWER IN YEARS) 2.4 Is 1. 2. 3. 4. 5. Never married Married and living with spouse Separated Divorced Widowed 9. DON'T KNOW 2.5 Is currently working? [IF YES ASK, part time or full time?; 1. NO 2. 3. 9. YES,PART TIME < 35 HOURS PER WEEK YES, FULL TIME >. 35 HOURS PER WEEK NOT SURE/DON'T KNOW 2.6 Approximately how long have you known (RECORD ANSWER IN YEARS - ROUND TO NEAREST YEAR) �2.7 's ethnic background? What is 01. IRISH 09. NO PARTICULAR ETHNIC BACKGROUND 10. OTHER (SPECIFY:) (1) 02. ENGLISH 03. FRENCH OR FRENCH CANADIAN 04. GREEK 05. ITALIAN 06. BLACK, AFROAMERICAN 07. JEWISH 08. HISPANIC 2.8 What is [CIRCLE ALL MENTIONED] () 2 (3) 77. REFUSED 99. NOT SURE/DK 's relationship to you? 01 02 03 04 05 06 SPOUSE OTHER IMMEDIATE FAMILY MEMBER LIVING IN HOUSEHOLD OTHER RELATIVE NOT LIVING IN HOUSEHOLD FRIEND NEIGHBOR CO-WORKER 07. CLERGYMAN/DOCTOR/OTHER/PROFESSIONAL, ETC. 08. OTHER 2.9 live: Does 1. In your neighborhood (or within 1 mile) 2. In your town/city (within 10 miles of you) 3. Elsewhere in your state, or 4. Out-of-state 2.10 How do you and 01. 02. 03. 04. 05. 06. usually contact each other? In person, By telephone, By mail, In person and over the telephone By telephone and mail, or All three (PERSON, TELEPHONE, MAIL) 2.11 How often do you and 01. 02. 03. 04. 05. 06. contact each other in this way? AT LEAST ONCE A DAY AT LEAST ONCE A WEEK AT LEAST ONCE A MONTH AT LEAST ONCE EVERY THREE MONTHS AT LEAST ONCE EVERY SIX MONTHS LESS THAN ONCE EVERY SIX MONTHS 2.12 Who usually makes the contact? 1. Do you make the contact most of the time, does 2. make the contact most of the time or does 3. Each of you make the contact equally SKIP TO Q #3 �3. Among the other? 1. NO 9. (NUMBER) people you have named, do any of them know each 2. YES DK ASK FOR EACH PAIR 1 Does [PERSON #1] know [PERSON #2]? Does [PERSON #2] know [PERSON #3]? RECORD NAMES BELOW [PERSON #3]? NO YES NOT SURE/DK a. 1 WITH 2 1 2 9 b. 1 WITH 3 1 2 9 c. 3.2 NUMBERS OF PAIRS 2 WITH 3 1 2 9 Are these people likely to contact each other independently of you, about something which does not have to do with you? NO 2. YES DK 3.2.1 [ASK ONLY FOR PAIRS WHO KNOW EACH OTHER] Would [INSERT PAIRS] contact each other independently of you about something which does not have to do with you? RECORD NAMES BELOW NUMBERS OF PAIRS fip_ YES a . 1 WITH 2 1 9 9 2 9 2 9 b. 1 WITH 3 1 c. 2 WITH 3 1 NOT SURE/DK �LIFESTYLE SECTION This next section asks several questions about lifestyle habits, LIFESTYLE: ALCOHOL 1. On the average, do you drink alcoholic beverages: 1. Daily; 2. At least once a week; 3. SKIP TO CM 2 At least once a month; 4. Less than once a month; or 5. 1.1 Not at all 9. DK 4, 4Have you ever drunk any alcoholic beverages? 1. 1.2 NO 2. YES Are there any particular reasons why you don't drink (now)? [RECORD VERBATIM] [CIRCLE ALL THAT APPLY] a. b. c. d. e. f. g. h. i. j. k. I'VE NEVER DRUNK IN MY LIFE. RELIGIOUS/MORAL REASONS/DON'T BELIEVE IN IT/BROUGHT UP NOT TO DRINK. FOR DIET/MEDICAL/HEALTH REASONS. (FAMILY) PROBLEMS CAUSED BY OTHERS WHO DRINK. PERSONAL/FAMILY/JOB/SCHOOL PROBLEMS CAUSED BY OWN DRINKING. I'M AN ALCOHOLIC; I HAVE A DRINKING PROBLEM/I NEEDED TO STOP DRINKING/I WAS SPENDING TOO MUCH TIME DRINKING/I JOINED AA. SOCIAL/PEER FAMILY PRESSURE TO STOP DRINKING/OTHER SOCIAL CIRCUMSTANCES/OTHERS DON'T DRINK. PERSONAL PREFERENCE/I DON'T LIKE THE TASTE/DIDN'T DRINK MUCH & DECIDED TO QUIT. TOO EXPENSIVE TO DRINK/TOO MUCH MONEY, PREGNANT. OTHER: SKIP TO INTERVIEWER CHECK AT TOP OF QUESTION # 5 �2. How often do you usually drink beer? 0. Never I 9. DK 1. Less than once a month, 2. Less than once a week, i 3. I or 2 days a week, 4. 3 or 4 days a week, or SKIP TO QUESTION # 3 5. 5 or more days a week. 2.1 Thinking of all the times you have had beer recently, when you drink beer, how many do you usually drink each time? 2.2 When you drink beer, what is the most you drink? BEERS 2.3 About how often do you drink this much beer? 1. Less than once a month, 2. Less than once a week, 3. 1 or 2 days a week, 4. 3 or 4 days a week, or 5. 5 or more days a week. �3. How often do you usually drink wine, or a punch containing wine? 0. Never I 9. DK 1. Less than once a month, 2. Less than once a week, 3. 1 or 2 days a week, y 4. 3 or 4 days a week, or SKIP TO QUESTION # 4 5. 5 or more days a week. 3.1 Thinking of all the times you have had wine recently, when you drink wine, how many glasses do you usually drink each time? GLASSES 3.2 When you drink wine, what is the most you drink? GLASSES 3.3 About how often do you drink this much wine? 1. Less than once a month, 2. Less than once a week, 3. 1 or 2 days a week, 4. 3 or 4 days a week, or 5. 5 or more days a week. �4. How often do you usually have drinks containing liquor (such as martinis, manhattans, highballs, or straight drinks)? 0. Never 1. Less than once a month, 9. DK 2. Less than once a week, J 3. 1 or 2 days a week, 4. 3 or 4 days a week, or SKIP TO QUESTION # 5 5. 5 or more days a week. 4.1 Thinking of all the times you have had liquor recently, when you have drinks containing liquor, how much do you usually drink each time? 4.2 When you have drinks containing liquor, what is the DRINKS 4.3 About how often do you drink this much liquor? 1. Less than once a month, 2. Less than once a week, 3. 1 or 2 days a week, 4. 3 or 4 days a week, 5. 5 or more days a week. �[INTERVIEWER CHECK: IF RESPONDENT NEVER DRANK. SKIP TO LIFESTYLE: TOBACCO] 5. I'm now going to ask you some questions about personal experiences you may have had when drinking. DK NO YES a. Did drinking ever cause you to have an accident or injury of any kind? 1 2 9 b. Have you ever been arrested for drunk driving? 1 2 9 c. Have you ever been arrested because of anything connected with your drinking alcohol (aside from drunk driving arrests? 1 2 9 Have you ever lost or quit a job because of your drinking alcohol? 1 2 9 Have your ever lost a close friendship because of your drinking alcohol? 1 2 9 Has your drinking alcohol ever been a cause of trouble in your household? 1 2 9 Have you ever been separated or divorced because of your drinking alcohol? 1 2 9 1 2 9 d. e. f. g. h. Have you ever gotten into arguments or fights while drinking alcohol? 6. Have your drinking patterns changed at all from the time you were 18 up until now? 1. NO 2. YES I 9. DK 6.1 Did you drink more or less when you were 18 than you do now? 1. MORE 2. LESS 9. DK 6.2 What were your drinking patterns when you were 18 and how have they changed since that time? 6.3 When (during what years) did the changes occur and why did they occur? �] LIFESTYLE: TOBACCO AND OTHER . Do you: A. smoke cigarettes? 1. NO 2. YES B. smoke cigarillos? 1. NO 2. YES C. smoke a pipe? 1. NO 2. YES D. smoke cigars? 1. NO 2. YES E. chew tobacco? 1. NO 2. YES F NO TO ALL F A THRU E IF YES TO ONLY ONE OF A THRU E IF YES TO MORE THAN ONE OF A THRU E I 1.1 SKIP TO QUESTION # 2 Which do you do most often? [CIRCLE ONE] 1. Smoke cigarettes? 2. Smoke cigarillos? 3. Smoke a pipe? 4. Smoke cigars, or 5. Chew tobacco? 1.2 (REFER TO MOST FREQUENT ABOVE) When you smoke/chew , about how many do you smoke/chew in a day (cigarettes, pipefuls, plugs) UNITS 1.3 In what year did you first smoke/chew? DK - 99 1.4 Have you tried to quit in the past 12 months? 1. NO 2. YES 9. DK �1 . 5 Have your smoking/chewing patterns changed at all from the time you began up until now? 1. NO I 9. DK 2. YES 1.5.1 Did you smoke/chew more or less when you began than you do now? 1. MORE 2. LESS 9. DK 1.5.2 What were your smoking/chewing patterns when you began and how have they changed since that time? 1.5.3 When (during what years) did the changes occur and why did they occur? -SKIP TO QUESTION # 3- �2. Have you ever smoked cigarettes, cigarillos, a pipe, cigars, or chewed tobacco? 1. NO 9. DK SKIP TO QUESTION # 4 2. YES I 2.1 Which did you do most often? 1. Smoke cigarettes? 2. 3. Smoke cigarillos? Smoke a pipe? 4. 5. [CIRCLE ONE] Smoke cigars, or Chew tobacco? [REFER TO MOST FREQUENT ABOVE] ., about how many did you 2.2 When you smoked/chewed smoke/chew in a day? (cigarettes, pipefuls, plugs)? UNITS 2.3 In what year did you first smoke/chew? 99. DK 2.4a. How long ago did you quit smoking/chewing tobacco? (b) What year was that? MONTHS or (b) 19 YEARS AGO �3. Over your entire lifetime, for how long have you smoked/chewed altogether? MONTHS OR YEARS 99 . DK 4. Does anyone else live with you who smokes cigarettes at home everyday? 1. NO 2. YES 9. DK 5. Do you work, on a daily basis with coworker(s) who smoke cigarettes around you everyday? 1. NO 2. YES 9. DK 6. Have you ever used any of the following substances? [READ a - h] (IF YES to a - h, READ QUESTIONS 6.1 - 6.3 FOR THAT ITEM) 6.1 In what year did you first try it or start using it? 6.2 Do you ever use it now? 6 .3 Did you ever have a problem with vour use of IF YES, ASK: Whe n (during what years)? YEAR TRIED NO YES DK NOW USE ? PROBLEM USE YEARS NO YES DK NO YES DK ( a ) Marijuana 1 2 9 1 9 1 2 9 1 2 9 ( b ) Hashish 1 2 9 1 9 1 2 9 1 2 9 ( c ) Barbiturates (Downers) 1 2 9 1 9 1 2 9 1 2 9 ( d ) Amphetamines (Uppers) 1 2 9 1 9 1 2 9 1 2 9 ( e ) Hallucinogens 1 such as LSD or mescaline 2 9 1 9 1 2 9 1 2 9 ( f ) Cocaine 1 2 9 1 9 1 2 9 1 2 9 ( g ) Heroin 1 2 9 1 9 1 2 9 1 2 9 ( h ) Opiates 1 2 9 1 9 1 2 9 1 2 9 �7. Have you ever had a gambling problem? 1. NO 9. 2. YES I 7.1 During what years did you have that problem? DK TO 19 8. Have you ever contemplated suicide? 1. NO 2. YES I 9. DK SKIP TO NEXT SECTION 8.1 Have you ever attempted suicide? 2. YES i 8.2 How many times? 1. NO I 9. DK SKIP TO NEXT SECTION ENTER # 8.3 Could you please tell me: (a) In what year(s) you made the attempt(s)? (b) And, what was going on in your life at that time? (a) #1 # 2. #3 19 (b) �QUALITY OF LIFE SECTION 1. I am going to read ycm a list of ways you might have felt or behaved. Please tell me on hovj many different days you have felt this way during the past week: ON AT MOST ()N UP TO ON 3-4 ON 5-7 During the past week: 1 DAY 2 DAYS DAYS DAYS I was bothered by thi.ngs that usually don't be>ther me . . . . 1 2 3 4 I did not feel like €.at ing; my appetite was poor 1 2 3 4 I felt that I could rlot shake off the blues even w: .th help from my family or fri ends 1 2 3 4 I felt I was just as good as other people 1 2 3 4 I had trouble keepingr, my mind on what I was dc inE 1 2 3 4 I felt depressed 1 2 3 4 I felt that everything I did was an effort 1 2 3 4 I felt hopeful about the future 1 2 3 4 I thought my life had been a failure 1 2 3 4 I felt fearful 1 2 3 4 My sleep was restless 1 2 3 4 I was happy 1 2 3 4 I talked less than usual 1 2 3 4 I felt lonely 1 2 3 4 People were unfriendl 1 2 3 4 I enjoyed life 1 2 3 4 I had crying spells . . 1 2 3 4 I felt sad 1 2 3 4 I felt that people dislike m e . . . 1 2 3 4 I could not cet "eoine" 2 3 4 1 �2. In general, how pleased are you with the way your life has gone so far? 1. Very Pleased, 2. Pleased, 3. You wish some things were different but are generally happy, 4. Unhappy, or 5. Very Unhappy 9. DK 3. Now looking towards the future, how do you feel about the rest of your life? 1. Very Optimistic, 2. Somewhat Optimistic, 3. Unsure, 4. Somewhat Pessimistic, or 5. Very Pessimistic 8. DO NOT THINK ABOUT IT 9. DK �MILITARY HISTORY Let's go next to your military history. 1. Have you ever served either on active duty, or in the reserves in any branch of the United States armed forces? 2. YES i 1.1 Did you serve in the (READ a-d)? FOR EACH YES ASK: During which years? YES YEAR(S) ra a. National Guard or Reserves 1 2 b. Army 1 2 c. Navy 1 2 d. Air Force 1 2 e. Marines 1 2 1.2 Were you ever in ROTC? 2. YES 1. NO 9. DK 1.2.1 When was that? (PROBE FOR YEARS) 1.2.2 What college were you in when you joined ROTC and what city and state was it in? NAME OF COLLEGE CITY 2. STATE Now, could you please tell me whether you are currently on active duty, in the reserves, retired or whether you have been permanently discharged? 1. ACTIVE DUTY 3. RETIRED 2. RESERVES A. PERMANENTLY DISCHARGED 2.1. In what year did you retire (were you discharged)? [IF>1 BRANCH, ASK FOR EACH BRANCH] ^ 19 (YEAR) BRANCH 19 (YEAR) BRANCH v �3. In what year did you first enter the armed forces? 19 YEAR 4. What was the highest grade of school that you had completed when you first entered the military? 1. 1-11 2. 12 (HIGH SCHOOL DIPLOMA OR GED) 3. 13-15 (SOME COLLEGE, TECHNICAL SCHOOL, ASSOCIATE'S DEGREE) 4. 16 (BACHELOR'S DEGREE) 5. 17+ (GRADUATE/PROFESSIONAL SCHOOL) 9. DK 5. What is the highest grade of school that you have completed up until now? 1. 1-11 2. 12 (HIGH SCHOOL DIPLOMA OR GED) 3. 13-15 (SOME COLLEGE, TECHNICAL SCHOOL, ASSOCIATE'S DEGREE 4. 16 (BACHELOR'S DEGREE) 5. 17+ (GRADUATE/PROFESSIONAL 9. DK SCHOOL) 6. Why did you decide to enter the armed forces? Any others?) (PROBE: Any other reasons? �FIRST BRANCH JOINED Why did you choose that particular branch of the service? (PROBE: ANY OTHER REASONS? ANY OTHERS?) [NOTE: ASK ONLY IF NOT CURRENTLY IN BRANCH 1]: Why did you leave that particular branch of the service: (PROBE: ANY OTHER REASONS? ANY OTHERS?) INTERVIEWER CHECK: IF RESPONDENT ONLY SERVED IN ONE BRANCH, SKIP TO NEXT SECTION. IF > 1 BRANCH CONTINUE. SECOND BRANCH JOINED Why did you choose that particular branch of the service? (PROBE: ANY OTHER REASONS? ANY OTHERS?) [NOTE: ASK ONLY IF NOT CURRENTLY IN BRANCH 2]: Why did you leave that particular branch of the service: (PROBE: ANY OTHER REASONS? ANY OTHERS?) �THIRD BRANCH JOINED Why did you choose that particular branch of the service? (PROBE: ANY OTHER REASONS? ANY OTHERS?) [NOTE: ASK ONLY IF NOT CURRENTLY IN BRANCH 3]: Why did you leave that particular branch of the service: (PROBE: ANY OTHER REASONS? ANY OTHERS?) FOURTH BRANCH JOINED Why did you choose that particular branch of the service? (PROBE: ANY OTHER REASONS? ANY OTHERS?) [NOTE: ASK ONLY IF NOT CURRENTLY IN BRANCH 4]: Why did you leave that particular branch of the service: (PROBE: ANY OTHER REASONS? ANY OTHERS?) �This next question deals with your tours of duty, beginning with your entry in the armed services. Please tell me where you served and for how long. Please include basic trainif^ and both temporary and permanent tours of duty. When you first joined the (BRANCH): (REPEAT UNTIL COMPLETE MILITARY HISTORY FOR ALL BRANCHES SERVED IN.) _ * NOTE: m AT END OF THE SECTION, FOR NURSES WHO SERVED IN VIETNAM SELECT THE LONGEST VIETNAM TOUR OF DUTY. IF 1 VIETNAM TOUR OF EQUAL LENGTH, SELECT THE FIRST/SECOND TOUR FOR ALL OTHER NURSES, SELECT THE LONGEST TOUR OF DUTY BETWEEN 1965 - 1972 T EXCLUDING ANY TOURS OF DUTY WHILE A STUDENT AND GO TO NURSING SECTION. ™ 7. (a) Where were you stationed? (COUNTRY, CITY, STATE, AND AREA) And, what unit were yen __ attached to? 4p 7.(b) For how long? (From when to when?) -• -2 7.(c) What was your rank during that time? • I 7.(d) What was your assignment and your primary military occupational specialty? _ 7.(e) FOR NURSES, ASK: What hospital were you assigned to? What type of ward did you work on? 7.(*f) FOR SELECTED TOUR, ASK: May I please have the name and address of another woman who served with you on that tour of duty? (b) (c) TIME (a) WHERE BRANCH RANK • • TO (1) MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR (UNIT) TO (2) (UNIT) (*f) NAME STREET ADDRESS CITY STATE ZIP �(d) ASSIGNMENT/MOS (e) (NURSES) HOSPITAL, WARD �TOURS OF DUTY CONTINUED * NOTE: AT END OF THE SECTION, FOR NURSES WHO SERVED IN VIETNAM SELECT THE LONGEST VIETNAM TOUR OF DUTY. IF 1 VIETNAM TOUR OF EQUAL LENGTH, SELECT THE FIRST/SECOND TOUR^, FOR ALL OTHER NURSES, SELECT THE LONGEST TOUR OF DUTY BETWEEN 1965 - 1972 ^ EXCLUDING ANY TOURS OF DUTY WHILE A STUDENT AND GO TO NURSING SECTION. 7.(a) Where were you stationed? (COUNTRY, CITY, STATE, AND AREA) And, what unit were yen _J attached to? ** 7.(b) For how long? (From when to when?) _, « 7.(c) What was your rank during that time? 7.(d) What was your assignment and your primary military occupational specialty? ^>. ^ 7.(e) FOR NURSES, ASK: What hospital were you assigned to? What type of ward did you work on? 7.(*f) FOR SELECTED TOUR, ASK: May I please have the name and address of another woman who served with you on that tour of duty? (b) (a) WHERE BRANCH (c) RANK TIME TO (3) MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR (UNIT) TO (4) (UNIT) . (*f> NAME STREET ADDRESS CITY STATE ZIP �(d) ASSIGNMENT/MOS (e) (NURSES) HOSPITAL, WARD �TOURS OF DUTY CONTINUED * NOTE: AT END OF THE TOUR OF DUTY. FOR ALL OTHER EXCLUDING ANY SECTION, FOR NURSES WHO SERVED IN VIETNAM SELECT THE LONGEST VIETNAM IF 1 VIETNAM TOUR OF EQUAL LENGTH, SELECT THE FIRST/SECOND TOUR. , NURSES, SELECT THE LONGEST TOUR OF DUTY BETWEEN 1965 - 1972 jjf TOURS OF DUTY WHILE A STUDENT AND GO TO NURSING SECTION. 7.(a) Where were you stationed? (COUNTRY, CITY, STATE, AND AREA) And, what unit were you~ attached to? ** 7.(b) For how long? (From when to when?) • I 7.(c) What was your rank during that time? 7.(d) What was your assignment and your primary military occupational specialty? 7.(e) FOR NURSES, ASK: What hospital were you assigned to? What type of ward did you work on? m 7.(*f) FOR SELECTED TOUR, ASK: May I please have the name and address of another woman who served with you on that tour of duty? (a) WHERE BRANCH (b) TIME (c) RANK TO (5) MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR (UNIT) TO (6) (UNIT) (*f) NAME STREET ADDRESS CITY STATE ZIP �(d) ASSIGNMENT/MOS (e) (NURSES) HOSPITAL, WARD �TOURS OF DUTY CONTINUED * NOTE: AT END OF THE SECTION, FOR NURSES WHO SERVED IN VIETNAM SELECT THE LONGEST VIETNAM TOUR OF DUTY. IF 1 VIETNAM TOUR OF EQUAL LENGTH, SELECT THE FIRST/SECOND TOUR . FOR ALL OTHER NURSES, SELECT THE LONGEST TOUR OF DUTY BETWEEN 1965 - 1972 ^ EXCLUDING ANY TOURS OF DUTY WHILE A STUDENT AND GO TO NURSING SECTION. 7.(a) Where were you stationed? (COUNTRY, CITY, STATE, AND AREA) attached to? 7.(b) For how long? And, what unit were yo\ * (From when to when?) m 7.(c) What was your rank during that time? 7.(d) What was your assignment and your primary military occupational specialty? - 7.(e) FOR NURSES, ASK: What hospital were you assigned to? What type of ward did you work on? m 7.(*f) FOR SELECTED TOUR, ASK: May I please have the name and address of another woman who served with you on that tour of duty? (a) BRANCH (c) RANK (b) TIME WHERE TO (7) MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR (UNIT) TO (8) (UNIT) (*f) NAME STREET ADDRESS CITY STATE ZIP �(d) ASSIGNMENT/MOS (e) (NURSES) HOSPITAL, WARD �TOURS OF DUTY CONTINUED * NOTE: AT END OF THE TOUR OF DUTY. FOR ALL OTHER EXCLUDING ANY SECTION, FOR NURSES WHO SERVED IN VIETNAM SELECT THE LONGEST VIETNJfi IF 1 VIETNAM TOUR OF EQUAL LENGTH, SELECT THE FIRST/SECOND TOUR. NURSES, SELECT THE LONGEST TOUR OF DUTY BETWEEN 1965 - 1972 = TOURS OF DUTY WHILE A STUDENT AND GO TO NURSING SECTION. M 7.(a) Where were you stationed? (COUNTRY, CITY, STATE, AND AREA) attached to? 7.(b) For how long? And, what unit were yo w' (From when to when?) __ 7.(c) What was your rank during that time? ** 7.(d) What was your assignment and your primary military occupational specialty? * 7.(e) FOR NURSES, ASK: What hospital were you assigned to? What type of ward did you work on? 7.(*f) FOR SELECTED TOUR, ASK: May I please have the name and address of another womanm who served with you on that tour of duty? (b) (c) TIME (a) WHERE BRANCH • TO (9) MONTH MONTH YEAR MONTH YEAR MONTH YEAR YEAR (UNIT) TO (0. 1) (UNIT) <*f) NAME STREET ADDRESS CITY m RANK STATE ZIP �(d) ASSIGNMENT/MOS (e) (NURSES) HOSPITAL, WARD �TOURS OF DUTY CONTINUED * NOTE: AT END OF THE SECTION, FOR NURSES WHO SERVED IN VIETNAM SELECT THE LONGEST VIETNAM TOUR OF DUTY. IF 1 VIETNAM TOUR OF EQUAL LENGTH, SELECT THE FIRST/SECOND TOUR__ FOR ALL OTHER NURSES, SELECT THE LONGEST TOUR OF DUTY BETWEEN 1965 - 1972 ^ EXCLUDING ANY TOURS OF DUTY WHILE A STUDENT AND GO TO NURSING SECTION. * 7. (a) Where were you stationed? (COUNTRY, CITY, STATE, AND AREA) And, what unit were ycn^ attached to? ** 7.(b) For how long? (From when to when?) __ 7.(c) What was your rank during that time? 7.(d) What was your assignment and your primary military occupational specialty? 7.(e) FOR NURSES, ASK: What hospital were you assigned to? What type of ward did you work on? m 7.(*f) FOR SELECTED TOUR, ASK: May I please have the name and address of another woman who served with you on that tour of duty? (a) BRANCH (c) RANK (b) TIME WHERE TO (11). MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR (UNIT) TO (12) (UNIT) (*f) NAME STREET ADDRESS CITY STATE ZIP �(d) ASSIGNMENT/MOS (e) (NURSES) HOSPITAL, WARD �The following questions deal with any problems or difficulties you may have experienced while in the Military or may be currently experiencing. * 8a. While in the Military, did you: l 8b. Do you currently: [IF NO LONGER IN THE MILITARY, ASK:) 8c. Between then and now did you: (8a) NO YES DK (a.) Have trouble dealing with bad memories about your experiences i n t h e Military? (b.) Have trouble sleeping due to nightmares o r b a d dreams? (c.) Have trouble getting along with others? (d.) (e.) (f.) (8b) NO YES DK 1 2 9 i 1 2 9 1 2 9 129 '_ (8c) ' NO YES DK 129 129 1 2 9 1 2 9 1 2 9 1 Have any trouble with: (8a. superiors) (8b. t h e law)? 129 129 1 Have trouble getting emotionally close t o others? 1 2 9 1 - 2 9 1 2 9 , Have trouble controlling your temper? 1 2 9 1 2 9 1 2 9 2 9 § • (g.) Have trouble tolerating frustration? 1 2 9 1 2 9 (h.) Have sexual problems? 1 2 9 1 2 9 (i.) Have trouble expressing your feelings t o those y o u care about? 129 1 2 1 2 9 129 129 (j.) Ever feel depressed a lot? 129 129 129 (k.) Ever feel nervous a lot? 129 129 129 (1.) Have trouble feeling and expressing emotions (numbness)? 1 2 9 1 2 9 1 2 9 Have trouble trusting other people? 1 2 9 1 2 9 1 2 9 Have trouble dealing with stressful experiences? 1 2 9 1 2 9 1 2 9 129 129 (m.) (n.) (o.) Have trouble concentrating? (p.) Ever feel your actions in t h e military were n o t worthwhile? 129 129 12 12 �COMBAT EXPOSURE 9. For each of the following questions, please tell me whether or not it applies to your military experience. [READ a - i] NO a. Did you serve in area designated as a war zone? 1 b. Did you fly in an aircraft over a combat zone? YES DK 2 9 1 c. Were you stationed in a combat zone? d. Did you receive incoming fire from enemy artillery, rockets, or mortars? 1 2 e. Did you receive bombing attacks? 1 2 f. Did you receive sniper or sapper fire? g. Did you receive full-scale enemy attack? 1 h. Did you receive war-related wounds? 1 i. Did you see Americans being killed or being wounded? •. 1 2 j . Were you a prisoner of war? 1 2 �NURSING SECTION These questions refer to your general nursing experience prior to entry into the military. 1. At what type of school did you receive your basic nursing education? 1. Community or Junior College 2. Hospital based school of nursing 3. College Program 4. OTHER 9. (SPECIFY): DK 2. At graduation did you feel professionally competent to be a registered nurse? 1. NO 2. YES 9. NOT SURE/DK 3. At graduation did you feel emotionally competent to be a registered nurse? 1. NO 2. YES 9. NOT SURE/DK 4. What was your highest nursing degree when you entered the military? 01. SJUDENT [ SKIP TO Q # 18 [ 02. A.D. 03. R.N. 04. B.S.N. 05. M.S.N. 06. OTHER (SPECIFY:) 99. NOT SURE/DK �5. Before you entered the military, how much nursing experience did you have? 1. < 6 months 2. > 6 months, but 5l 1 year 3. > 1 "£- 3 years 4. > 3 ^ 5 years 5. > 5 years 9. DK 6. Before you entered the military, had you been a charge nurse? 1. NO 2. YES 9. NOT SURE/DK 7. Before you entered the military, had you worked evenings (3 - 11 PM)? 1. NO 8 2. YES 9. NOT SURE/DK . :fore you entered the military, had you worked nights (11 PM / AM)? 1. NO 2. YES 9. NOT SURE/DK 9. Before you entered the military, had you worked in a: [READ a - b] [IF YES, ASK: During which years?] NO a. Tax supported hospital (City hospital)? b. Private hospital c. OTHER (SPECIFY): 1 YES 2 YEARS �I'd like to ask you some questions regarding your work experience at the facility you worked in just prior to your entry in the military. 10. What type of facility was this? Was it a: (READ a - e) CIRCLE ONE ONLY. (a) General hospital, (b) Psychiatric hospital, (c) Outpatient facility, or (d) Doctor's office (e) OTHER (SPECIFY): 11. Was there adequate nursing staff at this facility? 1. NO 12. 2. YES 9. NOT SURE/DK In general, how were you treated by the civilian physicians at this facility? Were you treated: 1. As a colleague 2. As a servant, or 3. As a sexual object 4. OTHER (SPECIFY): 9. DK 13. Were equipment and/or supplies at this facility adequate? 1. NO 2. YES 3. NOT SURE/DK �14. Before you entered the military, in what area did you work the most? 01. MEDICAL NURSING 02. SURGICAL NURSING 03. OBSTETRICAL NURSING 04. PEDIATRIC NURSING 05. OPERATING ROOM 06. EMERGENCY ROOM 07. PSYCHIATRIC NURSING 08. PRE-ANESTHESIA HOLDING AREA (PRE-OP) 09. RECOVERY ROOM (POST-OP) 10. OTHER (SPECIFY): 99. DK 15. Before you entered the military, how much experience did you have with critically ill patients? Would you say you had: 1. A great deal of experience 2. A moderate amount 3. A limited amount, or 4. None 9. DK 16. Before you entered the military, did you regard nursing as a personally fulfilling profession? 1. NO 2. YES 9. NOT SURE/DK 17. Before entering the military, was nursing emotionally satisfying? 1. NO 2. YES 9. NOT SURE/DK �*SELECT LONGEST VIETNAM/OTHER TOUR OF DUTY '65-'72 PER INSTRUCTIONS AND EXCLUDING ANY TOUR OF DUTY WHILE A STUDENT* I'd like to focus on just one of your tours of duty, namely the time when you were stationed in ; from to . Now, I'd like to ask you a set of questions about that particular assignment. 18. What was your nursing position during this assignment? [READ 01 - 06 AND CIRCLE ONE ONLY] OjL. Operating room nurse 02. Staff nurse, 03. Charge nurse, 04. Flight nurse, 05. Intensive care nurse, or a 06. Triage/Emergency room nurse 07. OTHER (SPECIFY): [GO TO QUESTION # 19] \' 18.1 Which of the following anesthetics were used in the O.R.: was; [READ a - d] NO YES DK a . Fluothane, 1 2 9 b . Halothane, 1 2 9 c . Ketamine, o r 1 2 d . Nitrous Oxide a n d Oxygen 1 18.2 Were instruments sterilized, using: . Gas, YES 1 b. Ethylene Oxide, or c 18.3 1 . Steam NO 2. YES 1 9. NOT SURE/DK 9 DK 2 2 Were supplies of sterile equipment adequate? 1. 2 [READ a - c] NO a 9 9 9 2 9 �ASK FOR ALL NURSES 19. During this assignment was the nursing staff adequate? 1. NO 2. YES 9. NOT SURE/DK 20. During this assignment were there adequate supplies? 1. NO 2. YES 9. NOT SURE/DK 21. At the beginning of your assignment did you feel professionally competent to carry out your military assignment? 1. NO 2. YES 9. NOT SURE/DK 22. At the end of your assignment did you feel professionally competent to carry out your military assignment? 1. NO 2. YES 9. NOT SURE/DK 23. At the beginning of your assignment did you feel emotionally competent to carry out your military assignment? 1. NO 2. YES 9. NOT SURE/DK 24. At the end of your assignment did you feel emotionally competent to carry out your military assignment? 1. NO 2. YES 9. NOT SURE/DK 25. In general, how were you treated by military physicians? 1. As a colleague 2. As a servant, or 3. As a sexual object 4. OTHER (SPECIFY): 9. NOT SURE/DK 26. Were you prepared emotionally for the types of injuries you would see as a military nurse? 1. NOT PREPARED 9. NOT SURE/DK 2. YES, PREPARED 3. DIDN'T SEE INJURIES �27. Were you prepared professionally for the types of injuries you saw in the military? 1. NOT PREPARED 9. 2. YES, PREPARED 3. DIDN'T SEE INJURIES NOT SURE/DK 28. While in the military did you feel the workload was more than you could handle? 1. 29. NO 2. YES 9. NOT SURE/DK Were the hospital units where you worked noisy? 1. NO 2. YES 9. NOT SURE/DK 30. Were you concerned about physical injury to yourself while on the job? 1. NO 2. YES 9. NOT SURE/DK 31. Were you concerned about physical injury to your patients while you were working in the hospital? 1. NO 2. YES 9. NOT SURE/DK 32. In general, did you experience communication problems with other nurses? 1. NO 2. YES 9. NOT SURE/DK 33. While on this assignment were you able to adequately meet the physical needs of the patients? 1. NO 2. YES 9. NOT SURE/DK 34. Do you remember many nursing tasks as unpleasant on this assignment? 1. NO 2. YES 9. NOT SURE/DK 35. On this assignment, did new staff need to be oriented frequently? 1. NO 2. YES 9. NOT SURE/DK �36. Were your expectations of what you would be doing as a military nurse on this assignment realistic? 1. NO 2. YES 9. NOT SURE/DK 37. How stressful was it for you to perform procedures that patients experienced as painful or embarrassing? Would you say: 1. Very stressful, 2. Moderately stressful, or 3. Only mildly stressful 9. NOT SURE/DK 38. How frequently did you need to operate specialized equipment with which you were unfamiliar? Would you say: 1. Often, 2. Sometimes, or 3. Never 9. NOT SURE/DK 39. Did you personally need to make rapid decisions: 1. Often, 2. Sometimes, or 3. Never 9. NOT SURE/DK 40. Was there adequate opportunity to share your experiences and feelings with other personnel? 1. 41. NO 2. YES 9. NOT SURE/DK Were there frequently large numbers of admissions at one time? 1. NO 2. YES 9. NOT SURE/DK 42. Were non-nursing tasks often required of you? 1. NO 2. YES 9. NOT SURE/DK �43. Were you frequently without a physician available during medical emergencies? 1. NO 2. YES 9. NOT SURE/DK 44. Were you frustrated by the inability to take scheduled breaks or days off. 1. NO 2. YES 9. NOT SURE/DK 45. Do you remember many patients dying while you were on this assignment? 1. NO 2. YES 9. NOT SURE/DK 46. Were you able to follow up on the condition of your patients after they left your care? YES 1. NO 2. 9. 46.1 Did you follow up on the condition of your patients? DK I 1. NO 2. YES 9. DK 47. Did you take care of patients who were not Americans? 1. NO 9. I DK 2. YES i 47.1 Who were they? 47.2 Did you have emotional problems in dealing with these patients? YES 1. NO 2. 9. DK V (What nationality were they?) 47.2a I What types of problems? �48. On this assignment was military nursing satisfying to you in that you had the feeling of having helped your patients? 1. NO 2. YES 9. NOT SURE/DK 49. Did you receive feedback from your patients on-the nursing .care that you had given them? 1. NO 2. YES 9. NOT SURE/DK These next few questions ask about your current nursing status. 50. Are you currently employed as a nurse? 2. YES 1. NO 9. DK I SKIP TO QUESTION 51 I i 50.a How many years after this assignment did you leave nursing? 01. 0 - 3 YEARS 02. > 3 £.5 YEARS 03. > 5 ; . 7 YEARS £ 04. > 7 £ 10 YEARS 05. > 10 YEARS 06. NOT CURRENTLY EMPLOYED AS A NURSE, BUT HASN'T LEFT NURSING 99. DK 51. What is the highest nursing degree you have earned up until now? 01. A.D. 02. R.N. 03. BACHELORS IN NURSING 04. MASTERS IN NURSING 05. DOCTOR OF NURSING SCIENCE/PH.D. IN NURSING 06. OTHER (SPECIFY): 99. DK �VETERANS SERVICES [INTERVIEWER CHECK: IF RESPONDENT IS CURRENTLY IN THE MILITARY SKIP TO QUESTION # 3] Now I would like to ask you some questions about some programs for veterans. 1. Have you had any contact at all with the Veterans Administration since you got out of the service? 1. NO 9. DK 2. YES I 1.1 What have you been in contact with them about as best as you can recall? (DO NOT READ LIST -- CIRCLE ALL THAT APPLY] 01. LIFE INSURANCE 02. EDUCATION BENEFITS 03. HOME LOAN 04. MEDICAL PROBLEMS/BENEFITS 05. DISABILITY COMPENSATION 06. EMPLOYMENT, JOB ASSISTANCE 07. DENTAL CARE 08. INFORMATION ABOUT BENEFITS 09. OTHER (SPECIFY): 2. Are you currently receiving service-connected-disability compensation from the Veterans Administration? 1. NO 1 9. 2. YES I 2.1 What is your current VA disability rating? DK PERCENT 2.2 In what year did you first receive this rating? 19 3. Do you currently belong to any Veterans organizations? 1. NO 2. YES .1. 8.1 Which ones: (1.) NAME STREET ADDRESS CITY STATE ZIP NAME STREET ADDRESS CITY STATE ZIP (2.) �4. To the best of your knowledge, are you currently eligible for any Veterans Administration programs? 1. NO 9. DK I SKIP TO NEXT SECTION 2. YES I 4.1 Which ones? [RECORD VERBATIM AND CIRCLE ALL THAT APPLY] 01. HOSPITAL CARE FOR VETERANS WITH SERVICE-CONNECTED DISABILITIES 02. HOSPITAL CARE FOR VETERANS WITH LOW INCOMES 03. HOSPITAL CARE IN VA FACILITIES FOR ALL VETERANS 65 AND OVER 04. MONEY TO HELP VETERANS COMPLETE THEIR EDUCATION UNDER THE G.I. BILL 05. VOCATIONAL REHABILITATION TRAINING FOR VETERANS WITH SERVICE-CONNECTED DISABILITIES 06. FINANCIAL COMPENSATION FOR VETERANS WITH SERVICE-CONNECTED DISABILITIES 07. PENSIONS FOR LOW-INCOME VETERANS 08. NURSING HOME CARE FOR VETERANS AGED 65 AND OVER 09. DENTAL CARE IN VA FACILITIES 10. LIFE INSURANCE 11. HOME LOAN GUARANTEES 12. VOCATIONAL COUNSELING 13. TREATMENT FOR VETERANS WITH DRINKING PROBLEMS 14. TREATMENT FOR VETERANS WITH DRUG PROBLEMS 15. READJUSTMENT COUNSELING 16. PSYCHOLOGICAL COUNSELING OTHER THAN READJUSTMENT COUNSELING ' 17. DOMICILIARY CARE IN VA FACILITIES ' 18. OUTPATIENT CARE AT VA FACILITIES | i i , ' i �OVERSEAS VOLUNTEER WORK This question deals with any volunteer overseas assignments you may have had apart from your work history which we've already discussed. Did you ever go overseas or to another country as a volunteer? through the Peace Corps, or with a religious group? 2. For example, YES (a.) With what organization? (b.) Where did you go? (c.) When were you there? (d.) From when to when? What type of volunteer work did you do? (e.) Why did you decide to join the ? (f.) Why did you go to this particular country? [PROBE: Any others?] (a) (b) ORGANIZATION (c) TIME WHERE (d) TYPE OF WORK TO MONTH YEAR (e) MONTH YEAR MONTH YEAR MONTH YEAR (f) TO MONTH YEAR (e) (f) TO MONTH (e) YEAR (f) �PERSONAL HISTORY AND DEMOGRAPHICS Now I have just a few general background questions. 1. What is your date of birth? MONTH DAY I need the month, then the day and year. YEAR 2. How many people live in your household (unit) including yourself? TOTAL # 1. LIVES ALONE 2. LIVES WITH OTHERS (IF ONE OTHER MENTIONED) Who is that? (IF MORE THAN ONE OTHER) Who are they in relation to you? PROBE AT END: Anyone else? [RECORD # IN EACH BOX] a. SPOUSE/PARTNER b. MOTHER &/OR M-IN-L c. FATHER &/OR F-IN-L d. DAUGHTERS (STEPDAUGHTERS) e. SONS (STEPSONS) f. SISTERS g. BROTHERS h. OTHER FEMALE/FEMALES i. OTHER MALE/MALES �Did your mother ever take DES (Diethylstylbesterol) while she was pregnant with you or during any other pregnancy before you were conceived? 1. NO 2. DK 2. YES 3.1 Was that with you or during another pregnancy before you were born? 1. WITH RESPONDENT 2. WITH ANOTHER PREGNANCY BEFORE RESPONDENT WAS BORN 9. DK V Were any of your female blood relatives ever diagnosed as having breast cancer? 1. NO I 9. DK 2. YES 4.1 Who was that: I don't need the name, just the relationship to you. [PROBE: Any other blood relatives? CIRCLE ALL THAT APPLY] 01. MOTHER 02. SISTER 03. MOTHER'S SISTER 04. FATHER'S SISTER 05. MATERNAL GRANDMOTHER 06. PATERNAL GRANDMOTHER �5. Have you ever been fearful of having children, or of having more children for any reason? 1. NO 2. YES 9. DK 5.1 (a) When was that, (during what years)? (b) And, why were you afraid? (a) 19 TO 19 (b) V 6. While you were growing up, did anyone in your family have a drinking problem? 1. NO I 9. DK 2. YES v 6.1 Could you please tell me what that person's relationship was to you? [PROBE: Anyone else? CIRCLE ALL THAT APPLY] 01. MOTHER 02. FATHER 03. SISTER 04. BROTHER 05. SON 06. DAUGHTER 07. HUSBAND OR PARTNER 08. STEP-PARENT/FOSTER PARENT 09. OTHER RELATIVE (IN-LAWS, AUNTS, UNCLES, COUSINS, NIECES, NEPHEWS, ETC.) 10. MYSELF �7. Have you ever lived on a farm or ranch? 