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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War GULF WAR and HEALTH VOLUME 8 Update of Health Effects of Serving in the Gulf War Committee on Gulf War and Health: Health Effects of Serving in the Gulf War, Update 2009 Board on the Health of Select Populations INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract No. V101 (93) P-2136, TO 101-E8709(17) between the National Academy of Sciences and Department of Veterans Affairs. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-14921-1 International Standard Book Number-10: 0-309-14921-5 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2010 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2010. Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press.
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Advising the Nation. Improving Health.
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War COMMITTEE ON GULF WAR AND HEALTH: HEALTH EFFECTS OF SERVING IN THE GULF WAR, UPDATE 2009 STEPHEN L. HAUSER (Chair), Professor and Chair of Neurology, University of California, San Francisco, School of Medicine ALVARO ALONSO, Assistant Professor, Division of Epidemiology and Community Health, School of Public Health, University of Minnesota ROBERT H. BROWN, JR., Chair and Professor of Neurology, University of Massachusetts School of Medicine DOUGLAS A. DROSSMAN, Co-director, University of North Carolina Center for Functional GI and Motility Disorder, and Professor of Medicine and Psychiatry, University of North Carolina School of Medicine W. DANA FLANDERS, Professor of Epidemiology, Biostatistics and Bioinformatics, Emory University Rollins School of Public Health MATTHEW C. KEIFER, Co-director, Pacific Northwest Agricultural Safety and Health Center, and Professor of Occupational Medicine, University of Washington Harborview Medical Center FRANCINE LADEN, Associate Professor of Environmental Epidemiology, Harvard School of Public Health, and Assistant Professor of Medicine, Channing Laboratory, Brigham & Women’s Hospital JENNIFER D. PECK, Assistant Professor of Epidemiology, University of Oklahoma Health Sciences Center BEATE R. RITZ, Professor, Department of Epidemiology, Department of Environmental Health Sciences, and Vice Chair, Department of Epidemiology at the University of California, Los Angeles, School of Public Health REBECCA P. SMITH, Assistant Clinical Professor, Department of Psychiatry, Mount Sinai Hospital and School of Medicine EZRA S. SUSSER, Professor of Epidemiology, Mailman School of Public Health and Professor of Psychiatry, College of Physicians and Surgeons at Columbia University CHRISTINA M. WOLFSON, Director, Division of Clinical Epidemiology, McGill University Health Centre, and Professor, Department of Epidemiology and Biostatistics and Occupational Health, Department of Medicine, McGill University
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War STUDY STAFF ROBERTA WEDGE, Study Director RENEE WLODARCZYK, Senior Program Associate PATRICK BAUR, Research Associate JOSEPH GOODMAN, Senior Program Assistant CHRISTIE BELL, Financial Officer FREDRICK ERDTMANN, Director, Board on the Health of Select Populations
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War REVIEWERS This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s (NRC’s) Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Alberto Ascherio, Department of Epidemiology, Harvard University School of Public Health Floyd E. Bloom, Department of Molecular and Integrative Neuroscience, The Scripps Research Institute Gregory L. Burke, Division of Public Health Sciences, Wake Forest University School of Medicine Edward V. Loftus, Jr., Division of Gastroenterology and Hepatology, Mayo Clinic Anne Louise Oaklander, Center for Shingles and Postherpetic Neuralgia, Massachusetts General Hospital Robert D. Sparks, California Medical Association Foundation Carol A. Tamminga, Department of Psychiatry, The University of Texas Southwestern Medical Center Nancy Fugate Woods, University of Washington School of Nursing Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of the report was overseen by Harold C. Sox, American College of Physicians of Internal Medicine. Appointed by the NRC and the Institute of Medicine, he was responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the report rests entirely with the author committee and the institution.