2. YES V FOR EACH ASK: 1. NO 9. DK I (a) During what years did you live on a farm or ranch? (b) Was it a farm or a ranch? SKIP TO QUESTION # 8 (c) What was the street address, and the city, state and zip code? [PROBE: any others?] (a) DATES FARM 1 YEAR MONTH YEAR MONTH YEAR MONTH YEAR 1 MONTH YEAR 1 YEAR MONTH YEAR 2 YEAR MONTH 2 YEAR MONTH 2 YEAR MONTH 2 1 MONTH 2 1 TO MONTH (b) RANCH TO TO TO TO (c) STREET ADDRESS CITY, STATE, ZIP CODE �8. Did you ever live in an area that was subject to documented chemical or toxic exposures? (TIMES BEACH, MO, LOVE CANAL, NY) 1. NO 2. YES 9. DK [FOR EACH ASK:] I (a) When did you live there? (b) What was the street address and the city, state and zip code? SKIP TO QUESTION # 9 [PROBE: any others?] (b) (a) DATE S A STREET ADDRESS CITY, STATE, ZIP CODE TO MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR MONTH YEAR TO TO TO TO �9. Have you ever been exposed to any of the following substances in situations other than what we've already discussed [READ a - f] FOR EACH YES, ASK: (a) When were you exposed? (What were the dates?) (b) How were you exposed? (c) What was the street address and the city, state and zip code of the area? NO DK YES (a) DATES a. Asbestos b. Nuclear radiation c. Industrial chemicals d. Defoliants or herbicides e. Insecticides or pesticides 1 f. Degreasing chemicals 10. Have you ever used insect repellant on a weekly basis for a month or more? 1. NO 9. DK 2. YES 10.1 When was this? [PROBE FOR YEARS] �(b) HOW (c) STREET ADDRESS CITY, STATE, ZIP CODE �11. And, what state were you born in? [INTERVIEWER NOTE: IF R BORN OUTSIDE THE UNITED STATES, RECORD THE COUNTRY OF BIRTH.] STATE OR COUNTRY OF BIRTH 12. How would you describe your ethnic background? [CIRCLE ALL MENTIONED] 01. IRISH 11. SCOTTISH 02. ENGLISH 12. WELSH 03. FRENCH OR FRENCH CANADIAN 13. GERMAN, AUSTRIAN, SWISS 04. GREEK 14. SWEDISH, FINNISH, DANISH, NORWEGIAN 05. ITALIAN 15. NO PARTICULAR ETHNIC BACKGROUND 06. BLACK, AFRO-AMERICAN 16. OTHER (SPECIFY:) 07. JEWISH 08. HISPANIC, SPANISH 77. REFUSED 09. POLISH 99. NOT SURE/DK 10. RUSSIAN 13. What is your religious preference now? Are you: 01. Catholic, 02. Jewish, 03. Protestant, or 04. Something else? (SPECIFY): 05. NO RELIGION 14. What religion were you raised in? 01. CATHOLIC 02. JEWISH 03. PROTESTANT 04. SOMETHING ELSE 05. NO RELIGION (SPECIFY): ________ �15. Which of the following groups do you consider yourself to be a part of? 01. White, Non-Hispanic 02. Black, Non-Hispanic 03. White - Hispanic 04. Black - Hispanic, or 05. Asian or Pacific Islander 06. OTHER 99. DK 16. Which of the following groups represents the total income during the past 12 months for all members in your household added together. Think of all possible sources of income such as wages, salaries, social security, interest income and so forth. Is it: 01. Less than $5,000 02. $5,000 - $9,999 03. $10,000 - $19,999 04. $20,000 - $29,999 05. $30,000 - $39,999 06. $40,000 - $49,999 07. $50,000 - $79,999 08. $80,000 - $99,999 09. OVER $100,000 77. REFUSED 99. DK �INTERVIEWER CHECK: 1. NO WERE THERE ANY "CODE REDS"? 2. YES We would like to obtain copies of your medical records. We will mail you a release form in the near future. Please sign it and return it promptly. Thank you again. In order for us to re-contact you, should we need to do so, I'd like to get the name, address and phone number of someone who does not live in your household, but who is likely to know how to reach you. NAME LAST FIRST MI CITY STATE ZIP CODE STREET ADDRESS TELEPHONE NUMBER ( ) Thank you, this concludes our interview. If you have any comments regarding the interview in general or the questions I have asked please tell me and I will jot them down. �[PLEASE COMPLETE AFTER EACH INTERVIEW] INTERVIEWER'S NOTES 1. Please rate how comfortable Respondent was during interview. Not at all comfortable 1 Very comfortable 2 3 4 5 2. Please rate how cooperative Respondent was during interview. Not at all cooperative 1 Very cooperative 2 3 4 5 3. Did the Respondent have difficulty answering any of the questions? 1. NO 2. YES >Which ones? 4. Do you feel that the Respondent gave inaccurate or misleading information in any of the questions? 1. NO 2. YES >Which ones? 5. Were there any unusual circumstances at the time of the interview (e.g., R had difficulty hearing, concentrating, or there were frequent interruptions, etc.)? 1. NO 2. YES >Which ones? � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 068 Folder The folder containing the original item. 1849 Series The series number of the original item. Series III Subseries III Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource McKinlay, Sonja M. Description An account of the resource <strong>Corporate Author: </strong>New England Research Institute, Inc., Watertown, Massachusetts Title A name given to the resource Women's Vietnam Veterans Health Study Protocol Development, Questionnaire, Deliverable C Subject The topic of the resource Women Vietnam Veterans Health Study PTSD veteran psychological health VA ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/464c4ee717a0a2411a166973c82cc31d.pdf ab0da5137799558d60bc46d676ba46bf PDF Text Text Item ID Number 01848 Author Skinner, Katherine M. Corporate Author New England Research Institute, Inc., Watertown, Mass Report/Article HUB Women's Vietnam Veterans Health Study Protocol Development, Addendum, Literature Review and Bibliography, Deliverable A Journal/Book Title Year 000 ° Month/Day Color n Number of Images 9 DOSCTlptOn Notes Contract No. V101 (93)P-1138; Provides a brief review of occupational exposure of nurses to hexachlorophene. Wednesday, July 11, 2001 Page 1849 of 1870 �WOMEN'S VIETNAM VETERANS HEALTH STUDY PROTOCOL DEVELOPMENT CONTRACT NO. V101(93)P-1138 ADDENDUM LITERATURE REVIEW AND BIBLIOGRAPHY DELIVERABLE A SUBMITTED BY NEW ENGLAND RESEARCH INSTITUTE, INC. PRINCIPAL INVESTIGATOR SONJA M. MCKINLAY, Ph.D. NEW ENGLAND RESEARCH INSTITUTE, INC. 42 Pleasant Street Watertown, Massachusetts 02172 (617)923-7747 �This addendum provides a brief review of an important occupational exposure for nurses - hexachlorophene - not included in the original review. This review should be included as Sub-section 5.1 A Exposure; Hexachlorophene. in Section 5. Nursing: Occupational Risks. Author: Katherine M. Skinner, M.A. �5.1.A EXPOSURE; HEXACHLOROPHENE Fingerhut et al. (1985) in an update of an earlier article present a status report on the NIOSH Occupational Dioxin Registry. This report indicates, clearly, that 2,3,7,8-TCDD (abbreviated to TCDD) is a contaminant in the process of manufacturing hexachlorophene as well as 2,4,5-T. Figure 1, reproduced from this report, summarizes the chemical process which produces 2,4,5-T, hexachlorophene and TCDD as a contaminant. Hexachlorophene was used for many years as a cleansing and disinfecting agent, with nurses being a consistently exposed occupational group. This substance was used routinely by nurses all through the period of the Vietnam conflict, until the late 1970's, when it was gradually withdrawn from use. Primarily used as a bacteriostatic agent, patients showered with hexachlorophene (marketed as pHisohex) for three consecutive days before elective operations. At time of surgery, the operative site would once again be scrubbed with pHisohex. All operating room personnel were required to scrub their fingers, hands and arms (up to the area just above the elbow) with brushes and pHisohex for fifteen minutes before participating in any operations. In the delivery room, the vaginal canal was usually cleansed with pHisohex before pelvic examinations were performed. Infants were bathed in pHisohex immediately after birth to remove meconeum, amniotic fluid and the vernix caseosa covering them. Hospital personnel were encouraged to wash their hands before touching another patient to prevent crosscontamination and thereby limit nosocomial infections. An editorial by Husaey in JAMA (1985), was the first to warn of adverse effects in the brain of newborns who developed staphylococcal infections after having been bathed in hexachlorophene. Bhargava et al (1976) reported that the effect on the blood coagulation process after dermal application of hexachlorophene was a reduction in coagulation time, an increase in the number of platelets and an enhancement of the ESR (esinophil sedimentation rate). Steinbeck (1977), who studied the local and systemic effects of commonly used cutaneous agents on mice and rabbits, reported that the mice showed no local toxic changes or tumor formation, and the systemic tumor incidence, i.e. tumors of the liver, lungs, lymphatic system, and other organs was similar to that of control animals. In rabbits, a number of proliferative benign and malignant ear tumors were observed in the positive controls, thereby demonstrating the efficacy of this model. Local toxic changes were seen in the benzalkonium and Al �hexachlorophene treated animals, but no skin tumors. Four animals had uterine tumors. In addition, one lung and one kidney tumor unrelated to the method of treatment were seen. An F.D.A. bulletin (1978) warned of drug induced abnormalities when hexachlorophene was used during pregnancy. A study by Siddicui et al. (1978) reports that an emulsion containing 0.25% hexachlorophene, 9.5% turpinal, 1.5% oil of turpentine, 13% ethanol, 6% castor oil distillate and 6% sodium salt, when given orally or instilled into conjunctival sacs of albino mice, produced lethal and insignificant toxic manifestations respectively, but a dose equivalent to 50 mg/kg given subcutaneously was found to produce a subacute lethal effect in guinea pigs. Fischer (1978) reported drug induced abnormalities in newborns exposed to hexachlorophene. Brandt et al. (1970) examined transplacental passage and embryonic fetal accumulation in mice. An experiment conducted by Maxwell and Le Quesne (1979) reported that in rats exposed to hexachlorophene for 3 weeks, maximum motor nerve conduction velocity in sciatic nerves was reduced by 7.5%. Histological examination showed intramyelin edema affecting some fibers and axonal degeneration of other fibers. In addition to intramyelin edema and axonal degeneration, segmental demyelination was present in animals who had been intoxicated with hexachlorophene for more than three months. However, there was no correlation between the degree of edema and reduction of conduction velocity. A letter published in Lancet. 1982, described hexachlorophene poisoning. Another letter by Martin-Bouyer and Stolley published the following week in Lancet described the toxicity of hexachlorophene. Myers et al (1982) adapted a non-invasive method for measurement of nerve blood flow to test the hypothesis that increased endoneural fluid pressure causes a reduction in nerve blood flow in the vasa nervosum. Their study supports the results that increased endoneural fluid pressure exacerbates the neuropathy by diminishing local blood flow. Winchell et al (1982) in studying toxic effects of hexachlorophene reported myelin-associated glycoprotein was localized immunocytochemically in periaxonal regions of oligodendraglia during hexachlorophene intoxication. Using a technique for microgravemetric analysis of nerve edema, Castello, Powell and Myers (1982) demonstrated A2 �increased water content in hexachlorophene neuropathy since there was a marked difference between hexachlorophene treated and control nerves. The water content of hexachlorophene intoxicated nerves was approximately 10% greater than control nerves. Schwetz (1985) reported adverse effects of environmental agents including hexachlorophene on the central nervous system caused by prenatal exposure. Rapoport, Menshikova and Bobkova (1985) reported an embryo toxicity associated with hexachlorophene after experimenting with dose induced pathology in guinea pigs. Using Falck-Hillarp fluorescence histochemistry, Henschenl and Olsen (1983) reported possible toxic effects of hexachlorophene or sympathetic adrenergic nerves. The experiment demonstrated a new aspect of hexachloropheneneurotoxicity degeneration of peripheral adrenergic nerve terminals and suggested that neurotoxic action on this unmyelinated fiber system should be looked for also in the central nervous system. Brandt, et al (1983) when studying the placental transfer of hexachlorophene in the Marmoset Monkey found the highest concentration in the liver and intestinal contents of the late fetus and newborn monkey. Bouin, Buentzet, Pradal (1983) in a study of resorption of drugs through the vaginal wall concluded that hexachlorophene is rapidly and largely absorbed through vaginal epithelium. Strickland et al (1983) reported that hexachlorophene from vaginal lubricants is variably absorbed from the vaginal mucosa and appreciable amounts can be detected in maternal and cord serum. Because of the potential for neonatal hexachlorophene toxicity, they recommended the use of alternative lubricants for pelvic examinations during labor. In a comparative study of chemically induced fetal death of mice, Dymin, et al (1984) reported the embryotoxic, gonadotoxic (oligosperma) and mutagenic effects of hexachlorophene. While studying the effects of reported hexachlorophene treatments on the mouse brain, Prosad et al (1984) concluded the catalytic efficiency of the mouse brain was significantly decreased during repeated hexachlorophene treatment. The fall in the activity potential of ACLE may account for the interference of hexachlorophene which may contribute to its neurotoxicity. A3 �After observing 5 infants with transcutaneous intoxication resulting from hexachlorophene contaminated talcum powder, Larregue et al (1984) described the dermatitis as characterized by its red pants shape, occurring suddenly/ its papyraceous aspect, and its association with severe encephalopathy. The neurologic signs with edematous degeneration of myelin characteristic of hexachlorophene toxicity, start with epileptic fits and progress rapidly to coma. The prognosis is serious leading either to death or to paraplegia. A recently published article by De Caprio et al (1987) examined the in vitro "dioxin-like activity of the environmental contaminant 1,2,4,5,7,8 hexachloro (9H)xanthene. After a number of sites in Missouri had been contaminated with polychlorinated dibenzodioxins and dibenzofurons from improper application of waste oil for dust control, 1,2,4,5,7,8-hexachloro(9H) xanthene, a byproduct of hexachlorophene manufacture was also detected. In view of the potential importance of this class of environmental contaminants, studies were then conducted to examine the acute oil toxicity in guinea pigs of in-vitro "dioxin-like" activity of 1,2,4,5,7,8 HCX. No compound or dose related mortality, body weight loss, or organ weight changes were noted at any dose level. Results using an in vitro bioassay for "dioxin-like" activity confirmed preliminary data suggesting 1,2,4,5,7,8- HCX, is about 10(6) times less potent than 2,3,7,8, tetrachlorodibenzo-p-dioxin (2,3,7,8, TCDD). These findings indicate that 1,2,4,5,7,8 HCX may represent a relatively low environmental hazard compared to 2,3,7,8 TCDD. A4 �Baurin, M; Guenzet J, Pradal, G.; Resorption of drugs through vaginal wall; J. Gynecol. Obstet. Biol. Reprod. 1983; 12(7):717-26. Bhargava, A.S.; Staben, P., Nienweboer, b; Giunzel, P; Effect of Hexachlorophene on the coagulation process in beagle dogs, Arzneimittedforshung, 1976;26(12):2183-5. Brandt, I; Dencker, L; Larson, Y., Transplacental passage and embryonic-fetal accumulation of hexachlorophene in mice, Toxicol Appl. Pharmacol; 1979, June 30; 49(2):393401. Brandt, I, Dencker L; Larson, K.S.; and Siddall R.A; Placental transfer of hexachlorophene in the marmoset monkey, Acta Pharmacol Toxicol. 1983 Apr;52(4)310-3. Carefully avoid hand disinfection, M.M.W.; 1978, Nov.lO;120(45):1973. Castellomi, Powell H.C; Myers R.R.; Microgravi-metric analyses of nerve edema, muscle Nerve, 1982, Apr 5; (4):261-4. DeCapro, A.P. Briggs, R., Gierthy, J.L., Kim, J.C., Dleepfer, R.D., "Acute Toxicity in the guinea pig and in vitro "dioxin-like" activity of environmental contaminant 1,2,4,5,7,8 hexachloro(9H)xanethese," J. Toxicol. Environ. Health 1987;20(3):241-8. Dymin, V.V., lushkov, G.G.; Minchenko, V.A.; Bogachut, G.P. Adropova, S.N.; Experimental studies on the embryotoxic, gonadotoxic and mutogenic effects of hexachlorophene; Gig Sanit 1984. Aug; (8):25-26. Fingerhut, M.A., Marlow, D.A., Haperim, W.E., and Honchar, P.A. The NIOSH Occupational Dioxin Registry; A Status Report. Presented at the 5th International Conf. on Dioxin, Bayreuth, Fed. Rep. of Germany, Sept. 16-19, 1985. Fischer W, Malformations caused by hexachlorophene, M.M.W. 1978 Novio; 120(45):1973. Hanig, J.P., Yoder, P.O., Krops, S., Protection with butylated hydroxytoluene (BHY+T) and other compounds against intoxication and mortality caused by hexachlorophene; Food Chem Toxicol; 1984 Mar 22(3):185-9 Henschen, A; Olson,L; Hexachlorophene induced degeneration of adrenergic nerves; a\application of quantitative image analysis to Falch-Hillarp flurescence histochemistry; Acta Neuropathol (1983)59(2):109-14. A5 �Hexachlorophene-interim caution regarding use in pregnancy. F.D.A. Bui. 1978, Aug-Sep;8 (4)26-7. Hopkins, J. Hexachlorophene: more bad new than good, Food Cosmet Toxicol, 1979, Aug; 17(4):410-2. Hussey, H.H., Editorial: Hexachlorophene bating of neonates, JAMA. 1975, Jul.14:233(2):172 Larreque, M., Laidet, B., Ramdene, P., Dyeridi A; Caustic diaper dermatitis and encephalitis secondary to the application of talcum contaminated with hexachlorophene; Ann Dermatol Venereal 1984; 111(9):789-97. Martin, Bouyer G, Stolley P.P., Hexachlorophene poisoning/Lancet 1982, May 15; 1 (8281):1121. Maxwell, I.e., Le Quesne, P.M., Conduction velocity in hexachlorophene neuropathy: correlation between electrophysiological and histological findings; J. Neurol .; 1979 Sep 43(1) 95-110. Myers, R.R; Mizisin A.P.; Powell, H.C.; Lampert P.W., Reduced nerve blood flow in hexachlorophene neuropathy; relationship to elevated endoneurial fluid pressure. J. Neuropathal EXP Neruo; 1982 Jul; 41(4) 391-9. Prasad, G.V., Rayendra, W., India K; Catalytic potential of field mouse Mus bllduga brain acetylcholinesterase during repeated hexachlorophene treatment, Toxicol Lett; 1984; Nov. 23(2):177-82. Rapoport, K.A.; Menshikova, T.A., Bobkova, E.A., Experimental data on the study of the embryotoxic acton of hexachlorophene, a component of antimicrobial textiles and household chemicals; Gig. Sanit; 1982 Oct; (10)26-9. Schwetz, B.A., Reproductive toxicity of environmental agents; Annu Rev. Public Health 1982;3:1-27. Siddigui, M.A. Mahmood I, Basit, N; Ahmed S., Bukhariao, Antimicrobial and toxicological studies on an antiseptic based on hexachlorophene and destructive destillate of castor oil. G. Batteriol Viol. Immunol. 1978, JulDec;71(7-12):191-9. Stenblack F; Local and systemic effects of commonly used cutaneous agents: Lifetime studies of 16 compounds in mice and rabbits Acta Pharmaciol Tociol. 1977 Nov; 41(5):41-31. Strickland, D.M.; Leonard R.G.; Staochonskey, S.; Benoit T; Wilson, R.T. Vaginal absorption of hexachlorophene A6 �during labor; Aroer J. Obstet. Gvnecol; 1983, Decl; 147(7):769-72. Winchell K.H., Sternberger N.H., Welister H.D., Myelinassociated glycoprotein localized immunocytochemically in periaxonal regions of abigodendroglia during hexachlorophene intoxication; Brain Res, 1982, May 13; 239(2) 679-84. A7 � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 068 Folder The folder containing the original item. 1848 Series The series number of the original item. Series III Subseries III Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Skinner, Katherine M. Sonja M. McKinlay Description An account of the resource <strong>Corporate Author: </strong>New England Research Institute, Inc., Watertown, Massachusetts Title A name given to the resource Women's Vietnam Veterans Health Study Protocol Development, Addendum, Literature Review and Bibliography, Deliverable A Subject The topic of the resource Women Vietnam Veterans Health Study industrial exposure VA ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/6d7e361fc5632ef291cabb29eead8ca0.pdf 1b57bde29ef5f0a8c2419e97884edf17 PDF Text Text ItenHDNunber 01C47 Author McKinlay, Sonja M. COTDOratO Author New England Research Institute, Inc., Watertown, Mass RGpOTt/Artlde TIUB Womens Vietnam Veterans Health Study Protocol Development: Literature Review and Bibliography, Deliverable A. Journal/Book Title Year 000 ° Month/Day Color D Number of Images 129 DOSCriptOn NOtBS Contract No. V101 (93)P-1138 Wednesday, July 11, 2001 Page 1848 of 1870 �WOMENS VIETNAM VETERANS HEALTH STUDY PROTOCOL DEVELOPMENT CONTRACT NO. VlOl(93)P-1138 LITERATURE REVIEW AND BIBLIOGRAPHY DELIVERABLE A SUBMITTED BY NEW ENGLAND RESEARCH INSTITUTE AUTHORS SONJA M. MCKINLAY, PH.D SHARON L. TENNSTEDT, PH.D NEW ENGLAND RESEARCH INSTITUTE, INC. 42 Pleasant Street Watertown, Massachusetts 02172 (617)923-7747 �ACKNOWLEDGEMENTS The authors wish to acknowledge the contributions of: project staff, expert panel consultants, Dr. Kang of the Veterans Administration, and Richard Neugebauer, Ph.D., M.P.H., Columbia University, who permitted sections of his unpublished manuscript on stress and adverse reproductive outcomes to be reprinted in this review. ii �TABLE OF CONTENTS INTRODUCTION 1 1. WOMEN VIETNAM VETERANS 3 2. COMBAT-RELATED STRESS 9 2.1 War Stress 9 2.1.1 Measurement of War Stress 2.2 Post-Traumatic Stress Disorder 2.2.1 2.2.2 2.2.3 2.2.4 2.2.5 13 14 Clinical Symptoms and Diagnostic Criteria..15 Prevalence 16 Studies of Women Veterans 16 Studies of Male Veterans 19 Methodological and Measurement Issues 22 2.3 Stress and Adverse Reproductive Outcomes 2.3.1 Pregnancy Complications 2.3.2 Menstrual Disorders 24 24 27 2.4 Summary DRUG USE AMONG THE MILITARY IN VIETNAM 29 3.1 Antimalarial Drug Use 3. 28 29 3.1.1 Chloraquine-Primaguine 30 3.1.2 Dapsone 32 3.1.3 Summary 34 3.2 Illicit Drug Use 34 3.2.1 Marijuana 38 39 40 3.2.5 Studies of Female Veterans 3.2.6 Summary 4. 35 3.2.2 Heroin 3.2.3 Alcohol 3.2.4 Drug Use After Vietnam 43 44 CHEMICAL EXPOSURES 46 4.1 Phenoxy Herbicides 46 4.1.1 Animal Studies 4.1.2 Human Studies of Herbicide Exposure 4.2 Insecticides 47 48 56 iii �4.3 Summary NURSING: OCCUPATIONAL RISKS 65 5.1 Exposure: Trace Anesthetic Gases 5. 57 65 5.1.1 Clinical Studies 5.1.2 Animal and Tissue Studies 5.1.3 Summary ....65 68 68 5.2 Stress- and Mental Disorder 69 5.3 Smoking 71 5.4 Chemical Abuse 73 5.5 Conclusions 75 CONFOUNDING FACTORS 76 6.1 Smoking 76 6. 2 Alcohol 78 6.3 Caffeine and Other Drugs 80 6.4 Other Potential Factors 81 6.5 Summary 81 SUMMARY AND CONCLUSION . 82 6. SPECIAL REFERENCES 86 BIBLIOGRAPHY 87 iv �TABLES Table 1. Table 2. Table 3. Table 4. Estimates of Drug Use Among Enlisted Army Personnel 36 Vietnam Dioxin Exposure Studies A. Military B. Accidental Exposure 58 59 Non-Military Exposure Studies A. Industrial B. Environmental 60 62 Vietnam Experience Studies A. Case Control B. Retrospective Cohort Studies 63 64 �INTRODUCTION This review has been conducted as a first necessary step in designing the optimal study of women Vietnam veterans. As originally proposed, the review will, therefore perform the following important functions to inform study design: • Summarizing current knowledge in related areas of research; • Noting important gaps in current knowledge which may affect study design; « Highlighting methodological problems in other research which may be relevant; and e Acquiring instruments, definitions etc. which, because of wide, accepted use and/or excellence should be considered for inclusion in the planned study. In order to attain these goals within a very limited time period, the following limitations were put on the literature search: 1. A full literature search was only conducted for work published since January 1, 1980; 2. Selected studies reported before that date were included if they were clearly seminal and frequently cited in later work; 3. Emphasis was given to those areas of research about which least was known, with only key references provided for well-established findings; and 4. Only key references from the comprehensive bibliography on Phenoxy Herbicides already completed by the VA were included and this review was updated with reports since 1985. An important feature of this task, was evaluation of all original research reports on a three-point scale, according to methodological adequacy of study design. Those at the low end (evaluation = 1) were judged to be so methodologically flawed (usually through inadequate numbers or lack of an appropriate comparison group) that no credence could be given to their findings. In many areas these formed the majority of reports reviewed. Those at the high end (evaluation = 3) met minimal criteria for a study which could be considered methodologically sound, although this did not guarantee a flawless or optimal design. Those �reports rated with an intermediate evaluation score of 2 met sufficient of the criteria for their results to be considered seriously, although not with the same weight given to the most highly rated reports. This evaluation, as well as subject and function indexing is provided for each reference in the resulting computerized bibliography to facilitate the use of this work in the subsequent design tasks. (Not all references in the bibliography are cited in this review - rather the citations are illustrative of the literature reviewed.) A consequence of this evaluation mechanism is the emphasis given to methodolgical issues in the review, and to the value of certain findings. In organizing a review which had to encompass a wide range of research fields several options presented themselves. The structure finally accepted followed the. proposed basic study design of a retrospective cohort study (in which comparison groups are defined by exposure to hypothesized causes and the hypothesized effects are observed in each group). After setting the stage with a description of women Vietnam veterans as a population group in the first section, subsequent sections address the following exposures which together comprise what is termed the "Vietnam Experience" - combat (or combat-related) stress, drug use (licit and illicit) and chemical exposures (including primarily phenoxy herbicides and their derivatives). An additional section considers the health consequences of nursing as an occupational exposure (given that a conservatively estimated 75% of women Vietnam veterans were nurses). A last subsection reviews some important potential confounding exposures which may pre-date or be unrelated to the "Vietnam Experience" exposures. Within each section, not only is the exposure itself described and its measurement reviewed, but major known or potential health outcomes of the exposure are also considered. The review concludes by highlighting some of the important implications of the research (or lack of it) to date, for designing the planned study. �1. WOMEN VIETNAM VETERANS In reviewing what little has been written concerning the women Vietnam veterans, it is important to set this information in the historical context of women - especially nurses - in combat and in military situations in general. The history of nurses in the military is the longest and is distinct in many ways. The U.S. Army Nurse Corps was established in 1901 and the Navy Nurse Corps in 1908, following the Spanish-American War, in which civilian women volunteered to nurse the soldiers and were exposed to thousands of troop deaths from tropical diseases and infections under primitive, tropical living conditions. Since then, nurses have always followed troops into combat zones, providing needed care under similar conditions experienced by the troops themselves. This war-time service has always been voluntary, not subject to any draft. During the two world wars, nurses died, both from disease and as war casualties. In World War II, in the South West Pacific, nurses were actively involved in the retreat from Bataan and Corregidor living under fire in jungle conditions and several were imprisoned in Manila for thirty-seven months sharing the privations of male POW's, losing an average of 301bs in weight and suffering debilitating disease, while continuing to perform nursing duties (Kalisch and Scobey, 1983; Holms, 1982). With the outbreak of war in Korea, nurses again followed the troops into battle zones, with the first unit of 57 landing in Korea only four days after the first soldiers. Approximately 400 nurses served in this war, most of them World War II veterans who had joined the Reserves at demobilization. As pointed out by both Holm (1982) and by Kalisch and Scobey (1983), there was no hesitation on the part of military command in sending female nurses into these combat situations. Their ability to function effectively under such grueling conditions had been repeatedly documented in military testimony, along with the essential nature of the services they performed. It has been recognized, throughout the wars of this century, by most Western countries (including the U.S., Britain and Canada in particular) that well-trained female nurses are not replaceable with inadequately trained enlisted men. The need for adequate, efficient nursing care appears to have consistently overridden concerns in the military this century about exposing women to the combat zones of war. The experience of Vietnam follows this pattern, with the first nurses arriving in South Vietnam in 1962 as "advisors", attaining a maximum strength of about 900 in 1969. Most of these served in field hospitals exposed to enemy fire and attack. �In contrast, the history of women in other than nursing roles in the military has been much more limited. Although they served in large numbers in World War II in support occupations, first as the Women's Army Auxiliary Corps (WAAC) then as the Women's Army Corp (WAG), with full military status, most did not leave the continental U.S. (CONUS). Their involvement was the direct result of need, to free qualified military men for combat duty (Holm, 1982). The experience was similar in Canada and Britain. Almost all of these women left the forces with the end of the war. Only in 1947, was the Nurse Corps established as the first permanent staff corps for the Army and Navy. This was followed a year later by the Women's Armed Services Act which formally integrated women into the four permanent armed services (including the newly created Air Force) for peacetime service. At this time, approximately 7,700 women were on active duty in the Services, of whom nearly 1,300 were officers. At the beginning of the Korean War, in 1950, this number had increased to 22,000, including approximately 7,000 in the health professions (mostly nurses). Despite the increasing numbers of women on active military duty during peacetime, it is important to note that only nurses went to Korea during that war. A few other military women were sent in support (mostly administrative) roles to the Phillipines and to Japan. The pattern was similar in the Vietnam War, with the total number of WAC's in country never exceeding about 160 and all were stationed in or around Ho Chi Minh City (then Saigon), primarily at Tan Son Nhut Air Base or at Long Binh. Other women military personnel were stationed in larger numbers primarily in the Philippines, Japan and Thailand (including nurses). Even today, women are formally excluded from service in combat occupations, although they may perform equivalent roles (for example flying transport rather than fighter aircraft). The fact that nurses do indeed serve in combat zones has been largely ignored in this debate (Holm, 1982). Throughout this 80-year history, the image of women in the military has been somewhat schizophrenic as described graphically by both Holm (1982) and Kalisch and Scobey (1983), among others. While the services have recognized the invaluable role of women, especially the nurses and have accepted them as essential - at least in war - the public image has been at considerable variance, as typified by recruitment efforts, movies, other media reports and congressional responses to legislation attempts. This is well-described by Kalisch and Scobey (1983) who note that only the Major Hoolihan character of the television series M.A.S.H. approaches the true image of the army nurse (this was not so for the original movie character). The popular 4 �image is a confusing mixture of a woman of questionable moral character who gives lip service to nursing, or a nurse romantically serving her country in less than real circumstances, minimizing the grueling nature of the combatzone nursing situation. As noted by Holm (1982), this confusing image has persisted through the lack of testimony from the women themselves. It has remained true that, after each war most have left active service, merging into civilian life with little or no recognition and little or no reunion or continued contact with their fellow veterans. Perhaps because of their small numbers, perhaps because of negative or indifferent public attitudes, they have remained mostly silent and isolated, not even giving testimony during the land-mark legislation hearings of 1947 and 1948 (Holm, 1982) . Perhaps the most important point made by both Holm (1982) and Kalisch and Scobey (1983), among others, is the glaring lack of any research into exactly how women contributed during the wars of this century and the impact of this service on their subsequent lives. The opportunity for such a study was greatest immediately after World War II during which so many women served for the first time in occupations other than nursing - an opportunity which was irretrievably lost. It is not surprising, therefore, that very little has been written concerning women veterans of the Vietnam War and almost all of it since 1980, in a decade which is witnessing the emergence of women's voices motivated to close the gap between the reality of war service and the very inadequate public perception of it. Recent literature includes only four systematic research attempts to collect data and an increasing number of witness accounts providing a written oral history of women's experiences for the first time. History and science are never free of bias. This has been well documented by Kuhn (1970), for example. Oral histories are no exception. Those for whom an experience had a profound impact are most likely to want to describe it publicly. In the climate of anger and denial following the Vietnam War, compounded by fears concerning the health consequences of Agent Orange, most of those veterans who have spoken publicly have been no longer in the Services and negative in their attitudes. This has been true of the women veterans as well as of the men. The very negative description of her experiences provided by Lynda Van Devanter (1983) is a clear recent example. An attempt by Patricia Walsh to verify many of Van Devanter's statements was largely unsuccessful, in some part due to the lack of available military documentation but also because of �contradictory recall by other witnesses (Walsh 1982). Marshall (1987) attempted a more balanced document in her oral history, by deliberately including as wide a selection of experiences as possible, both negative and positive, from military and civilian women serving in Vietnam and provides, perhaps the most complete description ever published of the role of women in a combat zone. Certainly it represents an important first attempt to set the record straight on the reality of such service and verifies many of the inferences from the few systematic research attempts (Boyle et al, 1985; Paul, 1985; Stretch et al, 1985 and Schnaier, 1982). Of the four recent research studies cited above, only one (Boyle et al, 1985) selected subjects randomly. The number of Vietnam veteran subjects was very small in all four studies, ranging from 28 no longer in active service (Boyle et al, 1985) to 220 nurses still in active service as of 1983 (Stretch et al, 1985). No good estimate yet exists of the total number of female veterans of the Vietnam war although from the numbers cited above and from other estimates available (including estimates from the 1980 Census (Dienstfrey and Byrne, 1984) and from Boyle et al (1985), the numbers are probably of the order of 5000-6000, including about 1500 who served in occupations other than nursing. Over 250,000 women served in the military during the Vietnam War (Vietnam-era veterans), nearly two thirds of them in their early 20's. The small number of veterans who saw service in Vietnam in the survey by Boyle et al (1985) underscores the limited number in this group and is probably a good estimate of their relative numbers among Vietnam era veterans. In this survey, approximately four times as many (120) saw service in nearby Thailand, Japan, Philippines and other South West Pacific and South East Asian Countries. Despite these and other limitations, these studies and other histories provide a consistent profile of these women veterans and their war experience. A clear majority were well-educated nurses in the commissioned officer ranks, but they were young (predominantly in their early twenties during their Vietnam tour of duty) and inexperienced in the military. All were volunteers and upwards of 20% continued in active military service beyond their Vietnam experience. A majority were exposed to combat zone experience, working in field medical facilities subject to mortar, rocket and other enemy attack. Apart from the distinctive demography of these women veterans (they were younger, better educated and predominantly nurses, in contrast to women veterans of prior wars; Boyle et al, 1985), their war experience was also distinctive. Their patients were predominantly adolescent soldiers (the average age was 19.2 years, compared to 26 years in World War II, Brende and Parson, 1985), as well as �civilian women and children victims and very young North Vietnam and Viet Cong POW's (many aged 15 or 16). Moreover, efficient transport and deployment of (mobile) medical facilities resulted in treatment of casualties within minutes of occurrence. Cases of massive injury and mutilation were therefore surviving to be treated by medical personnel (and, in fact, surviving treatment) as never before in previous wars. Medical personnel were required to work 12 hour shifts, six days/week or longer under combat conditions, were sometimes short of essential supplies and equipment, and were forced to triage cases for treatment. These conditions were potentially exacerbated by individual rather than unit assignments, leading to transitory supportive relationships. Because of the apparent predominance of nurses in field assignments among women Vietnam Veterans, exposure to phenoxy herbicides in unknown concentrations was likely. Apart from disease exposure (primarily malaria) and the medications and insecticides to combat them, there is some indication that alcohol, in particular, was used during and after Vietnam service as a coping mechanism (Paul, 1985; Marshall, 1987), although no reliable estimates of any of these exposures are yet available (Ott, 1985). No reliable data on possible health outcomes are available for this group of women, although the studies of Schnaier, Paul and Stretch and co-workers suggest that these veterans were subject to Post Traumatic Stress Disorder (PTSD) at about the same rate as male Vietnam veterans. Unfortunately the subjects for these studies were selfselected volunteers (Schnaier, 1982; Paul, 1985) or sampled in unknown ways (Stretch et al, 1985). Moreover, the restriction of the sample to those still on active duty in 1983 in the study by Stretch and co-workers limits inference to a distinct, highly selected minority of veterans who were career military personnel. The health outcomes reported during interviews in the survey conducted by Boyle et al (1985) were compared across groups of women veterans, according to period of service (but not service area) and with comparable samples of male veterans. Unfortunately, for many outcomes which were gender specific (eg. pregnancy termination) or with age and genderspecific prevalence rates (certain cancers, heart disease), extensive comparisons among service area groups, for women veterans could not be made due to small numbers. It is not clear from this study that health outcomes among these women veterans are different from other women. There is no indication from available data on the non-institutionalized civilian population (Ries, 1986) that the health outcome rates estimated in this study are measurably different from what would be expected in a general female population of the same age range. �Finally, it should be noted that a clear majority of the Vietnam era veterans were under the age of 45 as of September 30, 1984. This cohort of women, including Vietnam veterans, has yet to reach the age when most would experience a natural menopause or have hypertension, cancer or heart disease diagnosed. Many have not yet completed child-bearing (Boyle et al, 1985). The oral histories, supplemented by the four limited studies and other histories indicate that, as in prior wars this century, nurses volunteered for service and were assigned to combat zone hospitals where they served, alongside men under similar stressful conditions. In this respect, the experience of the majority of women veterans was not very different from experiences of women serving in prior wars. Ways in which experience during Vietnam service differs from service in prior wars include: • Limitation of service to permanent tours of one year (in prior wars women served for the duration); o The youth of the patients - both soldiers and POW's; o The stability of the hospital bases in Vietnam; e The widespread use of defoliants such as Agent Orange and related chemicals; • The lack of involvement of the civilian U.S. population in the war effort (and wide spread opposition to it); • The fact that the U.S. did not win this war; e The lack of a well-defined front-line in the war; and e The expectation that the U.S. military in Vietnam were not just fighting a war for the U.S. but for the Vietnamese, and the need to support the civilian Vietnam population despite the language and cultural barriers and the infiltration by the Viet Cong - resulting in the Medical Civic Action Program (MEDCAP) and related activities. No systematic and complete description of this cohort of women currently exists, in terms of its size, age range, occupation, prior and subsequent military experience, Vietnam exposure and subsequent health and life experiences. �2. COMBAT-RELATED STRESS The literature on war stress has focused on the major post military adjustment problems facing male veterans or what is now labeled post-traumatic stress disorder (PTSD) and chemical abuse. Even in the limited research on women veterans, health outcomes - especially reproductive outcomes - of war stress have not been addressed. This section begins with a description of combat-related stress, including stresses thought to be unique in the Vietnam arena and the relevance of current definitions to a study of women veterans. The next subsection considers the most researched outcome of war stress - PTSD. A final sub-section focuses on the relationship between different types of life stress and reproductive outcomes. 2.1 WAR STRESS The relationship between combat exposure and the perception of stress has been studied in major wars. However, the stress associated with the Vietnam war exposure has been described as unique in comparison with other wars in that chronic and/or delayed stress reactions or PTSD were more common (Fleming, 1985; Laufer et al, 1985). In testimony for the Royal Commission, Dr. Arthur Blank Jr., head of the American Outreach Program provided a succinct yet comprehensive outline of typical stresses experienced during war-time and post-war, including unusual stresses found in the Vietnam War. This testimony also included a description of the major delayed and chronic stress symptoms seen in Vietnam veterans. Excerpts from this testimony are quoted below as background for review of empirical data. (a) "Stress Typical_of All Wars • miserable living conditions (deprivation or denial of adequate food, clothing, shelter, cleanliness; exposure to the elements). a Fatigue. o Sensory assault. 9 The fighting itself. e Wounds (suffered by self, mates, witnessing of civilian and combat horrors). e Special stresses of the Combat Situation (i) Capture and torture (ii) Isolation, (iii) Acute survivorship. �(iv) Authoritarian organization (v) Command incompetence (vi) Observers (photographers, journalists, casualty clerks, psychiatrists, chaplains, communications operators, intelligence officers). Unusual stresses Found in_theL_yietnam War (but not limited to this war) e e e 9 o © Guerrilla warfare. Lack of clear objectives. Limitations on offensive actions. Terrorism. Climate and topography. Miscellaneous, bizarre physical dangers (flora and fauna). o Tropical diseases. 9 Immersion in an extraordinarily poor Third World society. 9 Chaos. Psychological Stresses Secondary to the General Political Character of the_War 9 The experience of absurd waste (including corruption, fraggings, avoidance of unnecessary or purposeless combat. e Government deceit and misjudgment. 9 Massive national conflict. e Defeat. (d) Atrocity Defined as destruction going beyond the usual boundaries of war, lying outside the requirements of military strategy. 9 Atrocity directed against the land: Defoliation of forests and fields with herbicides. o Meaningless destruction of human life: Captives pushed out of helicopters, shooting and napalming of non-combatants, massacres, etc. (e) Additional Emotional.... Trauma. 9 Failure to live up to one's expectations. o Overwhelming fear reactions. « Self-inflicted wounds. 9 Accidental killing of comrades or civilians. 9 Vietnamese left behind. 10 �Stresses of the ^Immediate Homecoming Period o Absence of sanction, presence of hostility. 9 Absence of normal debriefing. Long Term Factors Exacerbating the Effects of War Stress o Further fading of a sense of purpose, o Impossibility of further contact with Vietnam, o Unavailability of psychotherapeutic treatment. o Continuing blackout of the war as history. Relating the concept of stress to combat was seen also in other major wars. However, the Vietnam war has been described as unique in comparison with previous wars, the differences having been related to the characteristic symptoms of PTSD and especially to the increased prevalence of chronic and/or delayed PTSD (Fleming 1985; Laufer et al, 1985). A succinct yet comprehensive outline of the stresses experienced during war-time and post-war, including unusual stresses found in the Vietnam War, as well as of the major delayed and chronic stress symptoms seen in Vietnam veterans, provided by Dr. Arthur Black Jr., head of the Australian Outreach Program, in testimony for the Royal Commission, is reproduced here as background for review of empirical data. Major Delayed and Chronic Stress Symptoms Seen in Vietnam Veterans Type l. Manifesting Primarily by Psychological Symptoms (i) Classical traumatic neurosis symptoms. Flashbacks, nightmares, irritability, rage, dizzy spells, anxiety, insomnia, depression. (ii) Depression. Without other symptoms, masking impacted grief about war experiences and related conflicts (Shatan 1981). (iii) Psychosomatic syndromes. Headache, low back syndrome, ulcer, migraine, irritable colon, hypertension. (iv) Violent paranoid states. Without psychotic symptoms, or indicators of pre-war borderline personality disorder, these veterans manifest diffuse hostility, suspiciousness, paranoia, irritability, and crowd phobia. This state represents a persistence of the paranoid, hyper-vigilant state that was lifesaving for 11 �many participants in the terrorized guerrilla atmosphere of Vietnam. (v) Addictive disorders. Addiction to alcohol, marijuana, heroin, cocaine, thrills, risks, gambling - including gambling with fate as in chronic high-speed driving. (vi) Exacerbated character disorders. Dramatic exacerbation of character problems, such as impulsive behavior or sociopathy, present in a minor degree before the war. (vii) Suicides and homicides. These are categorized separately for two purposes: to highlight them as problems, and also to indicate our lack of knowledge of the diagnostic background of Vietnam veterans who kill themselves or others. Fortunately, the number of homicides is quite small. That may not be the case for suicides; there is not a single study of the incidence of suicide in Vietnam veterans; but there is a persistent, almost universal impression among clinicians who work with this group, that the incidence of suicide is high and continuing. (Note that this is not so amongst Australian Vietnam Veterans, see Chapter X). (viii) Psychotic syndromes. This outcome, longrecognized in the literature from previous wars, has remained largely hidden in Vietnam veterans until recently. Type II. Manifesting _Primarily By General Alteration In Life Course (i) Underachievement. Lacking, significant symptoms, these veterans' lives are characterized by chronic underachieving or instability in education or work. (ii) Wandering lifestyle. Though not necessarily underachieving in any obvious way, the veteran goes from job to job, school to school, town to town without progression toward any goal. (iii) Crime. Some veterans commit antisocial acts not as a result of pre-existing criminality, but as a part of stress disorder. (c) Type III. Problems Manifested Primarily in Relating to Significant Others (i) Difficulties in intimacy with spouse or lover. 12 �(ii) Special interferences in relating to children. (iii) Marked change in relatedness to the country and its institutions. Loss of political attachment may have occurred because the soldier in Vietnam felt himself sacrificed by military and civilian leaders who, out of ignorance or cynicism, did not allow him to win a just war or, from the opposing perspective, sent him to fight an unjust war. (iv) General alienation. Affected veterans display a pervasive and generalized detachment from most processes of life - marriage, career, social and political institutions community, and friends. Some seem frozen at age 20, have not learned more adult skills for living, and are unsophisticated in subtle and diverse ways. (d) Type IV Veterans in this group have experienced a profound shattering of images of self and humanity. These Vietnam veterans have much in common with the survivors of Nazi death and concentration camps. They have lost some of their basic faith in .the capacity of humanity for goodness, as described in Holocaust survivors.ft (Royal Commissions on the Use and Effects of Chemical Agents on Australian Personnel in Vietnam, Vol.5, IX-12 to IX-16). 2.1.1 Measurement of War Stress It cannot be assumed that everyone who served in Vietnam had an equal level of exposure to war stress, nor to the same types of stress. This is especially pertinent to women veterans. Based on the unique character of the Vietnam war in comparison to other major wars, Laufer et al (1984, 1985) argues for a multidimensional measurement of war stress, which identifies three different types of stress (combat exposure, participation in abusive violence, and exposure to abusive violence) and allows for differing levels of exposure to these stresses. While this multidimensional model permits a more exact analysis of the influence of specific war stresses on adjustment outcomes, the model, as used in Laufer's work is not completely pertinent to the probable experience of women veterans. Women did not participate directly in combat nor were they likely to participate in or witness abusive violence. Their war stress differed, more likely consisting of perceived 13 �danger and threat to life, intense exposure to death and destruction, and the excessive physical and emotional demands of their work (Paul, 1985; Stretch et al, 1985; Ott, 1985). In addition, occasional accounts of killing the enemy in self defense do not rule out direct violence as a stressor. For example, Ott (1985) describes the nurse who used a machine gun on three Viet Cong who were attempting to infiltrate her hospital. Brende and Parson (1985) described a similar situation in which a nurse had to defend herself against a North Vietnamese patient for whom she was caring, who attacked her with a pair or scissors. Narrowly escaping, the patient was subsequently killed by military guards, resulting in recurrent nightmares for the nurse. Additional stressors of a more psychosocial nature, such as those suggested by Paul (1985: including exposure to sexual harassment, survival guilt, and interpersonal conflicts) may also contribute to post service adjustment problems. In conclusion, there is strong evidence to support use of a multidimensional model of war stress in a study of women veterans. However, current models based on studies of men, are inappropriate and must be revised. While the limited data on women veterans identifies some specific war stressors, it is suggested that descriptive data be gathered in a pilot study to inform development of a multidimensional model for women veterans. 2.2 POST-TRAUMATIC STRESS DISORDER Post-traumatic stress disorder (PTSD) refers to a group of symptoms now commonly associated with the mental disorders of Vietnam veterans. This label first came into use with the issuance of the American Psychiatric Association's Diagnostic and Statistical Manual (Version III) - DSM- III in 1980 with the further identification of subtypes, acute, chronic and/or delayed. The acute subtype is synonymous with that referred to as "shell shock" (World War I) or "combat fatigue" (Korean War). The chronic and/or delayed subtypes are particularly relevant for the veterans of the Vietnam war who manifested relatively fewer neuropsychiatric disorders during the height of the war but rather at the end or during the post-service period. While acute-traumatic stress disorder requires that the symptoms start within 6 months of the trauma and last less than 6 months, chronic or delayed PTSD require that the symptoms exceed six months in duration (chronic) and/or that symptoms are manifested six months or more after the trauma (delayed). This review begins with a clinical description of PTSD and the DSM-III diagnostic criteria for PTSD, followed by discussion of the unique character of the Vietnam war which contributes to the clinical manifestation of the disorder. A 14 �review of a representative sample of recent and frequently cited empirical studies will be presented, both for female and male veteran populations. This section concludes with a discussion of methodological and measurement issues most pertinent to the purpose of this review. 2.2.1 Clinical Symptoms and ^Diagnostic Criteria The majority of material for this section is taken from the comprehensive review of PTSD included in Volume 5 of the Final Report by Australia's Royal Commission in the Use and Effects of Chemical Agents on Australian Personnel in Vietnam, July 1985, and the DSM-III. According to the DSM-III, the essential feature of PTSD is "the development of characteristic symptoms following a psychological event that is outside the range of usual human experience. The characteristic symptoms involve reexperiencing the traumatic event; numbing or responsiveness to, or reduced involvement with, the external world; and a variety of autonomic, dysphoric, or cognitive symptoms." (p. 236). Further description of these symptoms can be found in the DSM-III's diagnostic criteria (p. 238): (a) Existence of a recognizable stressor that would evoke significant symptoms of distress in almost everyone. (b) Re-experiencing of the trauma as evidenced by at least one of the following: (1) recurrent and intrusive recollections of the event (2) recurrent dreams of the event (3) sudden acting or feeling as if the traumatic event were reoccurring, because of an association with an environmental or ideational stimulus. (c) Numbing of responsiveness to or reduced involvement with the external world, beginning some time after the trauma, as shown by at least one of the following: (1) markedly diminished interest in one or more significant activities (2) feeling of detachment or estrangement from others (3) constricted affect (d) At least two of the following symptoms that were not present before the trauma: (1) hyperalertness or exaggerated startle response (2) sleep disturbance (3) guilt about surviving when others have not, or about behavior required for survival (4) memory impairment or trouble concentrating 15 �(5) avoidance of activities that arouse recollection of the traumatic event (6) intensification of symptoms by exposure to events that symbolize or resemble the traumatic event These criteria are currently under some revision. 2.2.2 Prevalence Scientifically sound prevalence data for the extent of PTSD are lacking. Stretch et al (1985) reported estimates ranging from 18% to 54% of Vietnam veterans in the civilian community who are currently in need of psychiatric care for war-related problems. In contrast, they found lower rates of delayed or chronic PTSD among Vietnam veterans currently on active duty in the Army (5.1%) and the Army Reserve (10.9%). Most of these data have been based on clinical observations in treatment centers. Fleming (1985), on the other hand, claims that a relatively small number have PTSD to the degree that treatment is sought; however, he provides no data as the basis for this statement. Frye and Stockton (1982) surveyed 88 members of an officer candidate school class for the Army infantry during 1968-1969 for signs of PTSD, using DSM-III criteria for diagnosis, and found that 43.2% manifested moderate to strong symptoms. While objective measures and validity checks were employed, application of the findings from this study are weakened by the small sample size, nonrepresentativeness of the sample, questionable calculation of response rate (82%), and a retrospective design utilizing self reports. Therefore, while their estimate falls within the range of previous reports, it cannot be relied upon as a valid predictor of chronic or delayed PTSD prevalence. 2.2.3 STUDIES OF WOMEN VETERANS Stretch and colleagues (1985) reported an epidemiological investigation of PTSD among Army nurse veterans. Unfortunately, the study was limited to veterans still on active duty. A sample of 361 eligible army nurses (male and female) (RR=75%) were compared to 351 army nurses who had not served in Vietnam (RR=71%), finding a current 3.3% PTSD rate for Vietnam veteran nurses and a rate of only 0.85% for Vietnam-era veteran nurses. However, the difference in rates was not statistically significant. Further, the prevalence of PTSD among the Vietnam veteran nurses was found not to differ significantly from the prevalence of PTSD (5.1%) reported for other active duty army veterans. No gender differences were noted in this study. The subjects also responded to the same PTSD questions based on their recollection of how they felt in Vietnam, 16 �resulting in rates of 9.1% for Vietnam veteran nurses and 10.5% for other active-duty army Vietnam veterans. Examining both sets of rates revealed that for Vietnam nurse veterans, 7.2% suffered acute PTSD, 1.9% suffer chronic PTSD, and only 1.4% are suffering delayed PTSD. The investigators added these rates, resulting in an overall PTSD prevalence of 10.5%. A similar summative rate of 12.2% was calculated for the other active duty Vietnam veteran group, not a statistically significant difference. Determination of PTSD was based on the DSM-III criteria. However, only limited data were gathered regarding possible sources of trauma among the Vietnam nurses thereby allowing for the influence of non-war related events. Therefore, the investigators caution that this rate is likely to be overestimated. Two design issues are problematic in this study. First, as mentioned, the study was of nurses (male and female) currently on active duty. Consequently, the possibility that Vietnam veteran nurses who chose to leave the military may exhibit a higher rate of PTSD cannot be examined. Secondly, the time interval between the end of the Vietnam tour and the time of the survey was not reported, a potential confounder which might influence the manifestation of delayed PTSD. Further evidence on symptoms of nervous/emotional problems among women Vietnam veterans can be found in the Harris and Associates national survey (Boyle et al, 1985). However, since measurement of PTSD was not an intent of this study, the data are not conclusive enough to develop an estimate of PTSD prevalence. Limited to descriptive data, it was reported that Vietnam veterans were more likely than other veterans to have experienced seven of nine affective symptoms, including depression, nightmares, troubled thoughts about military experiences, and difficulty making decisions, and guilt feelings. The possible reasons for the similarities between Vietnam veterans and post-Vietnam veterans were not discussed but do not suggest a clear picture of a Vietnam-related stress disorder. Methodological limitations (e.g., not using the DSM-III criteria for PTSD) interfere with the use of these findings for determining prevalence. In conclusion, while prevalence estimates on both male and female Vietnam veterans are available, data are limited in quality and scope. However, available data do suggest a difference in prevalence rates among active duty and civilian veterans pointing out the importance of a representative sample of all veterans to adequately determine prevalence of PTSD. Data from two other studies (Schnaier, 1982; Paul, 1985), despite smaller, non-representative samples, provide consistent evidence of the psychological after-effects of the war experience. Current post-traumatic symptoms reported 17 �in the Schnaier (1982) study included: suicidal thoughts (27.6%), feelings of alienation (19%), and feeling depressed between 15-30 times per month (19%). Forty-three percent of the 50% who have sought professional treatment related their problems to the Vietnam experience. Clearly, the data show that these women are currently plagued by significant problems. However, a nonrepresentative sample without a comparison group limits the application of these findings. In the study by Paul (1985), fourteen adverse aftereffects (including recurrent nightmares, depression, flashbacks, and hyperalertness) similar to PTSD symptoms, were identified, with 39% reporting current symptoms at the time of the survey. Additionally, 68% reported current physical problems (headaches, ulcers, gastrointestinal problems) which.began in or sometime after Vietnam. In addition, war stressors were identified as: short time in service before Vietnam duty; the number, youth and severity of casualties; nursing roles in specific patient care areas; lack of supplies; sexual harassment; problems with professional relationships; survivor guilt; and threat to life. This study points out the importance of identifying war stressors specific to the experience of women. The previously cited study by Stretch et al (1985), in addition to estimating prevalence of PTSD among active duty Vietnam veteran nurses, further makes the important point regarding the measurement of war stress among veterans in noncombat positions. While nurses were not directly involved in combat or abusive violence (frequent measures of war stress among men), they routinely experienced the aftermath of such with intense exposure to death and destruction. Therefore, measures of war stress must be adapted to the experiences of women veterans. Investigating perceived danger and exposure to violent combat aftermath as measures of war stress, they found that nurses with high measures of both exposures reported the highest levels of PTSD during Vietnam (p is less than .01) as well as currently (p is less than .05). Further, they found that levels of PTSD were mediated by perceived social support both during and after service, a finding consistent with the large body of literature on the buffering effects of social support (see, for example, McKinlay, 1981). In summary, while limited, evidence from these data supports the manifestation of delayed and possibly chronic PTSD among women Vietnam veterans. While the larger body of male studies can be used to inform a study design of women veterans, careful attention to development of appropriate measures of war stress/trauma for women is indicated. 18 �2.2.4 STUDIES OF MALE VETERANS Review of a representative sample of 15 research reports published in the 1980 "s uncovered only four without serious methodological flaws. The remaining 11 reports suffered primarily from the limitations of small nonrepresentative samples. Several studies focused on the symptoms of PTSD (Amen, 1985; Berkheimer et al 1985; Benedikt, 1986), often attempting to validate the DSM-III diagnostic criteria (Atkinson, 1984; Malloy et al, 1983; Van Kampen et al, 1986). Other studies explored the etiology of PTSD (Borman, 1985), such as the influence of combat exposure or war stress on development of PTSD (Frye and Stockton, 1982) or investigated the other factors potentially influencing PTSD such as social supports (Keave et al, 1985). Finally, a study by Carroll et al (1985) related PTSD to problems with postservice adjustment. The following studies will be discussed in more detail because of their methodological implications for further studies. All investigate the link between traumatic experiences and subsequent psychological patterns. Laufer (1985) and colleagues (1984, 1985) conclude from their work on the relationship between war trauma and PTSD that discrete dimensions of PTSD are differentially affected by different types or levels of war trauma. Their model of war trauma contains three elements: 1) combat experience; 2) witnessing abusive violence; and 3) participation in abusive violence. In their 1984 study, a sample of 350 veterans was taken from a larger national stratified probability sample (n=1342) of the noninstitutionalized civilian population selected by random digit dial procedures in 10 sites matched in economic and demographic characteristics. Data were collected in 1977 and 1979. Measures included an additive scale of ten discrete events for combat exposure, a set of open-ended questions for abusive violence, and an additive scale of stress symptoms and the Psychiatric Epidemiology Research Instrument (PERI) to measure adjustment. Acknowledging the limitation associated with recall, data on the last two measures were collected for the three periods of before, during, and after service. Control variables included background factors, predispositional factors related to potential adjustment problems, and military and war-related factors (e.g., induction status, service during or after the 1968 Tet offensive, and branch of service). With the addition of these control variables, the investigators could more strongly state their finding that exposure to combat and participation in abusive violence contributed independently to greater incidence of stress. Veterans on average reported onset during the war of two or more stress symptoms if they participated in abusive violence and one or more symptom for every 7 points of combat exposure. The other military-related experiences that 19 �affected symptom level were induction status and branch of service. Marines and those who enlisted reported fewer symptoms. Of the background predispositional factors, only race was significantly related, with blacks and Chicanes reporting an average of one more symptom than whites. Turning to postservice symptoms, much the same pattern appeared, but symptoms were more prevalent at the time of the interview than during the service period (4.2 symptoms on averages. 1.6). The data suggest a pattern of cumulative development in the number of current stress symptoms, a trend which is stronger among blacks. Blacks seemed to respond more immediately to the stresses of war than whites. In a later study, Laufer et al (1985) attempted to relate their multidimensional war trauma model to discrete dimensions of PTSD based on the DSM-III criteria. With a sample of 257 drawn from the same large probability sample, they used the same measures as previously described but created four subscales from the larger stress scale (intrusive imagery, hyperarousal, numbing, cognitive disruption). Comparing service and postservice measures, the findings suggested a lagged process in which men exposed to life-threatening experiences respond only partially at the time, with the balance of the response emerging at a later point. Participation in abusive violence elicits an immediate unenduring response in terms of hyperarousal, numbing and cognitive disruption while its effect on intrusive imagery diminished with time. Similarly, combat exposure resulted in enduring hyperarousal and intrusive imagery. The effect of exposure to violence, on the other hand, emerged with intrusive imagery well after the experiences occurred. Clearly, the dimensions of PTSD vary over time and according to individual war experience as shown in these data. The findings of these studies point out important measurement issues in relation to PTSD and war trauma. First, the specific dimensions of PTSD may be related to differing etiological factors as well as adjustment outcomes, and therefore, measurement of specific PTSD dimensions may be useful. Second, the data clearly support a multidimensional model of war trauma looking at different types and degrees of exposure, rather than relying on a unidimensional measure of combat exposure vs. no exposure. Penk et al (1981) also found that combat veterans rated significantly more stress responses as problems than did noncombat veterans. Further, in this sample of 85 combat veterans and 121 noncombat veterans, post-military adjustment difficulties were not attributable to premilitary adjustment differences between the groups. While producing consistent findings, however, this study was limited by a nonrepresentative sample of drug abusers in treatment and a 20 �cruder, two-dimensional (light vs. heavy) measure of combat relating only to killing the enemy. Only one prospective study of Vietnam veterans, including measures of PTSD and other post-service adjustment has been conducted (Card, 1983). This study was unique, in that a large battery of psychological and aptitude tests as well as questions on vocational plans and socio-demographic measures had been administered to students in Grades 9-12 in 1960 as part of a large longitudinal study - Project TALENT. To reduce bias in the current study, sample of Vietnam veterans, non-Vietnam veterans and non-veterans were selected from those in the 9th grade in 1960 in the original TALENT study who also responded in a 1974 follow-up survey of the TALENT cohort. The final numbers in each of the three comparison cohorts were 481, 502 and 487 respectively representing response rates of 80%, 89% and 73%. The major design flaw in this study was that Vietnam veteran status was determined in an initial screening question in the 1981 survey, so that respondents were not blind to the purpose of the study. Potential reporting bias could have been investigated by using responses to the 1974 survey, but this possibility was not explored in the report. Despite this problem, a measure of PTSD which, while admittedly crude, contained the important features of this disorder was constructed in the analysis which clearly differentiated not only Vietnam veterans (19 percent with PTSD in 1981) from the other two groups (12 percent with PTSD in 1981) but combat exposure among the Vietnam veterans (from an analytically constructed scale). The reporting of PTSD symptoms was not consistently related to measures of predisposition, although most of these were obtained retrospectively in the 1981 survey, not from the 1960 survey. The healthy worker effect was also well controlled in the analysis. Evidence of negative effects of the war in terms of both PTSD and other measures of social adjustment was clear, 15 years after service in Vietnam. An important point to note with this study is that the Vietnam veterans in this particular cohort served prior to the 1968 Tet offensive. Therefore, noted differences between Vietnam veterans and other veteran/civilian groups in relation to PTSD manifestations should be greater among Vietnam veterans serving after 1968. Apart from the importance of this study for assessing the impact of the war on PTSD and other social adjustments, the design and analysis clearly demonstrate; (a) the importance of using non-Vietnam veterans as well as or instead of civilians as comparison groups; and .