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War PREFACE In war, there are no unwounded soldiers. —José Narosky The committee began its task with a sense of deep obligation to the servicemen and women who fought so bravely on our behalf in the Gulf War theater. Our appreciation of the risks, privations, and sacrifices that these courageous servicemembers undertook only deepened as our knowledge of the combat mission increased during the course of the committee’s meetings. There is no greater service that a human being can provide to one’s fellow citizens than to risk life and health on their behalf. We are honored to dedicate this report to these troops. As scientists and clinicians, the committee members are also aware of our responsibilities not only to those who served in the Gulf War coalition but also to the cause of science and evidence-based medicine. Only by being true to the latter do we serve the former. There is no doubt that many of the veterans deployed to the gulf region during 1990-1991 have continued to experience troubling constellations of symptoms involving multiple body systems; these have been variously termed multisymptom illness or Gulf War illness, and as such are emblazoned in the public’s mind as a consequence of military service in this battleground. Many other veterans have not experienced the full array of Gulf War illness symptoms but continue to suffer from seemingly related symptoms, including persistent fatigue, chronic fatigue syndrome, irritable bowel syndrome, memory problems, headache, bodily pains, disturbances of sleep, as well as other physical and emotional problems. Many of these symptoms are difficult to categorize as they have no known cause, no objective findings on clinical examination, no diagnostic biomarkers, no known tissue pathology, and no curative therapy. The inadequate basic understanding of the root cause of these symptoms highlights the limitations of current medical science and clinical practice. The committee recognizes that symptoms that cannot be easily quantified are sometimes dismissed—incorrectly—as insignificant, and that they receive inadequate attention—and funding—by the medical and scientific establishment. For example, chronic pain is experienced by 81 million people in the United States alone, yet funding to understand the biology of pain is woefully inadequate, clinical care pathways for individuals suffering from pain are underdeveloped, and training in pain medicine for clinicians lags behind the training for far less common maladies. Many of the complaints experienced by Gulf War veterans, veterans who arrived in the Gulf War theater after the hostilities ended, and nondeployed veterans, are also seen in the general population. It is beyond dispute, however, that the prevalence of symptoms such as headaches, joint pain, and difficulty concentrating is higher in veterans deployed to the Gulf War theater than the others.
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War During the past decade two groups, the Institute of Medicine (IOM) and the congressionally mandated Research Advisory Committee on Gulf War Veterans’ Illnesses (RAC) have been charged with evaluating the health of and research on Gulf War veterans. In the 2006 IOM report Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War, the authoring committee concluded that although Gulf War veterans reported higher levels of symptoms that might be associated with exposures in the field, no associations with any specific exposures could be identified. In contrast, a report issued by the RAC in November 2008 concluded that Gulf War illness resulted from exposure to pyridostigmine bromide, pesticides, and possibly other exposures. Although not formally charged with investigating evidence that exposure to specific environmental hazards may have been associated with multisymptom illness, this committee was asked by General Shinseki, Secretary of the Department of Veterans Affairs, to comment on it and did so in an appendix. To ignore this question would not serve the larger purpose of our inquiry. We conclude that current evidence is inadequate to determine whether an association exists between multisymptom illness and any specific battlefield exposure or exposures. Veterans who continue to suffer from these discouraging symptoms deserve the very best that modern science