(b) the importance of including pre-war data obtained con-currently, not retrospectively. A final study by Frye and Stockton (1982) will be discussed in relation to its implications for collection of appropriate background or predispositional data. In their survey of 88 members of an officer candidate school class 21 �(1968-1969) for the Army infantry, they questioned whether level of combat (degree of trauma) is the critical variable in the development of PTSD among Vietnam veterans. Using discriminant analysis, they found that four variables in addition to level of combat distinguished between those who developed PTSD and those who did not: Veterans with PTSD reported a negative perception of their family's helpfulness on return home; a more immediate discharge after the war; an external locus of control; and a more supportive attitude toward the war before they entered the service. Level of combat provided the second largest contribution (22%) to the discriminant function with a total of 62.1% of the variance between the two groups accounted for by the discriminant function. Methodological limitations, however, may contribute to this inconsistent finding regarding the importance of other variables in the etiology of PTSD, i.e., a small nonrepresentative sample (n=21 in the PTSD group), with cruder measures of both combat level and PTSD symptoms than in the work by Laufer et al (1984, 1985). However, the study does point out the importance of collecting background and predispositional data as control variables. 2.2.5 METHODOLOGICAL AND MEASUREMENT ISSUES Post-traumatic stress disorder appears to be the primary manifestation of post-war emotional adjustment problems in Vietnam veterans. Further, evidence indicates that delayed forms of the disorder, rather than acute, are more likely in this group of veterans as compared to veterans of other wars. A review of the PTSD literature points out two areas of methodological concern important for any future study of women Vietnam veterans: 1) the need for scientifically sound prevalence data on the disorder; and 2) careful measurement of both clinical manifestations of the disorder and possible etiological factors. (a) Prevalence Estimates. In estimating prevalence of PTSD, as for any other condition, cross-sectional data on current status are used to provide an estimate of "point" prevalence. This estimate may include all current cases (regardless of inception) identified over a defined period usually a year or less (see for example Monson, 1980). The difficulty in the retrospective studies reviewed is that current status provides (combined) estimates of chronic and delayed PTSD only. Estimation of the prevalence of acute PTSD (occurrence at anytime during war-time service, as defined in the particular study), depends on long-term memory recall. It is clear from studies of both male and female veterans that reliable point prevalence estimates for chronic or delayed PTSD are lacking. Any future study of Vietnam veterans should be carefully designed to obtain valid data on a representative sample of Vietnam veterans. While a prospective study design is the ideal allowing estimates of the incidence of acute, chronic or delayed 22 �PTSD, it is obviously impossible with any new study of these veterans. However, while a retrospective design admittedly has limitations, measurement of the point prevalence of delayed/chronic PTSD, since symptoms are likely to be current, should be possible. Measurement of acute PTSD, typically experienced during war-time service, of necessity will be based on self-reported recall data. None of the studies reviewed attempted to validate their inservice measurement of acute PTSD (if this is even possible); therefore, it is not clear to what extent problems with recall, of the war experiences may affect the validity of these prevalence estimates. Despite these problems, efforts should be made to collect data on at least chronic and delayed PTSD. Although desirable, it is doubtful that the full extent of PTSD, including the acute form, can now be estimated from a retrospective cohort study, as recommended by Laufer et al (1984). (b) Measurement Issues. Based on his own work and that of others, Laufer (1985) identified four dimensions of measurement central to the field of Vietnam veterans research: • predisposition; o the war experience; e symptomological and behavior outcomes; and o patterns of life course development after service. All of these dimensions are relevant to a study of health and reproductive outcomes of women Vietnam veterans. Measurement of Predisposition. The importance of gathering data on background and predispositional factors was apparent in the literature regarding drug use among the military as well as in the PTSD literature, especially in assessing the influence of the war experience on subsequent adjustment problems. For example, studies of postservice drug use by veterans consistently report that predispositional factors, particularly preservice drug use, rather than combat experience, account for continued drug use after Vietnam (cf. Robins et al, 1975). Laufer (1985) reviews this predisposition hypothesis in relation to his own work and that of others on PTSD, reporting that predispositional factors have an independent effect, but do not fully explain the effects of the war experience on development of PTSD. In the work of Laufer et al (1984, 1985), war stress clearly has a substantial long-term influence on postservice adjustment of Vietnam veterans. Laufer (1985) suggests, in conclusion, that the combined effects of predispositional factors and war stress be examined in relation to specific manifestations of PTSD or emotional/behavioral maladjustment. In addition to the standard sociodemographic factors, it is recommended on the basis of this review that the following predispositional factors should be considered: drug/alcohol use, school 23 �problems, arrests, attitude toward Vietnam conflict, age at entry into service, peer relationships, family problems (e.g., parental emotional problems or chemical abuse, single parent families, major financial problems) (Laufer, 1985; Carroll, 1985; Robins et al, 1975; Frye and Stockton, 1982). Measurement of War Experience has already been discussed in section 2.1.1 above. Measures of Adjustment. PTSD is clearly a major element in post-Vietnam psychiatric symptomatology (Laufer, 1985). The PTSD scale, a single additive scale of stress symptoms based on the DSM-III criteria, is the most frequently used scale to detect symptomatology in empirical research. Other scales, such as the Psychiatric Epidemiology Research Instrument (PERI), have been used less successfully. Since a standardized scale (PTSD Scale) has been used in several male studies, its use is recommended in a study of woman veterans for comparison. Laufer (1985) suggests that adjustment measures should not be limited to PTSD. Other health outcomes are certainly evident, as supported by the work of Paul (1985). Since systematic data relating war experiences to specific outcomes for women are lacking, data should be gathered in a future study which include not only a broad range of health outcomes (physical and mental) but significant life experiences, including marital and occupational histories. 2.3 STRESS AND ADVERSE REPRODUCTIVE OUTCOMES In the broader literature on stress and health outcomes, life change events and stress have clearly been related to adverse reproductive outcomes. Therefore, a brief review of the more recent literature in this area was undertaken to identify variables of interest for a study of health and reproductive outcomes of female Vietnam veterans. 2.3.1 Pregnancy Complications (contributed by Richard Neugebauer Ph.D., Columbia University). Sociodemographic and medical factors are established as major determinants of adverse reproductive outcomes, including preterm labor (NCHS, 1980; Hutchins et al, 1984; Niswander and Gordan, 1972). Evidence from epidemiologic studies (and those using an animal model) document a role for psychosocial stress in pregnancy complications without specifying any intervening physiological mechanisms. Studies of psychosocial stress and adverse pregnancy outcome have employed both retrospective case control and prospective cohort designs. These investigations conceptualize "stress" either as an internal psychological 24 �state or as representing the environmental challenges posed by external, so-called stressful life events. Psychological factors have ranged widely from the comparatively elementary constructs of anxiety or depression, assessed with psychometrically sophisticated instruments of adequate reliability (Crandon, 1979), to more complicated concepts of guilt and dependency, where measurement may involve projective tests (Grimm, 1962) and complex inferential processes on the part of clinicians. These latter measures often do not possess satisfactory or even known psychometric properties. External stressors have usually been measured with one of several life event checklists. Some investigators have adopted without change event inventories produced for work with general community samples (Norbeck and Tilden, 1983) ; others have developed lists especially suitable for the pregnant women under study (Newton et al, 1979; Chalmers, 1983; Barnett et al, 1983). Objective ratings of event magnitude, each woman's subjective appraisal of her events, event controlability, predictability and indices based on these and other event characteristics have all been evaluated as predictors of pregnancy complications (Norbeck and Tilden 1983; Chalmers, 1983; Newton and Hunt, 1984). Additionally, the temporal focus of the event checklist has either been restricted to pregnancy proper (Newton et al, 1979) or included periods of time prior to conception (Nuckolls et al, 1972; Jones, 1978). Some investigators have limited outcome to highly specific prelabor pregnancy complications, such as hyperemesis gravidarum (Chertok et al, 1963) complications of labor and delivery (McDonald et al, 1963) or neonatal complications, notably low birthweight and short gestational age (Newton and Hunt, 1984). Other studies have encompassed a wide spectrum of complications, often reflected in a single global index, originating in markedly different biological mechanisms (Nuckolls et al, 1972; Norbeck and Tilden, 1983; Gorsuch and Key, 1974). Clearly, this diversity of designs and of conceptualization and measurement of dependent and hypothesized independent variables renders interpretation of this literature difficult. However, there is a generally recognized (Chalmers, 1982) and notable failure across studies to demonstrate rigorously a consistent association between stressful life events or psychological symptoms, such as anxiety, and pregnancy complications. For example, while several studies report a positive, unconditional association between life events and risk of adverse reproductive outcome, other investigators fail to discover any association despite adequate sample sizes (Chalmers, 1983), find a negative association (Jones, 1978), or discern an association exclusively in the context of inadequate 25 �social assets (Nuckolls et al, 1972)\ A number of studies concur in finding a positive association between psychological symptoms and pregnancy complications but differ markedly as regards the period of risk and the specific effected outcomes. Gorsuch and Key (1974) implicated only first trimester anxiety in complications before and during labor and in infant status. However, Norbeck and Tilden (1983), noted an association only between emotional disequilbrium (this construct included anxiety but the time of administration of the anxiety measure was not clearly described) and neonatal complications. These contradictory findings reflect in part the shortcomings in design or measurement that hobble many of these studies. Case control designs are notoriously vulnerable to biases in subjects' recollection of the hypothesized independent variables. Retrospective designs cannot distinguish, in a compelling fashion, psychological symptoms resulting from and preceding the adverse outcome. Furthermore some studies, presented as prospective investigations, actually measure crucial independent variables during the postpartum period (Gorsuch and Key, 1974). In other studies, comparatively small sample sizes (Davids, Devault and Talmadge, 1961 [N=48]; McDonald and Christakos, 1963 [N=86]). and the unreliability of certain measures, render the lack of statistically significant findings uninterpretable. Small sample sizes have also hindered the use of powerful data analytic strategies to control for the effects of potentially confounding variables. Given the plethora of possible outcomes of interest and the need for biological coherence in the findings, the next wave of investigations in this area should examine individual adverse reproductive outcomes separately, rather than indices combining diverse complications, to permit the specification and testing of defined pathophysiological mechanisms. These studies must also be rigorously prospective. Three recent studies have investigated possible psychosocial influences in preterm delivery. Using case control designs Newton et al, 1979 and Berkowitz and Kasl, 1983, assessed in a postpartum interview, the frequency of life events during pregnancy of women delivering preterm and at 37 weeks gestation or later. Newton et al, found the mean number of events overall and in the last week of pregnancy was greater for women delivering preterm. During the entire pregnancy, 73 percent of women delivering preterm experienced at least one life event compared to only 43 percent of women going to term. Berkowitz and Kasl using a black and white population in New Haven, reported much the same findings for life events during the entire pregnancy. However, among Blacks this finding held only for women with wanted pregnancies. Finally, Newton and Hunt (1984) examined the role of life events and anxiety in prematurity and low 26 �birth weight in a prospective cohort study involving interviews at three time points during pregnancy and one postpartum. Life events were implicated strongly in risk for prematurity and low birth weight. For example, 73% of women delivering preterm reported at least one life event during pregnancy in contrast to 9% of women with term births. Despite the apparent consistency of results across these three studies, two used exclusively retrospective designs in which neither interviewers nor subjects were blind to caseness status. Newton and Hunt's study is also not immune to the major threats to validity posed by biased recall. Their final life event interview was conducted postpartum and, perhaps not surprisingly, events reported in this concluding interview contributed decisively to their results. As a consequence, these investigations, while offering provocative early evidence of a role for psychosocial factors in preterm delivery, await confirmation with more rigorous designs and elaborations as regards intervening biological mechanisms. 2.3.2 Menstrual, Disorders Few large scale studies have been conducted on the effects of environmental and social stressors on the menstrual cycle. Studies which have been conducted focus on either amenorrhea or perimenstrual symptoms. The cessation of menses has been associated with catastrophic events and strong emotional trauma, especially of chronic nature (Summer, 1978). However, the few available studies have instead focused on amenorrhea of psychogenic origin, with little conclusive data. In her review, however, Sommer cites several animal studies which suggest the effect of stress on menstrual function stems from prolonged or chronic stress in contrast to acute stress. In relation to perimenstrual symptoms, the majority of stress research has examined the influence of life events and daily stressors on symptomatology. These studies have consistently shown that negative life change is associated with reports of perimenstrual symptoms including pain, water retention, behavior change, negative affect, and amount of bleeding (Siegel et al, 1979; Woods et al, 1982; Jordan and Meckler, 1982). While two of these three studies are limited by nonrepresentative samples (typically college students), they do suggest that major life changes, occurring as long as a year prior to the study, were associated with more frequent and more severe symptoms. A study by Woods and colleagues (1985) is described both for its inclusion of daily stressors, as well as major 27 �life events, in a study of perimenstrual symptoms and for its use of a random sample. Seventy-four women aged 18 to 35, a subsample from a larger study, were asked to complete a health diary for two months, Moos' Menstrual Distress Questionnaire, and Holmes and Rahes's Schedule of Recent Events. Daily stressors were described in the health diary and related to work, familial relationships, etc. The study provided "modest support" for the previously reported relationship between major stressful life events, daily stressors,and perimenstrual symptoms. Notably, daily stressors had a greater effect than major life events or perimenstrual symptoms. Further, the investigators report that "a generally stressful life context is more influential than episodes of stressors during a particular menstrual cycle phase" (p.267). In summary, the available data, although limited both in scope and methodology, suggest a pattern between stress and menstrual disorder which has clear implications for a study of women Vietnam veterans. It is chronic stress, rather than acute or episodic stress, that has been reported to be more influential on menstrual disorders. If it can be assumed that an average one year tour or duty was experienced as chronic stress, then a higher incidence of menstrual disorders during and possibly following the war experience should be expected. What is not known from available data are the longterm effects of chronic stress on menstrual function, and posssibly fertility. Therefore, to assess the impact of the war experience as a stressor on menstrual function, data (albeit retrospective) regarding typical cycles and abnormalities should be collected for the periods during and after the war. 2.4 SUMMARY To summarize briefly this lengthy section, it is clear that there is no systematic study to date of the effect of war stress on the general and reproductive health of women veterans. Such a study is clearly needed - at least with respect to the most recent Vietnam conflict. However, in order to implement such a study, new definitions of war stress will be required for non-combatant female military personnel and a broad range of health outcomes beyond PTSD must be included. 28 �3. DRUG USE AMONG THE MILITARY IN VIETNAM Two types of drug use are considered in this section prescribed use of antimalarial drugs (Section 3.1) and illicit use of such drugs as heroin, marijuana and alcohol (Section 3.2) 3.1 ANTIMALARIAL DRUGS USE Malaria was seasonal and endemic in Vietnam and epidemic among U.S. troops, accounting for most of the morbidity from 1965-1969 in the military. Prevention consisted primarily of insecticides (aerial and ground spraying) and chemical phrophylaxis. Of the latter, Dapsone and Chloroquine-Primaquine were the drugs used to prevent and treat malaria in American troops. According to a Department of the Army internal memorandum (12/16/86), chloroquine-primaquine tablets (dose not stated, although typical dose was reported as 300 mgm chloroquine and 45 mgm primaquine; Willerson et al, 1972) were taken once a week, while Dapsone 25 mgm was taken on a daily basis. It is unclear from this memorandum if these two drugs were taken alone or in combination; however, other reports (Willerson et al, 1972; Eppes et al, 1967; Ognibene, 1970) indicated that both regimens were followed. On leaving Vietnam, Army personnel were instructed to continue the chloroquine primaquine for eight weeks and/or the Dapsone for 28 days. Chloroquine-primaquine is a combination aminoquinoline compound used both in treatment and phrophylaxis of vivax and ovale malaria. Dapsone, a sulfone, was used widely in Southeast Asia from 1966 until 1973 following the discovery of several antiraalarial resistant strains of Plasmodium falciparum malaria. The army has no records of how many or which troops took Dapsone. Similarly, data regarding use of Chloroquine-primaquine were not available to the reviewers. However, according to the Army Department memorandum of 12/16/86, "(d)apsone was mainly given to troops in the I Corps and Central Highlands areas where falciparum malaria was prevalent." Review of available literature focused on these two drug types. A primary source for this review was several chapters in the Handbook of Experimental Pharmacology edited by Peters and Richards (1984) which reviewed data from available studies to date. This review was supplemented with research reports published since 1984. Findings regarding toxicity of each drug group will be discussed separately. It should be noted that the scientific literature on antimalarial drugs is voluminous and highly technical in detail. The limited material presented here is considered that most pertinent to the purposes of this review. 29 �3.1.1 Chloraquine-Primaquine Chloraquine-primaquine is a combination of two aminoquinoline compounds effective against all stages of human-malaria parasites except for certain strains of P. falciparum resistant to chloroquine. In a review of antimalarial drugs edited by Peters and Richards (1984), serious toxicity of the aminoquinoline compounds has been recognized since the outset of human trials in 1926. The Peters and Richards (1984) volume (Chapter 3 by P.E.Carson) focuses more specifically on the 8-aminoquinolines (primaquine) in its discussion of toxicity, identifying three major areas as follows: 1) specific neurotoxicity of the plasmocid type; 2) general clinical toxicity of the pamaquine type; and 3) induction of hemolytic anemia in genetically predisposed individuals, especially those with G6PD deficiency. (a) Neurotoxicity. Pathological changes in the central nervous system have been documented in a number of animal studies using lethal and toxic sublethal doses of aminoquinolines. In Peters and Richards (1984) review, neurotoxicity associated with lethal doses of primaquine was less marked than with other compounds in this group. Further, neuronal damage resulting from sublethal, reversible intoxication was described as "low grade." No , human studies reporting neurotoxicity were found. (b) General Clinical Toxicity. Basic studies on toxicity were conducted principally in rats, dogs and monkeys with confirmation in human trials. Several studies cited in Peters and Richards, 1984, (i.e., dayman et al, 1952; Brewer et al, 1961; Craige et al, 1947; Atchley et al, 1948; Edgecomb et al, 1950; Brewer et al, 1961; Wisclogle, 1946; Alving et al, 1948; Jones et al, 1953; Zubrod et al, 1947) describe the toxic symptoms as primarily gastrointestinal and hematological with the prominent feature of lethal doses being hepatotoxicity. The most prominent toxic symptom is epigastric discomfort with other gastrointestinal symptoms including headache, anorexia, nausea, vomiting, and diarrhea. Drug fever was cited as common. Hematological changes include leucocytosis and neutropenia, with the former more common with primaquine. Reversible T-waye changes, postural hypotension, and cyanosis (primarily related to methaemoglobinanemia associated with high doses greater than or equal to 60 mgm/day) have also been identified. Notable is that reversibility of toxicity was demonstrated repeatedly in the studies cited in this review. (c) Hemolytic Anemia. Primaquine-induced hemolytic anemia occurs only in certain susceptible individuals, especially those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, hemolysis can also be precipitated in these individuals by the stress of serious intercurrent 30 �illnesses such as acute hepatitis, pneumonia, diabetic acidosis, etc. Two other classes of genetically determined conditions also predispose individuals to hemolysis of the primaquine type: enzyme deficiencies of the metabolic system that protects the erythrocyte against oxidant stress; and molecular variants of hemoglobins that are susceptible to oxidant stress (Carson and Fischer, 1966; Carson et al, 1981; Carson, 1968: cited in Peters and Richards, 1984). Reports of Other Side Effects. Studies completed since the Peters and Richards volume in 1984 have reported both similar and new findings regarding toxic side effects of chloroquine and/or primaquine. While a 1984 review of antimalarials focused on use in Africa (Salako, 1984) , one specific finding has important implications for a proposed study of women Vietnam veterans. In this work, ocular toxicity was cited with prolonged prophylactic use, defined as a total dose of 200g of chloroquine ingested over a period of two or more years. The retinopathy is characterized by macula and perimacular degeneration, patchy depigmentation of the macula, and retinal artery constriction. These corneal lesions result in loss of central visual acuity, which may progress to total blindness. Unlike other toxic effects, ocular toxicity is not reversible. Salako (1984) states that chloroquine retinopathy tends to be permanent after .discontinuation of the drug. Therefore while it is unlikely that the typical female Vietnam veteran ingested a toxic dose of chloroquine as noted above, this adverse outcome should be of interest in a study of their health outcomes. Salako (1984) cited other toxic effects not included in the Peters and Richards (1984) volume, namely pruritis dyskinesia, mild neuromuscular disturbances, pigmentary changes in the skin, and lesions of the inner ear. All of these symptoms were either mild, rare, or reversible. Animal studies report changes in drug metabolizing enzymes in rats (Emerole et al, 1983) and induced cardiomyopathy in chickens with prolonged use of chloroquine, but such findings have not been reported in humans . (e) Teratogenicity and Carcinogenicity. Reports of the teratogenic effects of the antimalarials have been limited to case studies. Data from large samples are lacking with the exception of a case-control study by Wolfe and Cordero (1985) . The teratogenic effects in the fetus, as reported in case studies, appear related to certain dosage regimens or prolonged use in pregnant women and include vestibular changes, deafness, retinopathy, prematurity, and death (Wolfe and Cordero, 1985; Bruce-Chwatt, 1983; Essien and Afamefuna, 1982) . Looking at normal dose ranges in their study of 169 pregnant women receiving chloroquine 300mgm/wk, 31 �Wolfe and Cordero (1985) found the proportion of birth defects not significantly different from that in the control group (n=454). However, because of their sample size, the investigators point out that their analysis cannot exclude risks lower than a 5-7 fold increase in the incidence of birth defects. No reports of other teratogenic, carcinogenic or toxic reproductive outcomes (e.g. infertility) were found. In fact, the literature supports careful and controlled use of antimalarial drugs both for treatment and prophylaxis, pointing out the potential complications of untreated malaria during pregnancy. 3.1.2 papsone Dapsone is a sulfone used in chemotherapy, mainly for leprosy and secondarily in malaria. As previously mentioned, it came into widespread use by U.S. troops in Vietnam following the discovery of resistant strains of P. falciparum malaria. Toxic effects include primarily hematological and neuropathic conditions. A comprehensive discussion of these toxic effects can be found in Chapter 4 by Scholer, Leimer and Richie, in Peters and Richards (1984) and is highlighted below. (a) Hematological. The hematological side effects were cited as significant in that they occurred with relatively low doses of sulfones, whereas the other side effects were observed mainly with higher doses used to treat dermatological conditions. These hematological side effects included methemoglobinemia, hemolytic anemia, and agranulocytosis. Methemoglobinemia was reported in cases of high doses of Dapsone for dermatological conditions in seven studies cited in Peters and Richards (1984: Hjelin and DeVerdier, 1965; DeGowin et al, 1966; Cooke, 1970; Shelley and Goldwein, 1976; Elonen et al, 1979; Manfred et al, 1979; Schvartsman, 1979). In addition, a study by Willerson et. al., (1972) cited in this volume documented methemoglobinemia in five of eight army volunteers receiving both dapsone and chloroquine-primaquine prophylactically in Vietnam, suggesting an interaction or synergistic effect between the two drug groups. This effect was independent of any G6PD deficiency. Hemolytic anemia, induced by dapsone, was first described in a leprosy patient receiving high doses (100-300 mgm daily) as reported by Ramanujam and Smith (1951) in Peters and Richards (1984). However, Eppes et al, (1967) also documented prompt falls in hematocrit values in G6PD deficient black Army soldiers who were on the typical army schedule for malaria prophylaxis, 25 mgm dapsone daily plus 32 �chloroquine and primaquine weekly. Chernof (1967) reported marked hemolysis, in some of the G6PD-deficient individuals treated according to this schedule. As with the other hematological disorders, agranulocytosis was first noted in a dapsone regimen for dermatological problems (McKenna and Chalmers, 1958; Firkin and Mariani, 1977: cited in Peters and Richards, 1984), but was also detected in U.S. soldiers in Vietnam receiving prophylactic dapsone, either alone or with chloroquine and primaquine, for 3 weeks to 3 months, with 8 cases being fatal (Ognibene, 1979; Catalano, 1971; Joplins and Ognibene, 1972: cited in Peter and Richards, 1984). These incidents led to the limitation of dapsone for malaria prophylaxis in the U.S. Army. (b) Neuropathic . Evidence of peripheral neuropathy is restricted to case studies of dermatological patients receiving high doses of dapsone for prolonged periods (Rapoport et al, 1972; Wyatt and Stevens, 1972; Epstein and Bohm, 1972; Fredericks, et al, 1976; Koller et al, 1977; Homeida et al, 1980; Waldinger, 1984). All of these case studies reported motor neuropathy, but Wyatt and Stevens, (1972) described both motor and sensory symptoms while Homeida et al, (1980) claimed to be the first report of optic atrophy after a daily dose of 600 mgm of dapsone for 10 days. All toxicity was reported as reversible in these case studies. No cases of peripheral neuropathy were reported in individuals using dapsone for antimalarial prophylaxis. Miscellaneousi .Side Effects. Hepatotoxicity and hypoalbuminemia have been reported in a small number of individual cases, but again with individuals receiving high doses of dapsone for dermatological conditions (Millikan and Harrell, 1970; Goette, 1977; Stone and Goodwin, 1978; Kingham et. al., 1979; Young and Marks, 1979: cited in Peters and Richards, 1984) . Teratogenecity and Carcinogenicity. Only two animal studies were cited in Peters and Richards (1984) . The teratogenecity study, conducted in Japan (Asano et al, 1975) found no significant increase in fetal defects in rats whose mothers were given high doses of a related sulfone from day 9-14 of gestation. In the carcinogenicity study (Griciute and Tomatis, 1980) rats and mice of both sexes were given daily oral doses of lOOmg/kg dapsone five times weekly over 2 years. The incidence of tumors was equal in treated and untreated animals, with the exception of fibrosarcomas and angiosarcomas of the spleen in male treated animals. No human data have been reported, but data from the animal studies do not suggest any concern for teratogenetic or carcinogenetic effects in humans. 33 �3.1.3 Summary In summary, the available literature on the two antimalarial drug groups used prophylactically in Vietnam troops is limited and provides no outstanding evidence of lasting toxicity at recommended doses. With the one exception of chloroquine-induced retinopathy, all other toxicity is reversible with reduction or termination of dose. Similarly, there is no convincing evidence of teratogenesis or carcinogenesis at recommended prophylactic dose levels. Congenital abnormalities or other conditions have been documented in cases of high doses and/or prolonged administration, usually for conditions other than malaria. Therefore, it appears from existing data of both animal and human studies that prophylactic use of antimalarials does not place the majority of female Vietnam personnel at high risk for adverse health and reproductive outcomes. However, for the most part human data are limited to case and small sample studies. A large-scale epidemiological study of possible long-term effects of antimalarial prophylaxis has not been conducted. Special attention to use of antimalarials during pregnancy or in excess of two years is warranted. 3.2 ILLICIT DRUG USE Many research studies on illicit drug use among the military in Vietnam have been conducted since the late 1960's with the majority conducted during the 1970's. These studies have focused on the extent of drug use pre-service, in-service and post-service, the types of drugs used, the characteristics of drug users and patterns of use, and the impact of drug use on performance. These studies have focused almost exclusively on male personnel. Only two recent reports (Ott, 1985; Boyle, 1985) were found which addressed the issue in female veterans. This section will cover those studies which are methodologically most sound and which provide findings which are most generalizable. Given the paucity of data regarding female veterans, the studies on male populations can be used to inform investigation of drug use among women in Vietnam. In reviewing 10 studies of male veterans, conducted over a course of approximately seven years, it becomes clear that the two illicit drugs most frequently used in Vietnam were marijuana and heroin. This trend becomes most apparent in later studies in the 1970's when heroin use increased dramatically in relation to other drug categories. Consequently, with the exception of a study in 1969 by Stanton (1972), data were not gathered routinely (or else not reported) on use of amphetamines, barbiturates, opium, and hallucinogens. Perhaps, as reflected in Stanton's (1972) 34 �report, the numbers of users of other drugs were too small for meaningful analysis. In fact, not only were marijuana and heroin more frequently used, these drugs were also the most socially acceptable, with users of other drugs being ostracized (Ingraham, 1974). Therefore, this review will focus on available data regarding marijuana and heroin use. Results of these studies are summarized in Table 1. 3.2.1 Marijuana One of the first surveys on marijuana use in Vietnam was conducted by Roffman and Sapol (1970) in 1967 with a sample of 628 Army enlisted men being processed for return to the United States. The sampling frame and strategy limits the generalizability of the findings since only a limited rank distribution was sampled, with the study further restricted to two southern tactical corps areas. The typical respondent was 22 years old, single, white, high school graduate, Protestant, a draftee, and had completed a 12month tour. The majority of respondents indicated that they had never smoked marijuana. Of the 31.7% who had, 61.1% first smoked after coming to Vietnam, and usually early in the tour. Users were slightly younger, single, from an urban background, of lower rank, and more likely to have experienced combat. One-quarter (n=44) of the users were considered to be heavy users (i.e. smoking on 21 or more occasions). These heavy users were younger, of less rank, more likely to have used marijuana before Vietnam, and used it earlier in the tour. Roffman and Sapol compared their data with estimates of marijuana use at the time in the United States. They concluded that, at that time, the prevalence and incidence of marijuana use in Vietnam was very similar to that in the United States. Rates of use among the military population were similar to rates found among civilian university communities or among the comparable age group in the general population. In a study two years later (1969), Stanton (1972) reached a similar conclusion despite higher use rates among Vietnam military. The sample in this study was both larger (n=2,547) and more representative, including ranks of E-l to lieutenant colonel, as well as both incoming and outgoing personnel. Sizeable increases were noted in the reported use of most drugs surveyed when compared to earlier research. In terms of marijuana use, 21.5% used the drug for the first time in Vietnam, a figure only slightly higher than the 19.4% found by Roffman and Sapol (1970). While this may indicate that the rate of increase of users did not increase dramatically between 1967 and 1969, further data on extent of use showed heavier use (i.e., 29.6% as compared to 7.4% in 1967). In a subsequent review, Stanton (1976) compared findings across several studies from 1966-1970, the results of which seemed to indicate a fairly constant increase 35 �!-• I Roffnan 1970 N=584 Imat jaf _. J| Us. iaonB Uilii-JI Stanton 1972 Rohrbaugh* 1974 N=997 N=169 Robins 1975 N=451 Yager 1984 N-1,342 Ritter 1985 N=668 MARIJUANA first used before Vietnam first used in Vietnam 35 19 41 22 40-48 28 50 50-63 69 37-43 45 first used in Vietnam 71-81 31 jsed while in Vietnam 24-27 34 ased since Vietnam 10-11 10 used while in Vietnam used since Vietnam 25 (used 21 or more times) HEROIN first used before Vietnam All numbers are rounded percentages based on number of respondents in the study. •- indicates data not available * Data based on 2 survey populations, N=169 in each group 32 37 37 �overall in marijuana use in Vietnam. However, in further review of the data, he attributed this apparent increase to the influx of a greater number of pre-Vietnam users who continued use than to an increase in the numbers who initiated use while in Vietnam. In other words, increased use in the U.S. was, in turn, influencing use rates in Vietnam. Stanton (1972) reported other findings consistent with those of Roffman and Sapol (1970). Marijuana smoking and combat exposure were slightly correlated (r=.22, df=27, p=.01), and the majority of users started smoking in the first three months of duty. Unlike the previous study, however, Stanton did not find any relationship between marijuana use and age, marital status, or volunteer status for duty. A final study on marijuana use to be reviewed was conducted in late 1974 - early 1975 by Ritter et. al., (1985) of 2510 men, randomly selected from Selective Service records, born in the years 1944 through 1954. Analysis for this study of post-service marijuana use was limited to the subsample of 836 respondents who had served in the military. The sampling frame allowed for three comparison groups as follows: Vietnam service; overseas other than Vietnam service; and U.S. service only. Data on pre-service, inservice, and post-service marijuana use showed that the highest increase from pre-service to in-service use occurred with the Vietnam troops. Further, the higher level continued during the one-year period of post-service. Contrary to what might be expected, regression analysis revealed that service in Vietnam (as compared to other areas) had no significant positive effect on the use of marijuana during military service. However, the period of service did have an effect on marijuana use; that is, marijuana use during service was most probable among men who had served in 1970 or later, a time when drug use was increasing in the U.S. An interaction effect between period of service and location of service was insignificant. Therefore, the time of service, rather than the Vietnam exposure, appears to explain more of the variance in marijuana use, Ritter et. al., (1985) reported other findings consistent with the two previous surveys, mainly that marijuana use was more common among pre-service users, blacks, and younger troops. In sum, the results of these three studies are generally consistent. The major conclusion is that the Vietnam experience influenced the use of marijuana less than the period of time in which it occurred, a time when drug use was epidemic in the U.S. and drugs were readily available in Vietnam. Therefore, as summarized by Ritter et. al., (1985), it appears that we have a "classic intersection of an historical effect.... and a cohort effect" (p. 129). 37 �3.2.2 Heroin Stanton (1976) reports that "(u)nlike marijuana, with which so many soldiers had had pre-Vietnam experience, heroin'use was clearly a Vietnam phenomenon" (p.562). The "heroin days" in Vietnam began in early 1970 with the influx of 90% to 96% pure heroin. The spread of GI heroin addiction has been attributed to an army crackdown on marijuana use or to boredom and feelings of victimization, driving troops to heroin use. However, McCoy (1972), in an indepth political analysis of heroin trafficking in southeast Asia, claims that the heroin epidemic was related to a "well-organized, comprehensive sales campaign" by the Vietnamese. In addition, the Cambodian invasion in mid 1970 improved smuggling conditions since unlimited quantities of heroin could be flown from southern Laos through Phnom Penh to Saigon. In terms of the extent of heroin use, data from three studies are available. Stanton's 1969 study (1972) indicated that only 2% of servicemen used heroin for the first time in Vietnam while an additional 4% had used it prior to Vietnam. The year of the study (1969) most likely accounts for these low rates. In a frequently cited study by Robins and colleagues (1975), a random sample-(n=470) was selected from a Department of Defense list of 13,760 Army enlisted men returning to the U.S. in September, 1971. In addition, from a list of 1400 men with positive urine samples for illicit drugs, a random sample of 495 men was selected. Exceptionally high rates were obtained for interview response (95%), military record retrieval (99%), and urine sample reports (92%), the latter allowing for validity checks on the data. As a group the general sample (n=457) did not differ in pre-service drug experience from a national sample of comparable ages. Less than half had ever tried an illicit drug (marijuana, amphetamines, barbituates, or narcotics). Only 2% had ever used heroin, and less than 1% had used any illicit drug more than a few times. Almost half (n=194 or 43%) of this sample had used narcotics. Approximately one-third tried heroin. Of narcotic users, 25% used these drugs more than weekly for at least 9 months. Forty-six percent were addicted by self report and confirmed by symptoms of dependence. Preferred use was smoking or snorting. Injection was rare but did occur with prolonged use. Similar to patterns of marijuana use, use began early in the tour, i.e., within the first two months. The most common reason for use was the drug's euphoriaproducing effects, with no correlation found between use and combat exposure. In fact, according to other descriptive accounts of drug use (Ingraham, 1974; Zinberg, 1972), heroin use was a social event carried on in small groups as 38 �compared to the typical pattern in the U.S. of solitary use. Ingraham described a cohesiveness and loyalty among "heads" or users of heroin, who were accorded higher status than users of alcohol, amphetamines, barbituates and hallucinogens. Finally, Robins et. al., (1975) identified pre-service predictors of narcotic use similar to predictors of in-service marijuana use - younger age, urban background, pre-service drug use, heavy drinking, and behavior problems. Contrary to expectations, they also found that volunteers were more likely than draftees to use narcotics in Vietnam. In another study regarding effects of the Vietnam experience on subsequent drug use, completed about the same time, Rohrbaugh et al, (1974) found somewhat lower rates of heroin use. A stratified random sample of enlisted men (grade E5 and below) returned to the U.S. was drawn at three points in time: February, September and December, 1971; n=782, 480 and 481 respectively. Data from September and December were used in this analysis. Approximately onefourth of the returnee group admitted using heroin or opiates at least once in Vietnam, with the greater proportion (51.1% in September, 65.9% in December) reporting daily use. Further, data revealed that the clear majority (71.1% in September; 81% in December) of veterans who had ever used opiates first did so in Southeast Asia. 3.2.3- Alcohol Alcohol use during Vietnam service has received much less direct attention than other drug use, with data frequently reported secondarily to narcotic or marijuana use. However, there is limited evidence to suggest that alcohol use was extensive among Vietnam soldiers as indicated in the following studies. In a large national study, Robins and colleagues (1975) found that 92% had used alcohol at least once while in Vietnam with 37% reporting problems with alcoholism postservice. This study did not gather more specific data on extent of alcohol use in Vietnam. Rohrbaugh et. al., (1974) also reported data to suggest extensive alcohol use. In two separate 1971 surveys, they reported that alcohol was used by 83.3% and 79.8% of their samples but that only a small minority (2.7% and 5.2%) began drinking while in Vietnam. No data are available regarding extent of use. These limited data are supplemented by a descriptive account (Ingraham, 1974) of alcohol and other drug use in Vietnam, but no data regarding use rates were reported. Finally, the Veterans Administration reported in 1978 that 107,000 inpatierits and 323,000 outpatients were being treated for alcoholism, and public health service figures indicate that as many as half a million Vietnam veterans (of 2.8 million) are alcoholics (Royal Commission on the Use and Effects of Chemical Agents on Australian Personnel in Vietnam, 1985). 39 �Although no systematically methodologically sound collected data are available on alcohol use post-Vietnam, all of the studies which have considered recent alcohol use at all, suggest consistently that it is on the increase and the major drug abused by male veterans. Considerable indirect evidence is available from the recent "Vietnam Experience" mortality studies reviewed in Section 4 of this review. All of them consistently report elevated death rates from Motor Vehicle accidents. Most recently, a report of post-service mortality in the CDC Vietnam Experience Study (CDC, 1987) indicates that, despite small numbers, alcoholrelated traumatic (mostly motor vehicle accident) deaths were more likely among Vietnam veterans in the first five years after discharge, then declined. Any future studies of follow-up of Vietnam veterans - both male and female should include this variable. 3.2.4 Drug Use After Vietnam Several of the studies cited above also examined whether Vietnam returnees differed in their patterns of stateside drug use from other non-Vietnam soldiers or civilians. The 1971 study by Robins et al, (1975) provides the best evidence. In their sample of 943 men, they found at 8 to 12 months after return that use of particular drugs and combinations of drugs decreased to near or even below preservice levels. The choice of which hard drug to use reverted to the pre-Vietnam pattern. Only in Vietnam were narcotics used more than barbituates or amphetamines. In addition, on return to the U.S., the susceptibility to addiction among continued narcotics users declined dramatically, resulting in addiction remission rates of 95% for those addicted in Vietnam. The investigators caution that the study period following return was short and that data gathered subsequently might show different use or addiction rates. However, while there was a striking decline in susceptibility to addiction after return to the United States, heavy use of each drug type did not show the same decline. Further, usual methods of administration of narcotics changed from smoking in Vietnam to injection in the U.S. Finally, the type of narcotic most frequently used changed from codeine before Vietnam to heroin after return. In-service predictors of continued narcotic use after Vietnam included injection of narcotics while in Vietnam, narcotic dependence, heavy use of barbiturates or amphetamines in Vietnam, narcotic dependence, and use of narcotics in Vietnam for longer than six months. Drug use in and before Vietnam was determined to be a powerful factor in poor post-Vietnam adjustment, but its effects were contingent on continued drug use. Adjustment problems included arrests, depression, unemployment, and divorce, with narcotics use being the strongest of the drug 40 �predictors except for arrests which were more closely associated with amphetamine use. Robins and Helzer (1975) followed up this study three years later (1974) with reinterviews of the same sample, adding a group of 300 nonveterans for comparison. The comparison group was selected from Selective Service System files of service eligible men who had not been inducted and was matched with the original sample for age, education, and area of residence. High response rates were again obtained: 94% of the veterans and 91% of the nonveterans. Among the veterans, the low rate of narcotics use and dependency found in the first survey continued to hold after three years. Only 2% of the veterans had been addicted at any time since their return. More than 90% who reported addiction in Vietnam had not become readdicted in the three years since return. Even among those who continued narcotic use (20%), only 12% had become addicted. While heroin continued to be the most frequently used narcotic (55%), opium and codeine were also used. While use of narcotics is a major concern, alcohol and marijuana were actually used more frequently and reported as causing more problems in daily life. For example, while 5% felt that narcotics had interfered with their lives, 18% felt that drinking had. In the comparison of veterans and nonveterans, for every drug of inquiry, veterans' use was greater in the-past two years than was nonveterans' use, and was not related to previous drug experience. The greatest differences were in the use of narcotics, LSD, and barbiturates. Marijuana use was common among both groups. Thus the authors concluded that Vietnam exposure led to increased drug use. However, veterans showed no inclination toward heavy or problem use, and, in fact showed a greater ability to use narcotics without becoming addicted. While this follow up study provides detailed information, no mention is made of obtaining objective measures of drug use (urine samples) as in the earlier study. The investigators do not discuss the implications of reliance on self reported data for validity of the findings. The rates of drug use may be undereported. Rohrbaugh and colleagues (1974) also used a control group of soldiers who had not served in Vietnam to investigate whether combat zone returnees differed in their pattern of stateside drug use from non-combat zone soldiers. They found greater use by Vietnam veterans only in relation to opiate use (p is less than .02) and only at one point of the three survey times. This relationship held when controlling for age, pre-service drug use, and length of time since return. Consistent with Robins (1975) study, Vietnam returnees reported using the same drugs stateside as in Vietnam but were more likely to discontinue opiate use stateside, supporting the contention that opiate users in Vietnam differ from typical opiate users in the U.S. 41 �Finally, no tendency to use drugs more frequently or heavily was found among Vietnam returnees. Despite consistent results, this study was marked by several methodological flaws, however. First, drug use was based on self report alone and further was defined only as "at least one experience with a given drug in the month prior to the survey." Second, the authors acknowledge the potential for sampling bias by the possibility of underrepresentation of Vietnam drug abuse casualties (e.g. those previously separated from the military for drug problems, AWOL, or actively involved in in-patient rehabilitation programs). Nace et al, (1978), also found consistent results in a controlled follow up study of army enlisted men who served in Vietnam during a peak period of heroin use (1971-72) conducted two years after discharge. Data were collected by interviews and urine samples. In a sample of 125 detected drug users and 77 controls in the Philadelphia area, selected from four hospitals and two drug treatment center's records, pre-service variables (including drug use) contributed as much to continued narcotic use as did drug use in Vietnam. Rates of addiction post-service were again low (18%) among the 28% who continued use as compared to a 63% in-service addiction rate. Marijuana and barbiturate use also declined since discharge. However, use of hallucinogens and amphetamines increased. Finally, data regarding postservice alcohol use were also collected. Alcohol-related problems were extensive involving 39% of the sample, with 16% categorized as problem drinkers. This study, while limited by a small, non-random sample, nevertheless provides further support for measurement of in-service and postservice drug use by Vietnam veterans. Finally, two studies are presented, both for their methodological strengths and results contrary to those above (Yager, 1984; CDC, 1987). A national probability sample (n=1342) of draft eligible age during the Vietnam War included 629 nonveterans and 713 veterans, of whom 350 served in Vietnam (Yager, 1984). The sample was stratified by age, race and veterans status. Data were collected in interviews in 1977 and 1979, 6 to 15 years after leaving Vietnam, on a number of outcome variables, including drug use, related to post-service adjustment. Drug use (5 types) was consistently less prevalent among Vietnam veterans than nonveterans. However, use of amphetamines, barbituates and heroin was higher among Vietnam veterans than non-Vietnam veterans. Measures of weekly and daily drinking as well as drinking related problems were highest among Vietnam veterans. Vietnam veterans also reported more stress symptoms. Further analysis revealed that Vietnam veterans who experienced abusive violence reported greater stress and use of heroin and marijuana than did other veterans. Veterans who experienced no violent combat and did not take part in atrocities, however, did not differ appreciably from 42 �nonveterans. While the investigators are not reporting a cause-effect relationship between combat violence and drug use/stress, they do point out that relevant social background and other predisposing factors were controlled for in the analysis. The findings of this large national study, similar to that of Robins (1975) in scope, are roughly, consistent with other studies. Yet, by incorporating measures of exposure to combat violence, they do not support the premise that post-service drug use is more related to pre-service use than in-service use. Incorporating measures regarding both pre-service and inservice drug use as well as exposure to combat violence might uncover an interaction effect between pre-service drug use and combat violence which more completely explains continued post-service drug use. A rather different Vietnam experience mortality study (CDC, 1987) indicates that, although too small for formal analysis, the number of drug-related deaths remained elevated and was increasing through 1983 in Vietnam veterans, particularly for those drafted into service, in tactical or combat operations and those who served immediately after the TET offensive, in 1969. Approximately 9000 Vietnam veterans and an equivalent number of Vietnamera veterans, serving in the Army at the pay grade of E5 or below with a military occupational specialty (MOS) other than "trainee" or "duty soldier" were included in this study. In these large cohorts, 446 deaths were identified by the end of 1983. 3.2.5 Studies,of Female Veterans Only two studies were located which even mentioned drug use among female veterans, both of which were published within the last two years. The descriptive account by Ott (1985) of the war experience for women reports only that drugs and alcohol were used to deal with the pain and horror of suffering and death. In the most comprehensive study to date of women veterans by Louis Harris and associates (Boyle, 1985), interviews were completed with 3003 women, not all of whom served in Vietnam. Only one percent of all women veterans reported having problems with drugs. However, Vietnam and post-Vietnam veterans were more likely to have reported drug problems. The differences between groups are reported as small but consistent; however, no data are provided in the report. Further, less than 0.5% of women veterans who served during the Vietnam period (although not necessarily in Vietnam) rated drugs/drinking problems among the two or three most serious problems faced by female veterans since leaving the service. The Wisconsin Vietnam experience mortality study (Anderson et al, 1986) suggests a significant excess of all external causes of death compared to non-veterans among all 43 �female veterans, which may include an excess of drug or alcohol related deaths, but this finding is not pursued in the report. Clearly, there are no even minimally adequate data on even in-service, let alone pre-service and post-service, use of drugs among women Vietnam veterans to determine if drug use was an issue of importance as it was with male veterans. Available data are not even adequate to suggest if a serious problem existed or not. As noted by, for example, Anderson et al (1986), the Armed Forces have had access throughout this century to subsidized tobacco and alcohol. The high rates of tobacco product use are clearly evident in all studies reviewed of veteran mortality experience, including the female veterans included in Phase I of the Wisconsin study (Anderson et al, 1986). Elevated death rates due to respiratory cancer, lung cancer and emphysema are typical among veterans in these studies. Moreover, from the oral histories reviewed in Section 1 as well as other oral reports, it is clear that alcohol was the clear drug of choice among nurses serving in Vietnam. Collection of valid data on alcohol and other drug histories will be essential in any study of health and reproductive outcomes of women who served in Vietnam. 3.2.6 Summary In conclusion, data from a number of sources consistently indicate that the drugs most frequently used in Vietnam were alcohol, marijuana, and heroin although data on the latter two are very limited in women veterans. While heroin use escalated in the 1970's following a decline in marijuana use, use of alcohol appears to have been constant. In relation to the postwar public health concern regarding addicted returning veterans, the fear of continued narcotic use and addiction is unfounded. Both narcotic use and addiction were reported to decline in all studies reviewed which provide this information. This may have been a result of the differing social environments, most notably the social system which supported heroin use in Vietnam, as described by Ingraham (1974), as well as the necessity to change routes of drug administration from smoking to injection in the U.S. Marijuana use continued stateside at higher rates than narcotic use, but there is no evidence to suggest that it was related to the Vietnam experience. Finally, alcohol use/abuse remained at high levels and caused more adjustment problems than other drugs. This may be particularly true of women veterans. From a methodological perspective, a review of this literature underscores the following points in design of any future studies: 44 �e measures of pre-service, in-service and post-service drug use must be included; e measures of exposure to combat violence and atrocities must be included to adequately assess any cause-effect relationship between the war experience and subsequent drug use; o appropriate control groups must be identified for comparison purposes; and « specific data regarding alcohol use, as well as other drug use, should be collected. 45 �4. CHEMICAL EXPOSURES This section deals with chemical exposures specifically during Vietnam service. Other confounding chemical exposures likely to occur pre- or post- Vietnam (or Vietnam-era) service are discussed in Section 6, Confounding Factors as well as in Section 5 which addresses Nursing as an important occupational exposure. The two primary chemical exposures during Vietnam service were: Phenoxy herbicides and insecticides. The health outcomes identified from these two exposures will be reviewed, with emphasis on most recent findings. Measurement issues in the determination of exposure will also be considered. 4.1 PHENOXY HERBICIDES The most controversial chemical exposure subject to debate, particularly in the last decade, is to the family of phenoxy herbicides - specifically 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5 - trichlorophenoxyacetic acid (2,4,5-T), and a highly toxic contaminant found in the manufacture of the latter (2,3,7,8-tetrachlorodibenzo-para-dioxin or TCDD). Commonly know as Agent Orange, this combination of chemicals was sprayed as a defoliant in South Vietnam in an Air Force operation called Ranch Hand. However, in varying ratios, these phenoxyacetic acids have been used as defoliants at least since the 1940's, in agricultural applications in many countries and in Malaysia, by the British military forces. The proliferation of studies are reviewed in the following sub-sections: * Animal studies; e Human studies of herbicide exposure; o Vietnam experience studies (including more general Vietnam exposures); and e Studies of direct exposure in women. In reviewing these studies, the authors do not intend to replicate the extensive review of studies through 1985, already conducted by the Veterans' Administration (VA, 198185). Rather, this section will highlight findings from this extensive work, including methodological evaluation of key studies, and supplement it with a review of more recent reports. The focus is to assess the relevance of these findings for a study of exposed women of reproductive age. 46 �4.1.1 Animal Studies A considerable number of animal studies on the effects of phenoxyacetic acids and particularly of the contaminant TCDD have been reported since the early 1970's. These studies have been typified by large, unexplainable differences in both toxicity and reactions among the different species tested (recent examples include chickens (Sawyer et al, 1986) and species of fresh water fish (Kleeman et al, 1986a and b). Moreover, the reactions observed in animals do not necessarily resemble outcomes observed in humans. The exact mechanisms of toxic action which can cause death in animals are still not fully understood, either for dioxins in general or TCDD, but include a general wasting and failure to thrive (McConnell et al 1978; Greig et al, 1973; Poland et al, 1982). Perhaps the most consistently and rapidly established toxic outcomes in a variety of animal species is the carcinogenicity of TCDD - particularly the promotion of liver cancer in rodents (Poland et al 1982; IARC, 1982) although TCDD does not appear to be mutagenic (even in human tissue) at single or low doses (Beatty et al, 1975; Green et al, 1977; Khera and Ruddick, 1973). The mechanism by which TCDD promotes cancer growth in mice has been identified from recent studies, to be centered on the cytochrome P-,-450 gene in hepatoma cells (see for example, Jones et al 1986 a, b). Other receptor mechanisms whereby TCDD promotes other toxic effects are also being identified (for example, Morrow and Creese, 1986). A potentially important recent avenue of research indicates that TCDD may have a primarily immunosuppressive effect. This was originally thought to be characterized by thymic atrophy, mediated by the thyroid gland (Knutson and Poland, 1980; Clark et al, 1981, 1983; Greenlee et al, 1984; Rozman et al, 1984 a,b, among others ). More recent studies indicate the possibility of direct toxic effects on the suppression of B cell differentiation, without measurable effects on the thymus (Holsapple et al, 1986; Tucker et al, 1986). The latter report, in particular indicates that subchronic exposure (less than 14 days) of mice to TCDD was sufficient to suppress antibody response. Low doses of TCDD (less than or equal to 0.2mg/kg body weight) administered to pregnant rabbits, Rhesus monkeys and rodents did not accelerate the fetal loss rate, but TCDD appears to be a powerful teratogen at high doses (Smith et al, 1976; Sparschu et al, 1971; Giavini et al, 1982; McNulty, 1983). Silbergeld and Mattison (1986) provide an excellent review of animal and human studies on the reproductive toxicology of dioxins and TCDD. Perhaps most relevant for this review, they note that: 47 �© all human studies have involved exposure to mixtures of dioxins and TCDD in unknown ratios: » the pathway for reproductive toxicity is complex, involving other organ systems; o in animal studies, direct gonadal toxicity has been demonstrated, including changes in uterine and ovarian structure (Mattison et al, 1983; Kociba and Schwetz, 1982; Giavini et al, 1982), but equivalent effects have not been considered in human populations, including fertility, hormone levels, timing of menopause and menarche. In summary, although the wide range of toxic responses in different species has not yet been adequately explained, the major toxic effects of TCDD appear to have been identified. In particular, TCDD promotes cancer at varying doses and suppresses immune function at relatively low (subchronic) doses. Teratogenicity in animals occurs at high doses only, from the work done to date. The potential toxic impact for humans, according to the animal research available, will clearly depend on the strength of acute exposure as well as the duration of chronic exposures. 