and medicine can offer to delineate the true underlying cause of these symptoms in order to speed the development of effective treatments, cures, and, it is hoped, preventions. The committee suggests a path forward to accomplish these goals and we believe that, through a concerted national effort and rigorous scientific input, answers can likely be found. The committee would like to thank the many Gulf War veterans who spoke with us about their experiences in the gulf and upon their return to the United States. They provided valuable insights into the symptoms and medical conditions that have been the legacy of the Gulf War for many of the men and women who served in the military. The committee also appreciated hearing from representatives from the Department of Veterans Affairs about the facilities and programs available to Gulf War veterans and from representatives of the RAC who presented the findings of that committee and answered this committee’s questions. And finally, the committee would like to thank the IOM staff—Patrick Baur, Joseph Goodman, Renee Wlodarczyk—who assisted in this effort. In particular, we thank Roberta Wedge, who guided the entire process with flexibility, provided many invaluable insights, and displayed a sure hand at every step along our path. Stephen L. Hauser (Chair) Committee on Gulf War and Health: Health Effects of Serving in the Gulf War, Update 2009
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War CONTENTS PREFACE ix ACRONYMS xvii SUMMARY 1 Charge to the Committee 2 Committee’s Approach 2 Volume 4 Conclusions 3 Considerations in Identifying and Evaluating the Literature 4 Primary and Secondary Studies 4 Categories of Association 5 Major Cohort Studies 6 Health Outcomes 6 Quality of the Studies 7 Recommendations 9 1 INTRODUCTION 11 Background 11 The Gulf War Setting 12 Deployment 13 Living Conditions 13 Environmental and Chemical Exposures 13 Threat of Chemical and Biologic Warfare 14 Charge to the Committee 15 Committee’s Approach to Its Charge 16 Complexities in Resolving Gulf War and Health Issues 17 Multiple Exposures and Chemical Interactions 17 Limitations of Exposure Information 17 Individual Variability 18 Volume 4 Conclusions 18 Organization of the Report 20 References 20 2 CONSIDERATIONS IN IDENTIFYING AND EVALUATING THE LITERATURE 23 Identification of the Literature 23 Types of Evidence 25 Epidemiologic Studies 25 Associations in Epidemiologic Studies 25 Inferring Causality 27 Types of Epidemiologic Studies 28 Cohort Studies 28 Case-Control Studies 29 Cross-Sectional Studies 30
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War Standardized Mortality Studies 31 Inclusion Criteria 31 Methodologic Rigor 32 Exposure Assessment 32 Health Outcome Assessment 32 Considerations in Assessing the Strength of Evidence 33 Categories of Association 33 Additional Considerations 35 Bias 35 Confounding 35 Sampling Error 35 Multiple Comparisons 36 Limitations of Gulf War Veteran Studies 36 References 36 3 MAJOR COHORT STUDIES 39 General Limitations of Gulf War Cohort Studies and Derivative Studies 39 Organization of this Chapter 41 Department of Veterans Affairs Study 45 The Iowa Persian Gulf Study 49 United Kingdom Veteran Studies 51 Australian Veteran Studies 54 Danish Peacekeeper Studies 56 Oregon and Washington Veteran Studies 57 Canadian Gulf War Veterans Study 58 Kansas Veteran Study 58 Fort Devens and New Orleans Cohort Studies 59 Seabee Studies 60 Pennsylvania Air National Guard Study 62 Hawaii and Pennsylvania Active Duty and Reserve Study 62 New Orleans Reservist Studies 63 References 63 4 HEALTH OUTCOMES 71 Organization of the Chapter 71 Cancer 73 Summary of Volume 4 73 Updated and Supplemental Literature 75 Summary and Conclusions 78 Diseases of the Blood and Blood-Forming Organs 83 Updated and Supplemental Literature 83 Summary and Conclusions 85 Endocrine, Nutritional, and Metabolic Diseases 89 Diabetes 89 Thyroid Disease 91 Obesity 92 Hospitalization Studies 93