4.1.2 Human Studies of Herbicide Exposure For environmental and occupational epidemiologists, the problems associated with reliable exposure measurements are well known (see for example, Monson, 1980). For a substance to be clearly identified as causing a disease or adverse health outcome, the following minimal conditions must apply: © the substance must exist at a documentably high level in the environment or in measurably variable levels; © the adverse outcome must be unambiguously observed; and © the relative risk of the outcome, associated with exposure to the substance, must be sufficiently high not to be explainable by methodological flaws in the study. A recent example which meets these minimal criteria is the detection of an association between unopposed estrogen use and subsequent uterine cancer in the mid-1970's. Casecontrol studies indicated that prior use of unopposed estrogen was associated with a four-to-eight-fold increase in uterine cancer ( Smith et al, 1975; Ziel and Finkle, 1975; Mack et al, 1976), with evidence of a dose-response relationship (the longer the treatment with estrogen, the higher the relative risk). The exposure was well-defined and 48 �measurable. The outcome was also verifiable through pathology reports and was not a rare cancer. The measured relative risks were high and could not be dismissed despite potential self-selection biases between cases and controls in all of the studies (Kaufert and McKinlay, 1985). The only study of phenoxy herbicides which meets the first two of these criteria is the "Ranch Hand" study of Air Force personnel who completed the spraying missions in Vietnam (USAF, 1983; Lathrop et al, 1984). It has been estimated that the average exposure of these personnel was at least 1000 times greater than that of a naked man being sprayed with herbicides in an open field (Lathrop et al, 1984) . That is, the exposure was documentably high, although not measurable. All other epidemiologic studies, including studies of Vietnam Veterans, Vietnam residents, industrial and agricultural workers and industrial accidents (See Tables 2 and 3) are typified either by higher levels of exposure than would be expected in a general civilian population, possibly over several years, but within an unmeasurable exposure range or by one or more accidental exposures of short duration at relatively high levels. For example, exposure among New Zealand Chemical Sprayers (Smith et al, 1982a,b) was difficult to determine given the use of aerial spraying techniques. In the industrial accident near Seveso, Italy, heavy exposure was very limited in both area and duration (Reggiani, 1979). Another recurring problem in these studies has been biased reporting or observation. A subject experiencing a potential adverse outcome would be more likely to "remember" or inflate reports of exposure to herbicides. Similarly, subjects who considered themselves to be dangerously exposed would over-report outcomes (Lathrop et al, 1984; Reggiani, 1979). In most cases, observers could not remain blind to the exposure status of subjects (for example the Swedish studies: Hardell, 1977; 1979; Hardell et al, 1985) thus creating potential bias - particularly in outcome reporting. Notable exceptions were the Australian Vietnam Veterans (Donovan et al, 1983) and CDC (Erickson et al, 1984) studies as well as the study of Kansas agricultural workers (Hoar et al, 1986). The three primary adverse outcomes associated with phenoxy herbicide exposure to date, are: chloracne - a rare skin disorder associated with TCDD, reproductive abnormalities, (with emphasis on congenital defects and fetal loss) and rare cancers including soft tissue sarcomas (STS) Hodgkins Disease (HD) and non-Hodgkins Lymphomas (NHL). There are two major problems in focusing on such lowfrequency outcomes in epidemiological studies. First, diagnosis or definition may be difficult (as in the case of 49 �STS) or unreliable (as in the case of birth defects) and therefore more vulnerable to over-reporting bias under political or public pressure. Second, when the total observed number of outcomes may be less than 10 in a study of thousands of subjects (as with STS and some birth defects), misclassification error and/or spurious clustering of cases can produce artifactual associations or dilute the chance of detecting real associations. Finally, some of the studies of phenoxy herbicide exposure have been conducted in political climates which have severely compromised their findings. For example, the studies of Swedish Agricultural workers by Hardell and coworkers were conducted during considerable media attention and Dr. Hardell himself took a prominent advocacy position (Colton, 1986). Studies of Vietnam veterans and of the Vietnam civilian populations which involved subject interview have suffered from similar limitations. These political biases can only be overcome by careful validation of self-reported data (for example Hoar et al 1986; Lathrop et al, 1984) or by use of exisiting record systems which are minimally affected by political climate. The remainder of this section will highlight methods and problems in the measurement of phenoxy herbicide exposure, followed by an attempt to synthesize outcome findings with those of animal studies. A summary of major studies is presented in Tables 2 and 3 divided by population type (Vietnam veterans or civilian). (a) Exposure Measurement Three primary methods of exposure measurement have been applied in studies to date: Reported levels, assessed from available documentation, soil analysis and, most recently, analysis of adipose tissue. The use of existing documentation and verbal reports is the typical method of measurement in industrial settings. This was, for example, used to differentiate long-term occupational exposure among workers at Monsanto!s Nitro plant in West Virginia and those involved in the clean-up of a large accidental spill of phenoxy herbicides in 1949 (see for example, Zack and Suskind, 1980; Suskind and Hertzberg, 1984; Hay, 1986 and earlier reports). The resulting exposure classification was into: those exposed to the large, acute doses in the clean up; those exposed directly only during the regular manufacture process; and those minimally or not exposed among Monsanto employees who were not directly involved in production. Because of the time lag (over 30 years) and the changing political climate and memories, existing documentation were not adequate for validation of exposures. In contrast, Hoar et al (1986) validated a sample of self-reported use from suppliers' records. In Swedish and �New Zealand agricultural spraying studies, exposure was estimated according to usual herbicide strength, mode of application and length of time exposed (see, for example, Hardell et al, 1982; Smith et al, 1982) and self-reported mode and length of use was solicited. Other studies have relied on existing records of occupations to indirectly estimate relative exposures without recourse to self-report (Lynge, 1985; Wiklund and Holm, 1986; Nelson et al, 1979). Use of existing documentation has also been the primary method of exposure measurement in Vietnam. The "Herbs" tapes were compiled from Ranch Hand spraying mission instructions and logs combined with Army Morning Reports to locate troop movements in space and time. The deficiencies in these records have been well documented (see for example The Royal Commission on the Use and Effects of Chemical Agents on Australian Personnel in Vietnam, 1985). Perhaps the best differentiation which can be made in terms of Vietnam military exposure is into three groups: those troops assigned to I Corps where most of the spraying missions were concentrated; those assigned elsewhere in country; and those flying or supporting the Ranch Hand missions themselves (Lathrop et al, 1984). In the civilian Vietnamese studies, reliance has been on imputed exposures from known location of subjects during the years of spraying (Phuong and Huong, 1983; Trung and Chien, 1983; for example). The unreliability of selfreported exposure, post Vietnam war is well illustrated by the results of an experiment conducted by Korgeski and Leon (1983) on 100 Vietnam veterans. No correlation between self assessed and "Herbs" tape exposure was observed. Soil sampling has been used primarily to access accidental industrial exposures, notably in Seveso, Italy following the accidental release of TCDD from an industrial plant (Donna et al, 1984; Mocarvelli et al, 1986), and in Missouri where TCDD contaminated wastes were mixed with waste oil and used as dust-control sprays in recreational, residential and commercial areas near St. Louis (see, for example, Hoffman et al, 1986). In these examples, crude categorization was possible into high and low contamination areas. A recent review (Paustenbach et al, 1986) provides a thorough critique of existing U.S. and European guidelines on standards for limits of dioxin contamination in soil by considering the bioavailability to humans. The primary message of this review is that current assumptions on which bioavailability are based are very general and may overestimate the toxic potential of various levels of TCDD in soil. The increased risk to children from low levels is well-argued. The review concludes that amounts in excess of 1 part per billion (the current U.S. soil standard) are required to exceed a virtually safe dose (currently set at lOpg/kg/day). However, this conclusion relies on the same 51 �problematic extrapolations inherent in all of these toxic exposure estimates. Most recently, techniques have been refined for measuring TCDD levels in human adipose tissue (Patterson et al, 1986a; Gross et al, 1984). A recent report, also by Patterson and co-workers at CDC (Patterson et al, 1986 b) illustrates the use of this measurement as an exposure index in exposed and controls in Missouri. Most recently, Dr. Peter Kahn (1987) reported on the use of this measure as an index of exposure in Vietnam veterans. Both studies indicate that measurement of residual TCDD in adipose tissue is a reliable indicator of actual exposure, but as Patterson et al (1986a) note, the exact relationship between adipose tissue levels, total body burden and actual exposure have yet to be determined from well-defined cohorts. Extrapolation in animal and human studies indicates a halflife of TCDD in human adipose tissue of 5-8 years (Patterson, 1986b). This estimate would further indicate the usefulness of this measure in retrospective studies. Current research at CDC is cross-validating a blood test with adipose tissue measurement. If this test proves to be a viable alternative to a surgical procedure for obtaining adipose tissue samples, wider use of this measurement will be possible. Finally, added to the problems of measuring exposure levels are the varying combinations of phenoxyacetic acids used, only one of which contains TCDD. Agricultural herbicide use in Kansas, for example, was primarily 2,4-D without TCDD (Hoar et al, 1986), while in Arkansas, the combination varied by crop (Nelson et al, 1979). In Sweden, the primary herbicide was 2,4,5-T (with some 2,4-D use) until the 1970's (Wiklund and Holm, 1986). In Vietnam, Agent Orange was a combination of both herbicides. In summary, attempts to measure phenoxy herbicide exposure have been generally indirect resulting in relatively crude categorizations into high, low or no exposure. Comparability of exposures across studies have been rendered impossible by both the lack of quantification (in terms of amount/kg of body weight) and by the varying combinations of phenoxy-acetic acids used. (b) Toxic Outcomes The primary outcomes which have been clearly associated with phenoxy herbicide exposure fall into three groups: e chloracne and associated skin problems; o fetal loss and malformation; and o a group of rare cancers including STS, HD and NHL. 52 �Each of these outcomes will be considered, in relation to type of exposure and findings from animal studies as appropriate. Perhaps the best documented result of heavy, acute exposure is chloracne. It was reported in over 50% of workers involved in clean up at the Nitro plant (Cook et al, 1980; Suskind and Herzberg, 1984). It was also reported primarily in children exposed to heavy TCDD contamination in Seveso (Donatelli et al, 1981; Mocarelli, 1986). This distinct skin condition is typically not observed in the absence of TCDD exposure or in the presence of generally low level or non-topical exposure, and is well-defined. Although severe cases of chloracne may persist for 10 years or more, this skin condition generally disappears within 2-3 years (Cook et al, 1980). The increase in other less severe skin lesions has not been as well documented, although it is suggested in, for example, Hoffman et al (1986). Fetal loss and congenital malformations have been the outcomes of interest in a number of studies (see Tables 2 and 3). These have been typified by considerable problems and differences in measurement. Early fetal loss is difficult to document as it may appear to be a late menstrual period. Reporting also varies culturally and is affected by recall and political climate. These problems render fetal loss findings for Seveso (Donatelli, 1981; Marni et al, 1982; Tognoni and Bonaccorri, 1982; Bruzzi, 1983; Reggiani, 1983) and for Vietnamese civilians (for example Phuong and Huong, 1983; Trung and Chien, 1983; Can et al, 1983) of doubtful quality. Data on congenital abnormalities have been somewhat more reliable. The major differences between studies is the time of ascertainment (at birth or later in infancy). Obvious morphological abnormalities such as hydatidiform mole and cleft palate or other facial clefts are readily observed at birth whereas others will only become apparent during post-natal development. Self-report, validated by examination, or medical records are the most reliable sources. Studies in which unvalidated self-reports are likely to have produced biased results include the North Vietnamese studies and those conducted in Seveso (see Tables 2 and 3). Unvalidated self-report was less likely to be biased in the New Zealand studies (Smith et al 1982; Matheson et al, 1981), although it cannot be ruled out. The results are generally that there is no increase of either fetal loss or defects in exposed (compared to unexposed) groups. The only consistent differences found were in studies of Vietnam villages exposed to spraying (in 53 �which there was direct maternal as well as paternal exposure). The majority of studies have investigated paternal exposure only, through Vietnam exposure or industrial exposure. Agricultural studies have included the possibility of some direct maternal exposure. Despite the methodological problems, the potentially heavy spraying and subsequent soil contamination exposure of the Vietnamese may have been sufficient to cause fetal loss and/or congenital defects, consistent with the animal model. This reproductive effect certainly cannot be dismissed, given the consistently null findings from primarily paternal exposure. The final group of outcomes includes STS, HD and NHL. These cancers are rare, difficult to diagnose and may have long latency periods. Recent data presented by Hardell and Eriksson (1987) indicate that some STS lesions and lymphomas may have latencies of 30 years. A similar conclusion is reached by Hoar et al (1986) for NHL, given the rapidly increased risk in those exposed prior to 1946. The relationship of NHL in particular, to immune deficiency may provide a further plausible link. Even though the exposure of Kansas farmers to TCDD was very low the primary herbicide was 2,4-D), it may have been sufficient, over a long exposure period to lower immune function sufficiently to increase risk to NHL or there may have been a similar contaminant in the early manufacture of 2,4-D. It is important to note that the only other study relating NHL to herbicides was Hardell et al, 1981. The Swedish exposure was also of long duration (several years) and included TCDD levels through predominantly 2,4,5-T use. In relation to these findings, Hoffman et al (1986) demonstrated that long term low levels of exposure in contaminated soil are associated with depressed cell-mediated immunity, although there were considerable methodological problems - notably inter-reader differences in reading skin test for DTK responses. Elevated levels of alpha-gultamyl transferase (GGTP), AST, ALT and alkaline phosphatase, and lower cholesterol levels were observed in the exposed group. In studies with latency periods of 20 years or less, exposures at relatively low levels and for shorter periods, the results have been conflicting (see Tables 2 and 4). No cases have been found among the Ranch Hands, but they are young, healthier than average, exposed for a short time period and number only about 1200. With a point prevalence rate estimated at less than 1 in 1000 for STS, HD and NHL combined, in the entire adult population, the chances of observing differences in cohorts is low, unless numbers are very large. The 18,000 in the recent CDC Vietnam Experience Study cohort (CDC, 1987) is insufficient to detect significant differences in current mortality from these causes. 54 �(c) Vietnam Veterans.^Experience Studies The most recent studies of Vietnam veterans have avoided attempts at categorization according to Agent Orange exposure and have rather limited comparisons to those with "in-country" Vietnam service and Vietnam-era veteran or civilian controls. These studies are of two general types: » retrospective cohort studies, comparing veterans groups with respect to mortality; and e case/control studies of congenital defects or STS relating these outcomes to paternal Vietnam service. Such studies, categorized by the above two types, are presented in Table 4. The case/control studies of congenital defects (Donovan et al, 1983; Erickson et al, 1984) are both well-done and show no consistent associations. The studies of STS (Greenwald et al, 1984; Kang et al, 1986) also show no association with Vietnam service. Both studies verified cases of STS from pathology reports. The remaining retrospective cohort studies have used death and cancer registers to identify Vietnam and/Vietnam^ era veterans or civilians as comparison groups. These studies have all documented that veterans, compared to civilians, have higher rates of tobacco-related and accidental deaths (particularly motor vehicle accidents). Varying excesses of accidental and alcohol-related deaths have been found in Vietnam veterans compared to Vietnam veterans (CDC, 1987; Kogan and Clapp, 1985), the latter group of deaths indicating recent increases. With the exception of the CDC (1987) study, all of these report on STS cases. All have few such cases and only Kogan and Clapp (1985) appear to have verified cases through pathology reports. Holmes et al (1986) report three STS cases in West Virginia Vietnam veterans, none in Vietnam-era controls. Kogan and Clapp report a similar significant excess (9 versus one expected). No differences are found by Anderson et al (1986) in their Wisconsin study (5 cases in each group). Holmes et al also report an excess of HD deaths (4 versus 1) and an excess of one testicular cancer death. These variable results may be the result of small numbers and short latency periods (generally 15-20 years). They may also reflect socio-economic differences related to the drafting of men into service and general health status, which could not be investigated in these data sets. 55 �Studies of Women The only studies of phenoxy herbicides which have included women exposed directly, have been general population studies in Vietnam (Cutting et al, 1970; Kunstader, 1984; Sterling and Arundel, 1986) in agricultural areas exposed to relatively high levels such as Arkansas (Nelson et al, 1979) and Kansas (Hoffman et al, 1986), New Zealand (Hanify et al, 1981), Hungary (Thomas and Czeizel, 1982) and other occupational groups (Honchar, 1982; Axelson et al, 1974; Hardell, 1977, 1979; Hardell et al, 1981; Huff et al, 1980) and from industrial accidents such as in Seveso, Italy (Reggiani, 1979; Donna et al, 1984). All of these studies exhibit major methodological problems which render findings doubtful and/or report no adverse reproductive outcomes, as discussed above. As noted above for the Vietnam studies, heavy maternal exposure may be necessary to produce measureable adverse reproductive effects. Donna et al (1984) reported an isolated case/control study which estimates a four-fold risk of ovarian cancer in exposed Seveso women, although numbers are barely sufficient (only 60 cases) and exposure is crudely measured. This finding has not been replicated. Other reproductive outcomes such as infertility (in the woman) and menstrual disorders have not been considered as outcomes in any study reviewed. These are outcomes indicating ovarian or hormonal dysfunction which may result from toxic exposures (Silbergeld and Mattison, 1986). Recent human studies indicate that ovaries are sensitive to toxic exposures such as cigarette smoking and that this sensitivity can be manifest in delayed fertility (Baird et al, 1985; Olsen et al, 1983), menstrual irregularity (Hammond, 1961) and early menopause (McKinlay, 1985; Baron, 1984) . These findings are corroborated by animal studies (Mattison, 1983). 4.2 INSECTICIDES There have been no direct studies of the impact of insecticides either applied directly to the skin or clothing (dimethyl phthalate, dibutyl phthalate) or sprayed (primarily malathion) to reduce exposure to mite-born and mosquito-born diseases such as malaria and scrub-typhus. The methodologically sound Vietnam veteran experience studies which compare Vietnam veterans with other groups, irrespective of chemical exposures (Donovan et al, 1983; Erickson et al, 1984, for example - See Table 4), by including all chemical exposures, provided some indirect evidence of no adverse reproductive outcome from chemicals other than .dioxin. 56 �It is important to note that Hoar et al (1986) in their study of agricultural exposure found no independent effect of insecticides. Most studies - including those of Vietnam veterans - are unable to separate out the effects of insecticides and herbicides. 4.3 SUMMARY To date, the only methodologically sound studies of dioxin exposure (Donovan, 1983, Lathrop et al, 1984; Erickson et al, 1984; Smith et al, 1982a,b) have not shown any significant associations between dioxin exposure and adverse reproductive outcomes, including spontaneous abortion, sterility and congenital defects. The highly exposed Ranch Hand personnel have shown small, statistically insignificant but consistent increases in a majority of adverse reproductive outcomes which are suggestive of a toxic effect. The Vietnam veteran cohorts are still too young for adequate observation of potential cancer outcomes and results to date are conflicting (for example, Kogan and Clapp, 1985; Greenwald et al, 1984), primarily because of small numbers of cases. All other studies report small relative risks of adverse health outcomes including softtissue sarcomas (generally under 1.5 in magnitude), most of which can be explained by methodological problems such as those discussed above or confounding fact'ors which were inadequately controlled in comparisons. It is plausible that relatively low levels of toxic exposure in women will produce measurable changes in fertility or menstrual function but not necessarily in fetal loss rates or rates of congenital malformation. This is in contrast to the lack of a toxic effect on sperm produced by the relatively high levels of exposure in the "Ranch Hand" personnel (Lathrop et al, 1984). Other potential health outcomes from dioxin and other insecticide exposure are more problematic, including rare soft-tissue sarcomas, and possible increases in heart disease. As most of the veteran cohort will be under 50 years of age at the time of the planned VA study, the chances of observing sufficient cases of these diseases to make any valid estimates of association are small. A potentially important outcome to be considered in any future study of depression of immune function, which may result from relatively low, long term exposures to TCDD. 57 �TABLE 2. VIETNAM DIOXIN EXPOSURE STUDIES A. MILITARY STUDY REFERENCES DESIGN RANCH HAND II STUDY USAF ( 9 3 18) Lathrop (1984) Retrospective Matched Cohorts ( : ) 15 Matching Variables: job, race, age / POPULATION & SAMPLE SIZE EXPOSURE MEASURE OUTCOMES FINDINGS Surviving Severe (highest) Dioxin exposure vs . minimal exposure (not measured) All mortality (300 deaths) Healthy worker effect Cause-specific mortality Generally lower mortality in all veterans. Veterans of Period 1962-1971 1269 (Operation Ranch Hand) Matched on other USAF self-report. Ranch Hands more fertile. Birth Defects (last 3. self-report) No diffs. in fetal loss, birth defects • Fetal loss Case/Control Matched 1:1 Cases: 8517 Infants bom with anomalies in NSW, Vic~ S, ACT Fathers Vietnam Veterans Non Vietnam Vets Matching Variables: hospital , maternal age. 1966-1979 incl. 1962-72 with identified fathers YOB, Donovan et al (1983) 3 Cohort still too young for some endpoints. Some bias in Fertility Viet. Vets AUSTRALIAN VETERANS BIRTH DEFECTS STUDY EVALUATION Controls : infantes matched with fathers payment method . Abnormalities No difference 3 No bias in observar 90% power to detect ICD-9 codes 553,740-759 SR = 1.5 Only included defec detected at birth. identified CDC 3IHTH Erickson et. al DEFECTS STUDY (1984) Case/Control 1:1 Matched Cases: 7133 births 1963-30 Atlanta , GA Matching Variables: Abnormalities Fathers ICD-S codes Vietnam and Non Vietnam Vets (not given) first vear 1962-72 of life No consistent differences . to minimize bias Low reponse rates: 70% mothers. 56% fathers Race, TOB, 100% Power to detec hospital MINNESOTA VETERANS STUDY Korgesfci i Leon (1983) Experiment 100 subjects from free Agent Orange Screening at VA Hospital Two Measures Psychological and medical problems for Dioxins subsequent to (a) objective using HERBS tapes , exposure. (b) Self-rated. All Vietnam Veterans (male) NEW YORK VETERANS STUDY Greenwald et al (1984) Case/Control 1 : 1 Matched Matching Variables: Age, residence 2 Used 2 Interviews Cases: 2B1 (130 dead) Vietnam Service from H .v . Cancer cases = 10 controls (a) = 18 Registry controls (b) = 9 ICD-9 code 171. Controls (a) 281 live from Registry of M.V. files. Psychological and psychomatic sviaptoms related to self-rated but not objective exposure measure. Sample limited Problems of inaccuracies in "objective" measure of exposure. Soft Tissue sarcoma (ICD-9 code 171) + histological typing on subset. No Signficiant Difference 2 insufficient power to detect Otherwise careful study . Cause-specific deaths. (ICD-9 codes) 2 Significant Diff. for ICD-9 Code 171 Soft-tissue ccsroared to Sarcomas both grouDS. (9 in Viet Vets ) Hot verriiec (b) 130 deceased controls from S . Y . Death Certs. - no cancer deaths. All were males. MASSACHUSETTS VETERANS STUDY Kogan and Ciacp (1985) Cohort Study Not matched. Viet Veterans Non- Viet Veterans Civilians. White males only. All deaths in Massacnusetts 1972-33 inci. 340 Vietnam Veteran deat-s. tiJi Veteran Status determined from benefits clamed. •I •i I ! •1 �. VIETNAM DIOXIN EXPOSURE STUDIES A. MILITARY (continued) STUDY REFERENCES KANSAS STUDY Hoar at al (1986) GRAY SUMMIT, MISSOURI STUDY Hoffman et al (1986) DESIGN POPULATION & SAMPLE SIZE EXPOSURE MEASURE Case/control 1:3 match on age and vital status Cases: 139 STS, 132 HD and 172 -Jm- from population based cancer registrv Controls: 1005 white men trom the general population Cohort (retrospective) Residents of the Quail Run Mobile Home Park (X = 154) and residents of a similar park not exposed (N=155) B. SEVESO ITALY, 1976 Donatelli ec al (1981) Marni et al (92 18) Tognoni and Bonaccorsi (1982) Bruzzi (19S3a,b) Reggiani (1983) Mocarelli ec al (1986) Cohort (retrospective) NITRO, WEST VA. , 1964 Cook et al (90 18) Zack and Suskind (1980) Suskind and Hertzberg (1984) Hay (1986"p Cohort (retrospective) ACCIDENTAL Self-report survey of pesticide suppliers Soil D US r frcr. hoae samples samples mobile interiors OUTCOMES FINDINGS EVALUATION Soft tissue sarcoma Hodgkin-Ls disease Non-hodgkin's -Lymphoma Increased risk of nonHodgkin ' s lymphoma among exposed. No association for other outcomes- 3 Careful validation of self-reported data. Separated effects of insecticides and herbicides • Abnormal celluar immune function Liver damage Exposure associated with depressed cellmediated immunity However , no excess of clinical illness. Subclinical alterations in liver functions among exposed. 2 Self-selected sample, otherwise well done. Analysis completed without knowledge of exposure. Adjustments in analysis. EXPOSURE Plant employees i families and Seveso residents (varying numbers) Plant employees (varying numbers) Soil samples Plant records Wind direction etc. High/ low exposure areas Plant records Chloracne Fetal loss Birth defects Cancers Liver damage Short term increase in Chloracne. No clear association for other outcomes . Chloracnelike lesions Mortality Cardiovascular disease Renal damage ^"S problems Diff, in rates of skin lesions, not in other outcomes. 1 Lack of preaccident records of known quality and political clinate postaccident render all data questionable except perhaps choracne cases. i Probable healthy worker effect. Small number of deaths. Documentation inadequate to validate exposure. �TABLE 3. NON-MILITARY EXPOSURE STUDIES A. INDUSTRIAL STUDY REFERENCES DESIGN HEH ZEALAND APPLICATOR STUDY Smith et al (1982) Hatheson et al (1981) Cohort ( retrospective ) Smith et al (1984) Case/Control 1:1 Matching NEW ZEALAND CANCER STUDY POPULATION & SAMPLE SIZE .EXPOSURE MEASURE Agricultural Sprayers Spraying year (registered) and ctner of pregnancy agricultural workers, or prior year OUTCOMES FINDINGS EVALUATION Fetal loss Congenital defects No difference 2 Excellent response rates (89% and 83%) Potential for reporting Eras.. No difference. 2 Design minimizes recall bias and sanpl= size adequate. , Problems with ascertaining exposure to herbicides. Total Sample: 989 Period: 196S-SO • Marching variables: age, year of registration Cancer Registry Cases (95% coverage of NZ) Male only. 1955-1979 ( 1 Ca. cases) . 12 Soft tissue Exposure to s phenoxy herbicides sarcoma (ICD-9 code 1 1 7 ) in industry. i- h.istoJ.og.ical confirmation. HUNGARIAN STUDY Registry Study Congenital malformation registry for Hungary 1968-1977 Census data. Increased use of pnenoxy herbicides in agriculture. Concrenital malformation rates by year. No association, 3 Well-documented registry and national statistics . }fEW ZEALAND EC3IX3GICAL STUDY Hanifv et al (1981) Ecological descriptive study . Birth defects at area hosnitais 1959-60 & 1572-76 Use of time period 1972-76 as proxy for heavy spraying. Malformations at birth. No consistent association. 2 Problem with, exposure ,; measure. '. DOH CKEHICAL COMPANY • Thomas (1980) Thomas and Czeizel (92 18) Townsend et al (1982) Cook and Sooner (1983) Conort ( retrospective ) Matcned 1 : 1 Matching variable: date of hire . Hale employees Exposure to of Dow 1935-1975 pnenoxy (370 exposed at herbicides from least one month . conpany records. + 345 matcned controls Response rate 63%, 62% Fetal loss Malformations . No differences. DANISH STUDY Lynge (1985) Cohort ( retrospective ) Pension contributors Exposure to from manufacturers hersicides OL phenoxy heroicides by deparment. linked with national Cancer Registry. (n"4563, nale & female) Cancer all types. No consistent differences. ITALIAN STUDY Donna et al (94 18) Case/ Control Hatched 1:1 - 1:4 Cases: 60 ovarian tumors 1974-1980, one clinic source. Controls: 127 other tumors Same source Diagnosis of Cancer RR = 4.4 Matching Variables: Year of diagnosis, residence. Exoosure self-reported use herbicides or farmer after 1960 2 Hell done but self-reported ma If onaations and low response rates. ; 2 Problems in determining exposure,. but large numbers fell analyzed. 2 Design minimizes bias Exoosure measure careful J>UL scill prot>. Adj. in analysis. Numbers barely adequate II I I �TABLE 3. BON-MILITARY EXPOSURE STUDIES A. INDUSTRIAL (continued) DESIGN POPULATION & ' SAMPLE SIZE EXPOSURE MEASURE OUTCOMES STUDY REFERENCES SWEDISH STUDIES Hardell (1981a,1981b) Hardell et al (1982) Hardell and Bengtsson (19S3) (a) Case/control 1 : 1 matching Wiklund and Holts (1986) (b) 354,620 agri(b) 1960 National (b) Soft tissue (b) Cohort culture and forCensus sarcoma (retrospective) estry workers "Estimates" of herbicide use potentially exposed to in occupational categories. phenoxy herbcides. 1,725,845 men employed in other industries. ARKANSAS STUDY Nelson et al (1979) (a) Cases: specific (a) Exposure to ^a) cancers, referred herbicides to Oncology Dept. by occupation. Matching or Swedish Cancer variables: Registry (males age, residence only). Controls: same source' Oncology Dept./ Registry Ecological Descriptive Study. Countries categorized according to crop. Birth certificates 1943-74 screened for facial clefts + records of Rehab Svcs. (n= 1,201) Countries categorized by crop as surrogate for herbicide spraying. FINDINGS (a) RR less Lyrophoma, than 3.5 STS, for Color. Cancer, agriculture hodgkir. ' = and forestry Disease, etc. workers. Facial clefts (b) No significant difference No consistent association EVALUATION (a) 2 Measure of exposure to herbicide selfreport only. Not clear on adjustments or selection of controls. u fb") \ / •> Indirectly estimate relative exposure from occupational records, iso self -reported data * 2 Carefully done. Well analyzed . Potential biases in case finding in records. �TABLE 3. SON-MILITARY EXPOSURE STUDIES B. ENVIRONMENTAL STUDY REFERENCES DESIGN POPULATION & SAMPLE SIZE TWO-COMMUNITY STUDY Nguyen Thi Ngoc Phuong & La Thi Diem Huong (1983) Cohort, Retrospective FOUR VILLAGE STUDY HOSPITAL STUDY NORTH VIETNAM STUDY I OUTCOMES FINDINGS EVALUATION Village -tHerbicide 10th district of exposure from Ho Chi Minh City heavy spraying All women and all (village) pregnancies . 1249 women in village 1126 women in 10th Dst. Fetal loss Congenital abnormalities Hyatidiform mole Higher risk in village for ail 3 outcomes 1 Sample selection? No adjustment for maternal diffs. Potential observer and respondent bias. Cung 3inh Trung Cohort, and Retrospective Nguyen Iran -Chien (1983) Heavy spraying Families in all in 3 villages villages. (Total i pregnancies/ not in one. village, 436-324) Fetal loss Birth detects (external) Before/After 1 diffs. in rates Incorrect analysis in exposed villages No adjustments for maternal diffs. only. Respondent recall and interviewer bias Sample selection? Numoers small . Le Diem Huoncr i Nguyen Thi TJgoc Phuong (1983) Cohort (and Case/Control) (a) All births at one (a) 'Year of birth, (a) Rate of" (a) Increase by No adjustments hospital in 3o Chi Hydatidiforsi mole. Year. "for maternal diffs. Minn city, 1952-1981, Incorrect analysis. minus 3 yrs. (b: Increased Risk Unavailability of (b) Cases of (b) Exposure to r-^, presence of complete records. Hydatidiform moles. Herbicide spraying.Hvaatidifcm males (32 = 12) PrcDiem of referrals 1982 i age, addmission to this main matched controls. hospital. Bias in recall. Cohort ( retrospecive ) Military Women in 3 North service in Vietnam districts. 29,041 married to Soutr. Vietnam. possibly exposed men. 11,023 married to unexposed men . (1983) EXPOSURE MEASURE Exposure to • 38% increase ir ^3-5 or ccr.senital defects . 19% increase in fetal loss. Liver Cancer Risk of liver cancer 1 increase Numbers too small (RR > 5.0) and no adjustment . Use of cancer control questionable Congenital Abnormalities Sex ratio No consistent results . 1 Too many potential problems with the hospital records . No difference. 2 Careful study. Limitations in data well documented . NORTH VIETNAM STUDY II Ton Due Lang et al (1983) Case/Control matcned on age Cases: 21 liver cancers Controls: 42 stomach cancers , ulcers . Admitted to one hospital, 1982. HOSPITAL RECORD STUDY 1 Kunstadter (1982) Cohort (retrospective ) Hospital case records in Ho Chi Minh City for 4 hospitals. Periods of study not clear. Matarr.al He'"™11 cide exposure (usir.g HERBS tapes) HOSPITAL RECORD STUDY II Cutting et al (1970)" Cohort (retrospective) 22 Public hospitals in Sth. Vietnam. Records of deliveries 196O-1969 incl. 470,200 live births 15,312 still births ,2840 Hydatidifom moles. Still births Year of record as surrogate for Hydatidiform hemcide spraying moles. Malformations 1960-65 (preher^icide) * An important source is the excellent review by Sterling and Arundel, 1936. 1 No adjustments. Incorrect analysis. Potential observer and recall bias. Not clear on sample selection. Still births external birth defects. Fetal loss. �TABLE 4. VIETNAM EXPERIENCE STUDIES A. CASE CONTROL STUDY REFERENCES DESIGN POPULATION 5, SAMPLE SIZE EXPOSURE MEASURE OUTCOMES FINDINGS EVALUATION AUSTRALIAN VETERAN BIRTH DEFECTS STUDY Donovan et al (1983) Case/Control Matched 1:1 Matching variables: hospital, maternal age, YOB , payment method. Cases: 8517 infants born with anomalies in NSW, Vice & ACT 1966-1979 incl. with identified fathers. Controls: infants matched with fathers identified. Fathers Vietnam veterans Non-Vietnam vets 1962-72 Abnormalities ICD-9 codes 553,740-759 No difference 3 So bias in observation 90% power to detect RR=1.5 Only included defects detected at birth. CDC 3IRTH DETECTS STUDY Erickson et al (1984) Case/Control 1:1 Matched Matching Variables: race, YOB, hospital . Cases: 7133 births 1968-30 Atlanta, GA Fathers Vietnam and Non-Viecnaa Vezs 1962-72 Abnormalities ICD-8 codes (not given) first vear of life No consistent differences 2 Used 2 interviews to minimize bias Low response rates: 70% motrers, 56% fathers -o".' V.ORK VETERANS ST'JDY Greenwald et al (1984) Case/Control 1:1 Matched Matching variables: age, residence. Cases: 281 (130 dead) iron N.Y. Cancer Registry ICD-? code 171. Controls (a) 281 live from Registry of M.V. files, (b) 130 deceased controls from N.Y. Death Certs. - no cancer deaths. All were males. Vietnam service cases = 10 controls (a) = 18 controls (b) - 9 Sof t-cissue sarcoma (ICD-? code 171) -r histoiogical typing on suoset. •;° significant difference VETERANS ' ADMINISTRATION STUDY Kang.et al (198t>) Case/Control Cases: 234 VietnamVietnam service era veterans with STS. Controls: 13,496 Vietnam veterans from the same era as the cases, selected from all Vietnam-era veteran patients. 2 Insufficient power co detect Otherwise careful study ' Soft tissue sarcoma (ICD 171) and pathology report review No significant difference 3 Well done Records located and abstracted for all cases and 90% of controls. �TABLE 4. VIETNAM EXPERIENCE STUDIES B. RETROSPECTIVE COHORT STUDIES STUDY REFERENCES DESIGN POPULATION & SAMPLE SIZE EXPOSURE MEASURE WEST VIRGINIA STUDY Holmes et al (1986) Cohort study Not matched Vietnam veterans Non-veterans All deaths in West Virginia 1968-83 Vietnam service MASSACHUSETTS STUDY Kogan and Clapp (1985) . Cohort study Not matched. Vietnam veterans Non-Vietnam veterans Civilians While males only. All deaths in Massachusetts 1972-83 incl. 840 Vietnam veteran deaths. Veteran status determined from benefits claimed 9,234 in country Vietnam veterans 8,989 Vietnam-era veterans. Selection from National Personnel Records Center Vietnam service Cohort study Males and white Not matched females. All deaths Vietnam veterans in Wisconsin in Other veterans 1960-1983 Ron-veterans Vietnam service CDC STUDY WISCONSIN STUDY (1987) Anderson et al (1986) Cohort OUTCOMES Mortality Cause-specific deaths. (ICD-9 codes) Mortality Mortality FINDINGS Excess mortality among veterans Significant difference for ICD-9 code 171 compared to both groups Excess mortality among Vietnam veterans, mainly in first five years after discharge. Excess mortality among Vietnam veterans and all other veterans. EVALUATION 9 Self-selected sample Small numbers for some cause specific mortality rates. 3 Soft-tissue sarcomas (9 in Viet Vets) verified by pathology. 2 Validation of death certificate data by physician review of pertinent medical and legal documents. Insufficient numbers for some cause specific mortality rates. 2 Small numbers for some cause specific mortality rates. �5. NURSING; OCCUPATIONAL RISKS As previously indicated, the majority of female personnel in Southeast Asia served as nurses. Therefore, in order to more comprehensively assess the impact of Vietnam duty on health and reproductive outcomes, occupational risks associated with the nursing profession were explored. In the context of an epidemiological study, these risks fall into three major categories: exposures, outcomes, and confounders. The primary exposure relevant to this population was trace anesthetic gases in operating room environments. Other potential exposures such as antineoplastic drugs or radiation are acknowledged but were not included in this review since the likelihood of this type of exposure during a Vietnam tour was low. The major outcome with implications for this population is stress and/or mental disorders, assumed associated with work conditions or type of nursing practice. Stress may also be considered a confounder in the analysis of certain research questions, e.g. in relation to reproductive outcomes. Finally the major confounders to be considered are smoking and substance abuse. A representative sample of recent literature in each category will be critically reviewed for both content and methodology. 5.1 5.1.1 EXPOSURE; TRACE ANESTHETIC GASES Clinical Studies In view of the fact that approximately 75 percent of female personnel serving in Vietnam were nurses, teratogenic risks associated with occupational exposure to chemicals must be considered. A likely frequent exposure in both field and base hospitals during that era was to volatile anesthetics. Waste anesthetic gases are widely distributed throughout the operating room (Cohen, et. al., 1975). It is assumed that neither scavenging apparatus nor air conditioning were used widely in field hospitals to remove waste gas in operating rooms. Further, while air conditioning may have been more prevalent in large base hospitals, scavenging equipment was not routinely used in the 1960's or early 1970's (Cohen et. al., 1974). A review of the literature regarding possible harmful effects of trace concentrations of anesthetic gases on operating room personnel is inconclusive, resulting in part from methodological flaws. Three of the more frequently cited studies as well as two major reviews will be discussed to illustrate the problems and issues. A survey (Cohen et al, 1971) to evaluate the possible relationship between spontaneous miscarriage and exposure to the operating room was carried out by personal interview 65 �with operating room (n=67) and general duty nurses (n=92 between the ages of 25-50 years. Data from a second study of female anesthetists (n=50) and physicians in other specialties (n=81) in the same age group were also reported for comparison. Data from this sample were collected via mailed questionnaires, however. The investigators report that both exposed groups had a substantially higher frequency of spontaneous abortions (29.7% and 37.8%) when compared to the controls (8.8% and 10.3%). Marginal significance (p=0.045) was reported. Further, it was noted that spontaneous abortions occurred earlier in the pregnancies of exposed women than in controls (i.e., eighth vs. tenth week of gestation). Several methodological problems raise skepticism about these findings. First, the small sample sizes makes the significance of the finding suspect (Ferstandig, 1978). Secondly, data consisted only of self-reports. Rushton (1976) points out that none of the aborted pregnancies were confirmed by a positive pregnancy and/or examination of the products of conceptus. Third, a non-specific measure of exposure, i.e. "practiced anesthesia any time during pregnancy," was utilized, preventing any analysis of a dose-response relationship. Finally, the retrospective design, in addition to self-report, raises the possibility of recall problems (e.g., with time of spontaneous abortion) which may influence the validity of the data. A British epidemological study analyzed frequency of congenital abnormality, spontaneous abortion, and involuntary fertility in 563 married female anesthetists and 828 female physician controls (Knill-Jones et al, 1972). Three groups were analyzed: anesthetists at work, and anesthetists not at work and other physicians as two control groups. The study reports that anesthetists working during pregnancy had a significantly (p < 0.02) higher frequency of congenital abnormality (6.5%) than those not at work (2.5%) but not significantly different from the control group of other doctors (4.9%). The authors neglect to discuss the implications of the significantly higher mean age (p < .001) in this latter control group for this finding. In addition, spontaneous abortion was significantly higher (p less than .025) in the working anesthetists (18.2%) than in the control physician group (14.7%), but not when compared to the anesthetists not at work (13.7%). As pointed out by Ferstandig (1978), the lack of congruence between the two control groups as well as the reversal of effects between the control groups "mitigates against any logical conclusion in this study." Finally, the study also reports that 12% of the anesthetists were infertile for unknown causes, twice as many as the controls (p < .001). However, how this was determined was not described. In addition, the small numbers involved make any relationship between exposure to anesthetics and fertility questionable (Ferstandig, 1978). Overall, this study also suffers from limitations of the 66 �previous study, i.e., a retrospective design, with no objective estimate of exposure, and reliance on selfreported data. The final epidemological study (Cohen et al, 1974) to be discussed is perhaps the most comprehensive study on this issue, yet is still characterized by methodological limitations. A mailed survey was conducted with 49,585 operating room personnel belonging to three professional societies and 23,911 medical personnel in two other societies who served as an unexposed comparison group. Comparisons were made to detect differences in occurrence rates of five major characteristics: spontaneous abortion,congenital abnormality, cancer, hepatic disease, and renal disease. Rates were standardized by the direct method adjusted for both age and smoking in the case of spontaneous abortion and congenital abnormality rates, and age alone in the case of disease rates. Exposure estimates were defined as work in an operating room during the calendar year prior to the event for both sexes, as well as exposure during the first trimester of pregnancy for women. Data regarding use of scavenging apparatus in the operating room were also collected. The investigators report that female members in the operating room-exposed group were subject to increased risks of spontaneous abortion, congenital abnormalities in their children, cancer, and hepatic and renal disease. The increased risk of congenital abnormalities was also present among the nonexposed wives of male operating room personnel. An increase in cancer and renal disease was not found among the exposed males, while an increased incidence of hepatic disease was found. With the exception of leukemia and lymphoma, there was no evidence of a specific type or location of cancer. While the report of this study appears convincing, several authors have raised sharp criticism which call the results into question. Ferstandig (1978) and Mennuti (1980) point out the inconsistencies of the data both within and across groups in this study, e.g., that operating room workers least exposed to anesthetic gases had the highest rate of spontaneous abortion; or that there is no statistical significance in differences in spontaneous abortion rates for female anesthesiologists exposed or not exposed to operating rooms. These inconsistencies and others weaken the argument for deleterious health and reproductive outcomes of operating room/anesthesia exposure. A further flaw in the study is the use of pediatricians as a control cohort. According to Ferstandig (1978), this group has the lowest mortality rate of any medical specialty which biases comparative statistics. The study also shares the limitations of self-reported data collected retrospectively. None of the three above studies has fully tested the hypothesis that a cause-effect relationship exists between 67 �exposure to trace concentrations of anesthetics and possible adverse health effects. While the nationwide survey by Cohen et al, (1974) considered age and smoking as confounders, the other studies did not, notably the study by Knill-Jones et al, (1972) where a statistically significant difference in mean age between exposed and non-exposed groups was reported. To detect a cause-effect relationship, other possibly significant causes, such as the stress of operating room work must be ruled out (Ferstandig, 1978). Similarly, differences in the characteristics of study samples (e.g., social class, health and reproductive history, substance abuse, stress levels) must be included in the analysis. A recent, excellent review of these and other studies (Buring et al, 1985) included a pooled analysis. The conclusion was that, although their findings were suggestive, studies to date have been beset by major, compromising methodological problems which devalue their findings. 5.1.2 Animal .and Tissu_e Studies The comprehensive review of the toxicity of anesthetics by Ferstandig (1978) was used to review animal and tissue studies. From approximately 46 tissue studies and 40 animal studies, Ferstandig concluded that only high levels of anesthetics and long times of exposure cause significant histotoxicity in laboratory studies on cells and animals. Trace concentrations, as typically found in operating room environments, produce none of these effects; "therefore, studies using high concentrations have no value in predicting the effects of trace concentrations" (p.341). Further, laboratory studies provide no evidence that commonly used anesthetics produce cancer in animals. 5.1.3 Summary In conclusion, despite some superficially convincing data, the epidemological studies to date on anesthetics and adverse health and reproductive outcomes are methodologically flawed and inconclusive. A properly designed study would include the following elements: a prospective design; random sample of adequate size; an appropriately matched control group; field methods, (including medical record abstraction) to ensure collection of valid data; ascertainment of a more specific exposure estimate than merely operating room exposure; and consideration of potential confounders in the analysis (Buring et al, 1985). A study of women Vietnam veterans, by its very nature, cannot incorporate all of these methodological elements. For example, a prospective design is not possible, nor is precise estimation of exposure likely. It is probable that scavenging systems on the Navy hospital ships were effective. The effectiveness of systems in the land-based hospitals - especially the mobile units are likely to have been very variable. No good measurement 68 �of exposure is likely to be obtainable. However, attention can be given to choice of an appropriate control group, adequate sample sizes and response rates, appropriate field methods and data collection protocols, and comprehensive analysis of potential confounders. 5.2 STRESS AND MENTAL DISORDER In a review article regarding stress among nurses (Marshall, 1980), several sources of stress were identified: specific nursing tasks; workload/overload; uncertainty and concerns about responsibility (especially in emergency room duty); relationships with patients, families, or other professionals; dealing with death and dying; role conflicts; the need to fulfill others1 expectations (including sanctions against showing stress); and the organizational structure in which nursing care is provided. In Marshall's model, only two sources of satisfaction which balance these pressures are identified: a feeling of having helped patients and receiving positive feedback from patients. If considered in the context of Vietnam duty, the potential for high levels of pressure and low levels of satisfaction are obvious. Most nursing duty took place in field hospitals where the work environment was less than ideal and the wounded, mutilated, and often near-dead were received constantly. Nurses were continually faced with uncertainty, death and dying, work overload, and unpleasant nursing tasks. Further, these field hospitals served as centers for triage and emergency care. Those soldiers who did not die typically were transferred to larger base hospitals for further treatment and recovery. Therefore, the satisfaction of seeing a patient recover or receiving feedback was unlikely sufficient to balance the pressures. It seems safe to assume that nurses in Vietnam experienced stress with little outlet for therapeutic expression of that stress. The literature on stress among nurses does not include any study of Vietnam duty. The majority of available work is descriptive or anecdotal, often in conjunction with recommended strategies for dealing with stress. Most of the limited research has been conducted by nurses. One of the better studies (Cronin-Stubbs and Schaffner, 1985) surveyed a random sample of 296 female nurses (response rate not stated) to explore the relationship of stress, social support and burnout in diverse groups of staff nurses. Using valid and reliable measures, data were collected by mail or in-person. The rationale and circumstances for the two field modes was not described, but the authors state that "standardized procedures" were used. In a stepwise multiple regression analysis, 35% of the variance in burnout (measured with the Staff Burnout Scale for Health Professionals) was explained by the following factors: intensity of occupational stress, negative and 69 �positive life stresses, low social support, and work setting. Regarding the last variable, critical care and medical nurses experienced more frequent and intense occupational stress than psychiatric and operating room nurses, yet all four groups experienced similar amounts of burnout. This apparent inconsistency was not discussed. Further findings indicated that burnout was positively and significantly correlated with absenteeism, tardiness, physical illness (undefined), use of prescription "calming" drugs, and job searches undertaken. Smoking and alcohol use were not mentioned. Clearly these data suggest that occupational stress and burnout are related to health outcomes and other exposures/confounders such as drug use. Another study (Gray-Toft and Anderson, 1981) of 122 nurses on five hospital units (medicine, surgery, cardiovascular surgery, oncology, and hospice) of a midwestern hospital found somewhat consistent results as to sources of stress: workload, dying patients, and inadequate preparation to meet the emotional needs of patients and their families. However, unlike the previous study, the investigators found that these major sources of stress were similar, regardless of unit or type of care. Further, path analysis indicated that the nurse's level of trait anxiety along-with level of training were significant predictors of stress. Sociodemographic variables (race, age, marital status, religious commitment, and nursing experience) were not found to be predictors of stress. As hypothesized, stress was found to have significant effects on job satisfaction and turnover. A third recent study on perceived job stress (Norbeck, 1985) is of interest because of its focus on critical care nursing, which along with emergency room nursing most closely approximates Vietnam nursing duty. However, unlike the previous two studies, a comparison group of nurses in other settings was not available. Data were gathered via mailed questionnaires to examine the relationships between job stress and both job satisfaction and psychological symptoms. Established and tested scales were employed for all major study variables. After controlling for work experience and shift (both correlated with job satisfaction), perceived job stress accounts for 6% of the variance in job satisfaction and 10% of the variance in psychological symptoms. Further, factors associated with perceived stress are consistent with other study findings: number of rapid decisions required, cardiac arrest, death of a patient, amount of knowledge needed, and workload.' Clearly these findings have implications for any study of stress and health outcomes of nurses serving in Vietnam. While increasing attention in the professional literature has been given to burnout of nurses, little focus has been aimed at the analysis of other emotional or mental �disorders. While a recent study by VanServellen and colleagues (1985) is limited methodologically, the findings do suggest that staff nurses may suffer higher rates of affective disorders in proportion to the general female population. A convenience sample of 64 nurses was administered six standardized survey instruments and an expert-administered diagnostic interview for depression. The incidence of clinical depression was significantly higher than that found in the female population at large. Further, major depressive illness was more prevalent than dysthymic disorder. The investigators point out the importance of recognizing and separating out clinical disorders from the more general burnout syndrome. Although the small convenience sample limits generalizability, and no attempt to control for major sociodemographic factors or life situation was reported, the study does emphasize the need for valid and reliable data on the prevalence of psychiatric disorder in the profession. This need is further underscored by an analysis of death certificate data from 1963-1977 (Katz, 1983) showing that when compared to a control group of other female workers, nurses have an elevated risk of death from suicide. In summary, the literature on occupational stress and related factors is limited and characterized by the following methodological limitations: primarily descriptive designs, small and non-random samples, and lack of control or comparison groups. However, the few studies reviewed here show general consistency regarding sources of stress, almost all of which are highly relevant for a study of a nursing population in Vietnam. Further, the suggested higher prevalence of depression and suicide among nurses warrants careful analysis in any study of nurses' Vietnam duty to determine if any evidence of stress or mental disorder can be attributed to the Vietnam experience itself or is related to the occupational stress of nursing in general. Selection of an appropriate control group, perhaps nurses in a critical care setting outside of Southeast Asia, will be critical to such an analysis. 5.3 SMOKING As discussed further in the next section, smoking is a confounder when investigating both health outcomes such as lung cancer and cardiovascular disease and reproductive outcomes, including birth weight and gestation. The literature was reviewed regarding smoking habits of nurses to determine if they differed from the female population at large. Among health professionals, smoking rates consistently have been reported higher for nurses than for physicians and dentists. While the actual rates have differed, the data indicate that a sizeable proportion of nurses smoke. For 71 �example, the American Cancer Society's prospective Cancer Prevention Study I found that, in 1959, 36.3% of female nurses were smokers and by 1972, 25.9% were still smoking (Garfinkel and Stillman, 1986). In an analysis of the 1975 Public Health Service Survey, Stillman and Stillman (1981) reported that 32.1% of female health professionals were current smokers. This figure, however, may include professionals other than nurses. A 1981 study of Connecticut nurses showed that 25.5% smoked (Morra and Knobf, 1983), while 28.3% were smokers in a western New York sample (Wagner, 1985). In a sample of 601 nurses in North Carolina, 31.9% were smokers (Dalton and Swenson, 1983), whereas in Michigan, only 19.1% of a sample of 448 hospital nurses reported smoking (Tagliacozzo et. al., 1982), suggesting possible regional differences in smoking rates. While these data clearly indicate that a large proportion of nurses smoke, comparison with smoking rates of the female population in general reveal that nurses have higher smoking rates. The more recent Cancer Prevention Study II, started in 1982, reports that even with a decline of 2.3% in nurses' smoking rate between 1972 and 1982, their current rate of 23.6% exceeds the rate of 21.5% for all women. Furthermore, important to a study of women in the Vietnam era cohort, the cohort of nurses with the highest smoking rate in CPS II is the 30-39 year age group, which contains a sizeable proportion of the cohort of interest. Data are limited concerning the characteristics of nurses who smoke or their reasons for smoking. No definitive explanation for differences in smoking patterns between men and women, or nurses and other professionals has been formulated. However, two interesting pieces of data from the western New York study (Wagner, 1985) and the North Carolina study (Dalton and Swenson, 1983) indicate respectively that almost half (43%) began smoking when studying nursing and that the vast majority of smokers were staff nurses. Occupational stress is frequently offered as a reason for the high smoking rate among nurses (Stillman and Stillman, 1981). Data from the few available studies provide only limited support for this hypothesis. In a mailed survey of 823 randomly selected nurses in Minnesota with a response rate of 82% (Feldman and Richard, 1986), two of the reasons for continued smoking were stress reduction (43%) and a primary means to relax (38%). The investigators did not inquire as to the source(s) of stress to determine if it was occupationally related. However, they did compare the characteristics of the sample with nurses nationally as reported by the American Nurses Association and concluded that the Minnesota sample was representative of nurses nationally. Further, consistent with the New York study by Wagner (1985), the data indicated that over 50% of both current and former smokers started to smoke between the ages �of 17 and 19 years, a period coinciding with the beginning of their nursing education. A study by Tagliacozzo et al, (1982) examined specifically the relationship between work-related stress and smoking among hospital nurses. Prevalence of smoking in a sample of 448 nurses was low (19.9%) in comparison to other studies. However, this finding may well have been influenced by the low response rate of 49.3% to a mailed questionnaire. Work-related stress was measured by Kahn's Job Tension Index, modified by the investigators to incorporate items specific to nursing. Subscales of this index were developed for analysis of several dimensions of work stress. Data revealed that nurses who smoked had an overall tendency to produce higher stress scores than nonsmoking nurses. More specifically, smoking nurses who were most likely to perceive the physical and emotional demands of the job as stressful were younger, single, had a BSN degree, work 40 or more hours per week, and worked on rotating shifts. The authors caution, however, that their data do not show a cause and effect relationship between work stress and smoking. In fact, for the majority of nurses, smoking was an established habit before starting work. The study does not explore if work-related stress contributes to continued smoking. In conclusion, therefore, smoking rates for nurses are generally higher than for other health professions despite a recent decline, and further, nurses are more likely than the general female population to smoke. Limited data regarding the tendency to start smoking at an early age and for continued high rates for the 30-39 year old cohort suggest that the cohort of nurses serving in Vietnam was likely to have high smoking rates. This is supported by findings that smoking nurses who perceived their job as stressful were young, single, and worked long hours and/or rotated shifts, a description most apt to fit nurses serving in Vietnam. These data support the inclusion of smoking as an important confounder in a study of women serving in Vietnam. 5'4 CHEMICAL ABUSE The lack of scientific data regarding chemical dependency among nurses has been repeatedly pointed out (Canfield, 1976; Bissell and Jones, 1981; Caroselli-Karinja and Zboray, 1986) and confirmed by this review. The majority of literature on this issue has been written by the nursing profession and consists of case studies to illustrate the problem (Pierce, 1976; Booth and Gillard, 1981) or descriptions of programs/approaches to deal with the problem (Pierce, 1976; Reed, 1983; Naegle, 1985; Caroselli-Karinja and Zboray, 1986; Penny, 1986). 73 �Concern with professional and legal reprisals, compounded by denial of the problem, is considered to contribute to the difficulty in obtaining reliable data (Bissell and Jones, 1981). Canfield (1976) asserts that any available data are likely to be underestimates of incidence for similar reasons. The few available studies are described here for informational purposes, i.e., to provide some estimates as to the extent of the problem and to describe characteristics of addicted nurses. All of these studies have obvious methodological flaws, openly acknowledged by the authors, but they provide what little data are available. Chemical addiction includes both alcohol and drugs, prescription and illegal. However, the literature to date focuses only on abuse of alcohol and prescription drugs by health professionals. The extent of use of illegal drugs such as cocaine and marijuana is not mentioned. Canfield (1976) cites 1973 data from the American Medical Association's Council on Mental Health indicating that 15% of known drug addicts are nurses or pharmacists. Several other studies from the late 1960!s and early 1970fs cited in this work reported on drug use by physicians, pointing up the dearth of data regarding nurses. Bissell and Jones (1981) estimate that roughly 5% of American women are alcoholic so that if nurses are considered at the same risk, then 5% of nurses can be considered alcoholic. In an attempt to learn more about alcoholism among members, Bissell and Jones (1981) conducted interviews with 407 professionals who were actively involved in Alcoholics Anonymous during the early and mid 1970's. One hundred of this sample were nurses and female. All were abstinent at the time of the study. Data revealed that 35% of the sample abused drugs in addition to alcohol, with barbiturates and amphetamines cited most frequently. The rates for combined chemical abuse were highest for physicians and nurses, in that order, when compared to other professional groups. The sequence of drug use was typically alcohol first, followed by non-narcotics and finally hard narcotics. The major flaw of this work is its nonrepresentative sample but it remains one of the few available studies. Suggested reasons for chemical abuse by nurses have included accessibility of prescription drugs and alcohol and work stress (Bissell and Jones, 1981; Reed, 1983; Naegle, 1985). Naegle (1985) proposes an interactional rather than causative role in the phenomenon of impaired practice, pointing out that while role strain and job stress pose challenges for the nurses, most nurses do not resort to drug/alcohol abuse as a coping mechanism. This latter point is consistent with the findings from a study of the characteristics of nurse addicts conducted in 74 �the late 1960's (Poplar, 1969). Among 90 nurse addicts admitted to a federal treatment facility, three basic reasons were found for drug abuse: physical illness, emotional problems too great to handle, and work pressure too demanding emotionally and physically. Psychological testing revealed that nurses used drugs to alleviate pain and escape from reality not for curiosity, desire for pleasure, or nonconformity as was typical for other addicts. Further, drug abuse began later in adulthood and was usually a solitary, not social, activity. Finally, more than other addicts, nurses claimed to be able to work while using drugs. To summarize, valid and reliable data regarding the extent of alcohol and drug abuse by nurses are unavailable. However, a few case reports and descriptive studies provide evidence that it is a problem, and one which is increasingly recognized of late. Data from more extensive studies on chemical use among the military, as reported elsewhere in this review, would strongly suggest that some nurses serving in Vietnam were likely abusers and may continue to abuse drugs, especially alcohol. A study of woman Vietnam veterans provides an opportunity to collect data for careful consideration of drug and alcohol abuse as a confounder in analysis of health and reproductive outcomes. 5.5 CONCLUSIONS In reviewing the literature on occupational risks, there are data, admittedly flawed, to suggest that the work of nursing itself may contribute to higher levels of perceived stress, higher rates of smoking, and, possibly, of chemical abuse, as well as exposure to possible toxins, such as volatile anesthetic gases. These factors may exist independently of the Vietnam exposure, but may also be intensified in a sample of Vietnam nurses. Therefore, it will be important to determine how much influence the Vietnam exposure had on these factors above and beyond what might be expected in a nonexposed population of nurses. The implications for a carefully matched control group are clear. 75 �6. CONFOUNDING FACTORS In observational studies in which the hypothesized exposure or cause cannot be randomized, it becomes particularly important to control for potential confounding factors likely to affect the outcomes(s) or likely to mask an association between exposure and outcome (Cochran, 1972; McKinlay, 1975; Schlesselmann, 1982). In the proposed study of Women Vietnam Veterans, the potential for confounding factors is further complicated because important potential confounding factors for health outcomes such as cancer and heart disease, and abnormal reproductive outcomes may themselves be important health outcomes resulting from exposure to the Vietnam war experience. Some obvious candidates for this category are: use of (licit or illicit) drugs including marijuana and tranquilizers; heavy alcohol use; and smoking. Some evidence is emerging that alcohol use in particular may be increasing among male Vietnam veterans (see the above on Drug Use in Vietnam section) With respect to other potential confounding factors, it is already well documented that full-time nurses - the major occupational category among women Vietnam veterans - are some of the heaviest cigarette smokers and are prone to increased alcohol and drug use (see section 5 above). This section, therefore, reviews current knowledge concerning the association of important potential confounders with outcomes of interest to the planned study. The two primary factors included here are cigarette smoking and alcohol use. The potential roles of caffeine, antihistamines, tranquilizers, and marijuana use are also considered. A final section reviews other potential intervening or confounding exposures which must be considered in designing a study of women Vietnam veterans. 6.1 SMOKING Of all the substances, the use of which is not generally restricted, cigarette smoking is almost certainly the most damaging to human health. It has been wellestablished as a primary risk factor for lung cancer (Hammend, 1961; Doll and Hill, 1952; Bross, 1968), heart disease (Shurtleff, 1974; Harlik and Feinleib, 1979), other cancers (Hammond, 1961; Levin et al, 1950) and Chronic Obstructive Pulmonary Disease - COPD - (Spinaci et al, 1985). The literature on these associations is considerable and will not be included here, beyond the key references cited above. The effect of cigarette smoking on the reproductive system is less well understood. The early finding that it results in increased fetal loss and pre-term deliveries as well as lower birth weight (adjusted for gestational age) 76 �has now been well documented. The early seminal work of Yerashalmy, among others on this effect (Yerashalmy, 1964; see also Wainright) has been recently confirmed in Sweden (Cnattingius et al, 1985), Australia (Lumley, 1985), United States (Kleinman and Madans, 1985; Shiono et al,1986), Finland (Pulkkinen, 1985) and France (Schwartz et al 1972). These and similar studies have been typically well designed using large samples with adequate response rates and independent outcome assessment. Potential confounding factors, given the large numbers, have also been adequately controlled in these studies. Apart from confirming these early associations, recent studies have considerably extended knowledge on the effect of maternal smoking on the fetus. It has been established in several studies that the effect of smoking on fetal outcome is independent of any effect of alcohol (Kline et al, 1981; Stein and Kline, 1983; Lumley, 1985; Shiono et al, 1986; Wright et al, 1984; Berkowitz et al, 1982; Hingson et al, 1982). A recent U.S. study (Kline et al, 1981) demonstrates that spontaneous abortions in smokers are of chromosomally normal fetuses. In other words, smoking is not teratogenic in humans. This is confirmed in an excellent review of recent literature (Mclntosh, 1984) which synthesizes results from methodologically sound studies. Mclntosh (1984) also identifies an increased risk of uterine bleeding during pregnancy among smokers. Three recent studies have documented increased infant mortality and/or morbidity, excluding neonatal mortality, for maternal smokers in Finland (Rantakallio, 1979), in New Zealand (VandenBerg, 1985) and in Sweden (Stjernfeldt et al, 1986). The last study focussed on an increase in childhood cancers. The impact of smoking during pregnancy appears to be immediate, with pre-pregnancy quitters showing no differences from non-smokers in fetal outcomes (Pulkkinen, 1985; Schwartz et al, 1972). The presence of a dose-response curve is well established for low birth weight, but there are indications that the dose-response relationship is small for fetal loss (Kline et al, 1981; Shiono et al, 1986). The association of smoking with other aspects of reproduction is not well understood and the literature is sparse, most of the reports being recent. Two recent studies in very different populations have demonstrated reduced fertility among smoking women. Baird and co-workers (1985) showed a marked increase in time to pregnancy for smokers in a representative sample of pregnant women who had been trying to conceive for less than two years. A similar effect was observed in a large sample of infertility referrals in Denmark who had not conceived in at least 2 years (01sen et al, 1983). Both studies controlled for confounders and other biases in assessing their findings. 77 �In the well-known U.S. study of smoking effects, Hammond (1961) found an increase among smoking women in irregular menstrual patterns which is consistent with the recent findings on infertility but which has not been confirmed in more recent large studies. Also consistent with these findings relating to infertility are recent reports of an earlier natural menopause among cigarette smokers (McKinlay, 1985; Baron, 1984; Adena and Gallagher, 1982; Kaufman et al, 1980). These reports, although reporting consistently that the median age at menopause (last menstrual period) is 1.5 - 2.0 years earlier in smokers than in non-smokers, are inconsistent in reporting a dose response and the effect for past smokers. On balance, from the evidence available, there does not appear to be a strong dose response, most of the effect deriving from any cigarette smoking, regardless of how much. This is consistent with similar findings by Baird et al (1985) regarding the impact of smoking on fertility and with the impact of smoking on fetal loss (Kline et al, 1981; Shiono et al, 1986). Apart from these studies, evidence of the toxic impact of smoking on the reproductive system as a whole has come from animal studies (see for example, Mattison, 1983). 6.2 ALCOHOL Apart from being classified as a disease itself, heavy alcohol consumption has been related causally to such degenerative health outcomes as cirrhosis of the liver, some cancers and brain disorders, (see NIAAA, 1980 for comprehensive data and review). As with smoking, these associations have been well-established from consistent studies and only key references are provided here. The potential effect of heavy alcohol consumption on aspects of the reproduction system has not, however, been systematically researched. Animal (primarily rodent) studies (for example Krueger et al, 1982; Van Thiel et al, 1980; Ryback, 1977) have demonstrated that in both males and females, heavy alcohol ingestion produces hypogonadism directly. There is also evidence for an indirect effect on the endocrine system through liver dysfunction (Ryback, 1977). In female rodents exposed to ethanol, fewer estrous cycles are observed (Ryback, 1977; Krueger et al, 1982), and Ryback cites two clinical cases of human amenorrhea apparently caused by heavy alcohol consumption. The studies of infertility and smoking (Baird et al, 1985; Olsen et al, 1983) also noted that the smokers reported higher alcohol consumption, but that this factor did not influence infertility, which seems to contradict the animal results. However, both studies were too small to 78 �adequately investigate this effect. Baird and co-workers included 678 women of whom 136 were smokers. Ten percent of smokers (14 subjects) and 3% of non-smokers (16 subjects) reported more than 7 drinks/week. The Danish study was larger (278 infertile and 2947 fertile couples), but the rates of smoking and alcohol use were not provided. If rates are assumed equivalent to those for the Minnesota study (Baird et al, 1985), then the number of couples providing information on the effect of alcohol use is still small (less than 300). These null results, therefore can only be considered suggestive and require confirmation in a much larger study. Perhaps the most controversial issue regarding alcohol and reproductive function has been its hypothesized effect on the fetus. Fetal outcomes attributed to alcohol include fetal loss and growth retardation (as for smoking) as well as a cluster of fetal abnormalities labeled the Fetal Alcohol Syndrome (FAS) by Jones et al (1973). This syndrome comprises central nervous system dysfunction including irritability, microcephaly and mental retardation, growth deficiency and distinct facial characteristics (including short palpebral fissure, abnormal jaw protrusion, marked vertical skin folds, thin upper lip etc.). Reports on this subject fall into three distinct groups: animal studies; epidemiological studies of the joint effects of smoking and alcohol (among other factors); and epidemiological studies of FAS. Adverse toxic effects of ethanol crossing the placenta, have been well documented in animal fetuses (see for example, the reviews by Furey, 1982; Strobino et al, 1978). The primary effects appear to be growth retardation, including microcephaly and central nervous system dysfunction. Recently, well-designed and analyzed epidemiological studies have investigated the potential joint effect of smoking and alcohol on the fetus. Lumley (1985), Kline et al (1981), Shiono et al (1986) have all demonstrated, using large samples that the effect of smoking on the fetus is independent of alcohol consumption, even though smoking women are much more likely to drink than non-smokers. Prager et al (1984) provide excellent statistics on these behaviors in mothers from the 1980 National Natality Survey). Only very heavy maternal alcohol consumption (generally the equivalent of at least 2 oz. absolute alcohol/day) is apparently associated with low birth weight (Kline et al, 1981; Wright et al, 1984; Berkowitz et al 1982). Studies of FAS have been typified by methodological problems. Studies including specialized neo-natal and/or pediatric examinations have either not blinded the examiner to maternal alcohol status (Sokol et al, 1980), have been 79 �unclear on such potential biases in the study (Streissguth et al, 1981; Ouellette et al, 1977) or have demonstrated lack of reproducibility in physician examiners (Alpert et al, 1981). Others, such as Marbury et al, 1983, used existing records to determine fetal outcome. While removing problems of observer bias, this approach suffers from lack of standard definitions among a large number of clinicians completing the records. Despite methodological difficulties, only the Boston Study (Alpert et al, 1981; Hingson et al, 1982) is large enough, with unbiased physician examinations. With adequate control of potential confounding factors, this study does not find an excess of adverse fetal outcomes due to alcohol except for shorter gestation (Hingson et al, 1982). Thirty-one cases consistent with FAS were identified in 1,384 infants examined. In summary, the adverse effects of alcohol on reproductive function possibly include reduced fertility and some retardation of fetal growth, although only in heavy drinkers. Stein and Kline (1983) provide an excellent review of these findings. 6.3 CAFFEINE AND OTHER DRUGS The health outcomes of heavy caffeine use (generally equivalent to more than three cups of coffee per day) are not clear. Most of the studies have been too small, have not consistently or reliably measured caffeine exposure (Wetherbee et al, 1977) or have been subject to other biases (Jick et al, 1973; Rosenberg et al, 1980). An excellent review recently completed by James and Sterling (1983) indicates that there is no sound evidence for an increase in myocardial infarction, that there is probably an increased risk of pancreatic cancer but that the evidence for bladder cancer is unclear. With respect to reproductive outcomes, there is no sound evidence of excess fetal loss or congenital abnormalities such as cleft palate or neural tube defects. Watkinson and Fried (1985) indicate a possible decrease in birth weight, but a relatively low response rate combined with retrospective data on caffeine consumption make these results questionable. Kurpa et al (1983) show no effect of caffeine on congenital abnormalities in a Finnish population, consistent with Linn et al, (1982) in the U.S. In another excellent review of factors affecting fetal outcomes, Goldman (1980) indicates that antihistamines and tranquilizers can produce cleft palate abnormalities in the fetus. Fried (1980) documents nervous system abnormalities in the offspring of maternal marijuana users and Hingson et al (1981) estimate that marijuana users are 5 times as likely to have offspring with features consistent with FAS, although the numbers are small. 80 �6.4 OTHER POTENTIAL FACTORS Apart from the major factors discussed above, the possibility of longer term TCDD exposure either from residential or occupational exposure must not be overlooked. For example, residents exposed near St. Louis, Missouri or other toxic waste sites may exhibit depressed immune function. Another factor emerging from oral histories and verbal reports is marriage to a Vietnam veteran, thus increasing exposure to fetal abnormality or loss. A recent report (Hogstedt et al, 1986) indicates that ethyline oxide, used as a sterilizer in hospital and commercial sterilization facilites may increase the risk of leukemia and possibly stomach cancer, although exposure in Vietnam veteran or Vietnam-era nurses post-Vietnam to this substance is probably low. 6.5 SUMMARY The literature reviewed in this section is not intended to be exhaustive, but highlights the current state of knowledge with respect to health outcomes of smoking, alcohol use and other drug use including caffeine and marijuana. Major adverse health effects are generally well documented for these factors indicating that smoking and alcohol at least must be included in any comparison of veterans involving disease endpoints such as cancer and heart disease. The state of knowledge is not so clear for outcomes relating to the reproductive system, but there is sufficient, consistent evidence from both animal and human studies to include both smoking and alcohol use in all comparisons involving reproductive health outcomes. To the extent feasible in the proposed study, other drug use should also be considered, particularly those possibly associated with congenital abnormalities (including marijuana, tranguilizers etc.). Other important confounders to be considered are spouse, residential, and occupational exposures to toxic substances, including TCDD in particular. A major methodological difficulty will be reliable ascertainment of these confounding exposures before and immediately after Vietnam or Vietnam-era military service. 81 �SUMMARY AND CONCLUSION The literature reviewed here has clearly indicated the need for: • A study of women war veterans; and e A study of women Vietnam veterans. The distinction is made between these two types of studies, because although, both are needed they have separate goals. The first type of study would have as its goal, the investigation of how women function under war conditions and the accompanying stresses as well as the impact of this experience on subsequent life. Are there differences according to occupation (nurse versus other military role) or according to age or prior life experience? Is subsequent post-war integration into society different for those who stay in the military compared to those who return to civilian life? Ideally such a study should be prospective, defining and measuring a cohort before it goes to war, immediately after completion of war service and subsequently. The chances of completing such a study, however, are negligible. The most feasible design is to begin immediately on completion of war service, to minimize recall problems, tracing difficulties and costly access to archived records. The proposed study of women Vietnam veterans can provide an investigation of the direct effect of war experience on women. It will however be limited in the following ways: * Already 15-20 years have passed since completion of war service, increasing the problems of recall; 0 The Vietnam war was a unique experience for the U.S., with a concurrent and subsequent political climate which created difficulties for veterans not usually expected after serving in a war; and « The period of war service was limited, for the first time, to one permanent tour of duty (one year). The second type of study has a more focused goal to investigate the effect of the Vietnam Experience (VE) on women veterans. This experience includes: the exposure to war as would be investigated in the first study; the potential exposure to phenoxy herbicides; the exposure to an unconventional guerrilla war with no well-defined front line; the knowledge that the U.S. did not win the war; and the lack of mobilization for (developing into active hostility towards) the war in the civilian U.S. population. 82 �Thus, while a study of women Vietnam veterans can address both sets of goals, to varying extents, it must be recognized that it will not provide a representative portrait of how war in general affects women who are participants. The impact of the war experience will be confounded with the impact of the unique Vietnam experience. In designing the proposed study, several issues must be addressed which are highlighted in this review. Some of the major issues are: 9 The retrospective nature of this study (requiring recall over 20 years, on average); e The impact of the.intervening and current political climate on participant responses (this is clearly demonstrated in the experiment by Korgeski and Leon, 1983 and is further emphasized by Colton, 1986); o The difficulties inherent in measuring exposure to phenoxy herbicides; o The need to define and develop measures for combat exposure and PTSD for women; and 9 The complex relationship between exposure, intervening and outcome variables. Each of these issues is reviewed briefly below. (a) Retrospectivity Reliance on memory recall, even over one year, is risky. Over longer periods, reliable data can only be obtained on major events or changes. In designing this study, decisions must be made on what data can be feasibly collected from an interview and what independent sources can be used to supplement or validate interview data. Potential supplemental sources include: « Results of medical examinations required by the military (minimally at in-take and discharge); and © Hospital and other medical records. Political Climate and Value-Free Data, This phenomenon clearly exacerbates memory recall by biasing it in certain directions. Vietnam veterans are more likely to respond positively concerning PTSD symptoms and possible toxic outcomes from Agent Orange exposure. In combination with the well-known problems of memory recall, this issue underscores the need to validate key items of 83 �information and/or to obtain independent, value-free assessments. This is true of both exposure and outcome variables. In terms of exposure, the "Herbs" tapes should be considered, if it is feasible to determine exposure in time and space from independent records. If a large proportion of nurses were moved around frequently between units then this may not be feasible. Alternatively, blood sampling (at least on a sub-sample could be considered for eventual determination of residual body TCDD levels. Exposure to combat situations, including enemy attack should also be determined, if possible form independent documentation (if available). All major health outcomes should be verified on either 100% of cases or a sample (depending on cost constraints and the reliability of self-report). Disease diagnoses (including cancers in particular) can be verified from medical records and pathology reports (if available in the 15-20 year time span being considered). Congenital anomalies in offspring can be verified from medical records and from pediatric examination. Potential low level effects of TCDD on immune function can be determined from a variety of blood, urine and skin tests. Psychological disturbance (including chronic or delayed PTSD in particular) can be determined from a series of tests and/or clinical examination. (c) Development of Measures for Women The currently available measures of combat exposure and PTSD in particular are designed primarily for men. Certain exposures are not within the likely experiences of women military (at least to date), including direct confrontation and killing of the enemy and combat field living conditions. The definition and measurement of PTSD must also be modified accordingly. Changing Roles of Variables The relationships among the variables and between different measures of the same variable are complex. For example, alcohol consumption in Vietnam becomes a component of the Vietnam Experience (if it was high and ubiquitous). It is also an important intervening variable, post-war, in assessing, for example, any reproductive effects of either prolonged stress or phenoxy herbicide exposure. Finally, current alcohol consumption may itself be considered an important outcome of the war experience. A similar set of roles can also be proposed for tobacco smoking. The confounding role of nursing as an occupation deserves special attention, as the majority (estimated at 84 �about 80%) of all women Vietnam veterans were nurses. This is well-known as a high-stress occupation which in this study will be confounded with a variety of unique stressors related to war. It may be that women able to successfully manage such stress differentially self-select from this occupation and for war-service. Design Recommendations The methodologies of prior studies reviewed here indicate that the strongest design will be a retrospective cohort design that compares Vietnam veterans with Vietnamera veterans who were otherwise eligible for Vietnam service but did not have a tour of duty "in country". This direct comparison can be supplemented for key health and sociodemographic characteristics, with comparisons involving civilian population data sets such as those generated by the National Center for Health Statistics. Within the cohort design, case-control studies should be imbedded which compare women with and without key outcomes, including measurement to verify these outcomes. For example, all women reporting offspring with congenital abnormalities could be matched with women of equivalent fertility and normal offspring. Pediatric examinations (done blind to group status) would then be conducted on all offspring in these two groups. Women with any cancer diagnosed and alive at interview could be matched with cancer-free women for immunological assessment. The final design will, therefore, include a subset of possibly over-lapping case-control studies for in depth study and verification of key outcomes. Because in-person measurement will be costly in this nationwide study, this design approach is considered the most efficient. 85 �SPECIAL REFERENCES Cochran, W.G.,"Observational Studies",111 Statisical Papers in Honor of George W. Snedecor (Bancroft TA, ed) Iowa State University Press, Ames. 1972. 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Stanton,M.D.,"Drugs,Vietnam,and the Vietnam veteran:An overview",American Journal of Drug,Alcohol Abuse,1976,3(4),557-570. Stanton,M.D.,"Drug use in Vietnam-A survey among Army personnel in the two northern corps",Arch. General Psychiatry,1972,26,279-286. Stein,Z., Kline ,J., "Smoking, alcohol and reproduction", AnuJ_.. Pub. Health.1983.73(10),1154-1156. Stellman,S.D.,Stellman,J.M. /'Estimation of exposure to Agent Orange and defoliants among American troops in Vietnam:A methodological approach".American.Journal of Industrial Medicine,1986,9,305-321. Stellman,S.D.,Stellman,J.M.,"Women's occupations, smoking and cancer and other diseases",Cancer,1981,31(1),29-43. Sterling,T.D.,"Health effects of phenothyberbicides",Scand J. Work Environ._ Hea1th,19 8 6,12,161. Sterling,T.D.,Arundel,A.,"Review of recent Vietnamese studies on the carcinogenic and teratogenic effects of phenoxy herbicide exposure",International, Journal,of Health Services.1986,16(2),265-278. Sterling,T.D.,Arundel,A.,"Vietnam veterans risk for fathering children with birth defects",Journal of American Medical Association.1985.254(5),609. Stevens,K.M.,"Agent Orange toxicity; A quantitative perspective".Human Toxicology,1981,1,31-39. Stj ernfeldt,M.,Berglund,K.,Lindsten,J.,et al.,"Maternal smoking during pregnancy and risk of childhood cancer".The Lancet.1986.6/14/86.1350-1352. 118 �Stockwell,T.,Hodgson,B.,Edwards, G.,Taylor,C.,Rankin,H.,"The development of a questionnaire to measure severity of alcohol dependence".Br. J. Addict.,1979,74,79-87. Streissguth,A.P.,LandesmanDwyer,S.,Martin,J.C., et al.,"Teratogenic effects of alcohol in humans and laboratory animals",Science,1980,209,353-361. Streissguth,A.P.,Martin,D.C.,Martin,J.C.,Barr,H.M.,"The Seattle longitudinal prospective study on alcohol and pregnancy",Neurobehayioral Toxic. and Teratology,1981,3,223-233. Stretch,R.H.,Vail,J.D.,Maloney, J.P.,"Posttraumatic stress disorder among army nurse corps Vietnam veterans",J.of Consultina&Clinical Psych..1985,53(5),704-708. Suskind,R.R.,Hertzberg,V.S.,"Human health effects of 2,4,5-T and its toxic contaminants".JAMAf1984.251.1372-2380. Taffel,S./'Factors associated with low birth weight".National Center for Health Statistics,1980,Apr.,. Tagliacozzo,R.,Vaughn,S.,"Stress and smoking in hospital nurses",AJPH,1982.72(5),441-448. Tanaka,H.,Suzuki,N.,Arima,M.,"Experimental studies on the influence of male alcoholism on fetal development",Brain and Development,1982, 4(1),1-6. Tennes,K.T.,Blackard,C.,"Maternal alcohol consumption, birth weight, and minor physical anomalies",American J. Obstet. and Gvnecol.,1980,138(7),774-780. The Herbicide Committee,"Health effects of herbicides 2,4-D and 2,4,5-T:A report to the Nova Scotia Forestry Commission",, Inverness-Victoria Medical Society, 1983 ,116-83,1-48. Thoits P.,"Undesireable life events and psychophysiological distress: A problem of operational confounding",A.S.R.,1981,46,97-109. 119 �Thoits,P. /'Conceptual, methodological, and theoretical problems in studying social support as a buffer against life stress ».jnl_pf^Health,nnd Social Behavior.1982,23,145-I§9 . Tognoni,G.,Bonaccorsi,A.,"Epidemiological problems with TCDD (a critical review)",Drug Metabolism Reivews,1982,13(3),447-469. Townsend,J.C,Bodner,K.M.,VanPeenen,P.F.et al.,"Survey of reproductive events of wives of employees exposed to chlorinated dioxins".Am. J. Epi..1982,115(5),695-713. Tretli,S.,Glund-Larsen,Foss,A. /'Reliability of questionnaire information on cardiovascular disease and diabetes: Cardiovascular disease study in Finnmark county",Jnl,of Epi.and Communt. Hlth..1982.36.269-273. Trung,Cung Binh,et al.,"Spontaneous abortions and birth defects in areas exposed to toxic chemical sprays in Giong Trom District,Ben Tre province,South Vietnam",Pres.Internat.Svmp. on Herbicides in War,1983.Jan.13.. Tucker,A.N.,Vore,S.J.,Luster,M.I.,"Suppression of B cell differentiation by 2,3,7,8,tetrachlorodibenzo-pdioxin",Molecular Pharmacology,1986,29,372-377. Urry,R.L.,"Stress and infertility",Male Infertility,Cockett,A.T.K.(ed)7Grune & Stratton, York,1977,145-157. New VanDevanter,Linda, Home Before Morning ,Beaufort Books,New York,1983,. VanKampen,M.,Watson,C.G.,Tilleskjor,C.,et al.,"The definition of posttraumatic stress disorder in alcoholic Vietnam veterans - Are the DSM-III criteria necessary and sufficient",J. of Nervousand Mental Disorder.1986,174(3),137-144. VanServellen,G.M,Soccorso,E.A.,Palermo,K.,et al.,"Depression in hospital nurses:Implications for nurse managers",NAQ,1985,9(3),74-84. VanThiel,D.H.,Gavaler,J.S.,Eagon,P.K.,Chiao,Y.B.,Cobb,C.F.et al.,"Alcohol and sexual function",Pharmacology, Biochemistry and Behavior,1980,13,125-29. 120 �VandenBerg,M. /'Smoking during pregnancy and post neonatal death",New England Medical Journal,1985,98,1075-1078. Veterans Administration,"Data on Vietnam era veterans",Off. Information Management^ &, StatisticsrWash.D.C.,1985,Apr.,1-34. Veterans Administration,"Veterans administration:Review of literature on herbicides, including phenoxy herbicides and associated dioxins", U.S. Goyt... Printing OfficerWashington,D.C.,1981,0ct.,1-6. Vitez,M. ,Koranyi,G. ,Gonczy,E. ,et al.,"A semiquantitative score system for epidemiology studies of fetal alcohol syndrome",American Journal of Epidemiology.1984.119(3),301-308. Vos,J.G.,"Screening and function studies in immunotoxicity testing",The Veterinary Quarterly.1981.3(4),190-195. Wagner,T.J.,"Smoking behavior of nurses in western New York".Nursing Research.1985.34(1),58. Wainright,R.L.,"Change in observed birth weight associated with change in maternal cigarette smoking",American Journal of Epidemiology,1983,117(6),668-675. Waldinger,T.P.,Siegle,R.J.,Weber,W.,Voorhees,J.J.,"Dapsone induced peripheral neuropathy",Archives of Dermatology,1984,120,356-359. Watkinson,B.,Fried,P.A.,"Maternal caffeine use before, during and after pregnancy and effects upon pregnancy",Neurobehayioral Toxicology & Teratology.1985.1,9-17. Weathersbee,P.S.,Lodge,J.R.,"Caffeine: Its direct and indirect influence on reproduction",J. Reproductive Medicine,1977,19(2),55-63. Weathersbee,P.S.,01sen,L.K.,Lodge,J.R.,"Caffeine and pregnancy".Postgraduate Med.,1977.62(3),64-69. 121 �Weisman M.,Sholomaskas o.,Pottenger M.,et al,"Assessing depressive symptoms in five psychiatric populations: a variation study".Am J. Epidemiology,1977,106(3),203214. Westing,A.H.,Cau,H.D./'International symposium on herbicides and defoliants in war:The long-term effects on man and nature".Proceedings Ho Chi Minn City.1983,1-13-83,1-29. Wiklund,K.,Holm,L.E.,"Soft tissue sarcoma risk in Swedish agricultural and forestry workers",JNCI,1986,76(2),229234. Wilcox,A.J.,Homey,L.E.,"Accuracy of spontaneous abortion recall",American Journal of Epidemiology.1984.120(5),727-733. Wolfe,M.S.,Cordero,J.F.,"Safety of chloroquine in chemosuppression of malaria during pregnancy",Brit. Med. J..1985.290.1466-1467. Woods,N.,Dery,G.,Most,A.,"Stressful life events and perimenstrual symptoms",Journal of Human Stress,1982,8,23-31. Woods,N.F.,Most,A.,Dery,G.K. /'Estimating perimenstrual distress:A comparison of two methods",Research in Nursing and Health.1982,5,81-91. Woods,N.F.,Most,A.,Longenecker,G.D.,"Major life events,daily stressors, and perimenstrual symptoms"fNursing Research,1985,34,263-267. Wright,J.T.,Harrison,I.G.,Lewis,I.G.,MacRae,K.D.,et al.,"Alcohol consumption, pregnancy, and low birth weight".Lancet.1983,26,663-665. Wright,J.T.,MacRae,K.D.,Barrison,J.G.,Waterson,E.J.,"Effects of moderate alcohol consumption and smoking on fetal outcome",Ciba. Foundation Symposium,1984,105,240-253. Wyatt,E.H.,Stevens,J.C.,"Dapsone induced peripheral neuropathy",British Journal of Dermatology,1972,86,521523. 122 �Yager,1!.,Laufer,R.,Gallops,M.,"Some problems associated with war experience in men of the Vietnam generation".Archives of Gen. Psychiatry,1984,41,327333.Young,A.L.,Shepard,B.M.,"A review of ongoing epidemiologic research in the United States on the phenoxy herbidides and chlorinated dioxin contaminants",Chemosphere,1983,12(4/5),749-759. Zack,J.A,Gaffey,W.R.,"A mortality study of workers employed at the Monsanto Company plant in Nitro, West Virginia", Human,and Environmental,Risksof chlorinated^Dioxins, and Related Compounds, Tucker,Young,Gray eds.,Plenum Pr.,New York,1981,575-591. Zack,J.A.,Suskind,R.R.,"The mortality experience of workers exposed to tetrachlorodibenzodioxin in a trichlorophenol process accident",Journal of Occupational Medicine,1980,22,11-14. Ziel,H.K.,Finkle, W.D.,"Increased risk of endometrial carcinoma among users of conjugated estrogens",New England Journal of Medicine,1975,293(23),1167-1170. Zinberg,N.E.,"Heroin use in Vietnam and the United States",Arch. Gen. Psychiatry,1972,26,486-488. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 068 Folder The folder containing the original item. 1847 Series The series number of the original item. Series III Subseries III Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource McKinlay, Sonja M. Sharon L. Tennstedt Description An account of the resource <strong>Corporate Author: </strong>New England Research Institute, Inc., Watertown, Massachusetts Title A name given to the resource Womens Vietnam Veterans Health Study Protocol Development: Literature Review and Bibliography, Deliverable A. Subject The topic of the resource Women Vietnam Veterans Health Study PTSD dioxin VA ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/28a87752e7dea2c38f0c97bee0045161.pdf bf51b580aefbcf6ce6c4d73eb3d04568 PDF Text Text Item ID Number 01437 Author Corporate Author RODOrt/ArtlClB TltlO Typescript: Updates on various Vietnam Veteran Health Studies, March 11, 1987 Journal/Book Title Year Month/Day Color n Number of Images 3 Desorlpton Notes Tuesday, May 15, 2001 Page 1437 of 1514 �Vietnam Veterans Mortality Study: The study was designed to assess mortality patterns ot U.S. servicemen in the Army or Marines who served during a portion of the Vietumn era (1965-1975). A sample of 75,000 veteran deaths was selected from the VA files. For each of the veteran deaths, military service and cause of death information were collected and coded. The two types of data were merged and analysed to compare the mortality experience of veterans who served in Vietnam with veterans of the same era who did not serve in Vietnam. This study began in December 1982 and the final report was completed in December 1986. Updato of the Vietnam Veterans Mortality Study: The Vietnam Veterans Mortality Study (WMS) will provid© the initial data on the mortality patterns of veterans who served in Vietnam and those who served elsewhere. However some of the diseases that were suggested as being associated with Agent Orange exposure or Vietnam service may take a long time to develop. For example, it takss about 20 years for certain cancers to manifest themselves if they are caused by environmental chemicals such as Agent Orange. We plan to periodically update the mortality data and monitor Vietnam veteran® mortality patterns. Retrospective Study of Dioxins and Furans in Adipose Tissue: The VA, in cooperation with the Environmental Protection Agency (EPA), i« performing a very detailed analysis of tissue specimens from approximately 200 males of th© Vietnam era ag© group. Th© specimens are analyzed for 2,3,7,8-TCDD and several other related dioxins and furans to determine if service in the military, especially service in Vietnam has resulted in increased levels of these compounds as compared to non-Vietnam veterans or civilians of the same age group. The final report for this study, which began in October 1983 is targeted for December 1987. Prospective Study of Dioxins and Furans in Adipose Tissue: A recent study estimated the half-life of dioxin in adipose tissue to bo 5-3 years. Therefore, among Army Vietnam veterans,dioxin in adipose tissue may still reflect exposure to Agent Orange during the Vietnam war. Prospective collection of adipose tissue specimens based on prescribed protocol will afford bettor control of factors that may influence the final outcome than retrospective specimen collection. This study will strengthen the retrospective study results and help to clarify the relationship between dioxin levels in the body and the risk of developing medical problems. �Soft Tisaue Sarcoma Study: In vic>w of the concerns raised by many veterans and conflicting findings in tha scientific literature, an independent epidsroiologic study was undertaken to determine r.he relationship of Vietnam service, probable Agent Orange exposure and other factors to the risk of developing STS. Thia study began in March 1983 and the final report was completed in December 1986. Cohort Mortality Study of Marine Vietnam Veterans; The CDC Epidemiology Study of Vietnam veterans includes only Army veterans in the study. The VVMS results suggest a possible difference in mortality patterns between Army veterans and Marine veterans. This proposed study will determine the overall mortality rate as well as cause specific mortality rats® of Marine* veterans who served in Vietnam and those who served elsewhere. This study is designed to complement the CDC study. Women Vietnam Veterans Mortality Study: None of the studies that were already completed or on-going is specifically designed to study women Vietnam veterans. This cohort study will assess mortality experience of women veterans who served in Vietnam compared to thosa women veteran© who served eluewhere during tha Vietnam war. Women Vietnam Vet«rana Health Study: Public kaw 99-272 mandates the* conduct of an epidamiologic study of any long-term adverse health effects {particularly gender-specific health effects) which have been experienced by women who served in the Armed Forces of the U.S. in the Republic of Vietnam during the Vietnam ara. These include health affects which may have resulted from traumatic experiences during Vietnam service, or from exposure to phenoxy herbicides (including Agent Orange), othesr herbicides, chemicals, medications, environmental hazards, or from any other experience or exposure during such service. This study will assist in determining appropriate treatment of condition®, if any, possibly related to that experience. The contract, for protocol development waa awarded to the New England Research Institute in October 1986, with anticipated completion of protocol development in July 1987. The target date for awarding a contract for the conduct of tha study is December 1987. Case Control Study of Non-Hodgkin's Lymphoma: Several epidemiologic studies suggested that individuals exposed to phonoxyherbici'Ses had a substantial increase in risk of non-Hodgkin'a lymphoma (NHL). A case control study is planned to investigate the possible association between NHL and Vietnam service, Agent Orange exposure or other possible environmental risk factors. �Health Surveillance of Vietnam Era Veterans: The existing VA records, such as the Pstiont Treatment File (FTP) and Agent Grange Registry, will be monitored periodically to duterrain® whether there are any unusual pattern© or trends that way indicate a need for an in-d«pth review. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 054 Folder The folder containing the original item. 1437 Series The series number of the original item. Series III Subseries II Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Typescript: Updates on various Vietnam Veteran Health Studies, March 11, 1987 Subject The topic of the resource veteran health and hygiene VA Mortality Study Women Vietnam Veterans Health Study VA/EPA TCDD Assay ao_seriesIII