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War Mortality Studies 95 Summary and Conclusions 95 Mental and Behavioral Disorders 99 Summary of Volume 4 101 Updated and Supplemental Literature 105 Summary and Conclusion 108 Neurocognitive and Neurobehavioral Outcomes 115 Summary of Volume 4 115 Updated and Supplemental Literature 116 Summary and Conclusions 118 Diseases of the Nervous System 121 Peripheral Neuropathy and Myopathy 121 Multiple Sclerosis 124 Amyotrophic Lateral Sclerosis 126 Other Neurodegenerative Diseases 129 Other Neurological Outcomes 130 Diseases of the Circulatory System 135 Summary of Volume 4 135 Updated and Supplemental Literature 136 Summary and Conclusions 140 Diseases of the Respiratory System 145 Summary of Volume 4 145 Updated and Supplemental Literature 147 Summary and Conclusions 149 Diseases of the Digestive System 154 Summary of Volume 4 155 Updated and Supplemental Epidemiologic Literature 156 Summary and Conclusions 159 Skin Diseases 164 Summary of Volume 4 164 Updated and Supplemental Literature 165 Summary and Conclusions 167 Diseases of the Musculoskeletal System 169 Summary of Volume 4 169 Updated and Supplemental Literature 170 Summary and Conclusion 171 Fibromyalgia and Chronic Widespread Pain 175 Summary of Volume 4 175 Updated and Supplemental Literature 176 Summary and Conclusion 178 Diseases of the Genitourinary System 180 Genitourinary Outcomes 180 Hospitalization for Genitourinary System Diseases 183 Summary and Conclusions 184 Adverse Reproductive and Perinatal Outcomes 189 Birth Defects 189
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War Adverse Pregnancy Outcomes 193 Fertility 195 Sexual Dysfunction 198 Multisymptom Illnesses 204 Factor Analyses and Surveys 204 Hospitalization Studies 207 Other Reports 208 Summary and Conclusions 210 Chronic Fatigue Syndrome 210 External Causes of Mortality 221 Summary of Volume 4 221 Updated and Supplemental Literature 222 Summary and Conclusions 224 Female Veterans’ Health 228 Deployment Experiences 228 Health Effects 229 Mental Health Effects 231 Military Sexual Assault and Harassment 232 Hospitalization and Mortality 233 Summary and Conclusions 234 References 235 5 CONCLUSIONS AND RECOMMENDATIONS 255 Quality of the Studies 258 Possible Causes of Multisymptom Illness in Veterans 259 The Path Forward 260 APPENDIX A CHOLINESTERASE INHIBITORS AND MULTISYMPTOM ILLNESSES 265 Exposures to Cholinesterase Inhibitors and Other Pesticides During the Gulf War 266 Pesticides 266 Long-Term Effects of Low Doses of Cholinesterase Inhibitors 270 Studies in Gulf War Populations 271 Animal Studies 275 Genetic Susceptibility to Cholinesterase Inhibitors 276 The Role of Cholinesterase Inhibitors and Pesticides in Multisymptom Illness 278 References 279 APPENDIX B COMMITTEE BIOGRAPHICAL SKETCHES 285 INDEX 289 Tables and Boxes TABLE 3-1 Reference and Derivative Studies for the Major Gulf War Cohorts 42 TABLE 4-1 Cancer 79 TABLE 4-2 Diseases of the Blood and Blood-Forming Organs 86 TABLE 4-3 Endocrine, Nutritional, and Metabolic Diseases 96 TABLE 4-4 Mental and Behavioral Disorders 110 TABLE 4-5 Neurobehavioral and Neurocognitive Outcomes 119
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War TABLE 4-6 Nervous System Diseases 132 TABLE 4-7 Circulatory System Diseases 141 TABLE 4-8 Respiratory System Diseases 150 TABLE 4-9 Digestive System Diseases 162 TABLE 4-10 Skin Diseases 168 TABLE 4-11 Musculoskeletal Diseases 172 TABLE 4-12 Fibromyalgia and Chronic Widespread Pain 179 TABLE 4-13 Diseases of the Genitourinary System 186 TABLE 4-14 Adverse Reproductive and Perinatal Outcomes 200 TABLE 4-15 Multisymptom Illnesses 215 TABLE 4-16 External Causes of Mortality 225 BOX S-1 Summary of Findings Regarding Associations Between Deployment to the Gulf War and Specific Health Outcomes 8 BOX 1-1 Brief Summary of Findings and Recommendations 19 BOX 4-1 CDC Case Definition of Chronic Fatigue Syndrome 212
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War ACRONYMS AChE acetylcholinesterase ACR American College of Rheumatology AFQT Armed Forces Qualifying Test ALS amyotrophic lateral sclerosis ANCOVA analysis of covariance BAI Beck Anxiety Inventory BDI Beck Depression Inventory BIRLS Beneficiary Identification Records Locator System BMI body mass index BSI Brief Symptom Inventory BuChE butyrylcholinesterase CAPS Clinician Administered PTSD Scale CCD Canadian Cancer Database CCEP Comprehensive Clinical Evaluation Program CDC Centers for Disease Control and Prevention CES Combat Exposure Scale CFS chronic fatigue syndrome CI confidence interval CIDI Composite International Diagnostic Interview CMD Canadian Mortality Database CMI chronic multisymptom illness CMV cytomegalovirus CNS central nervous system COD cause of death COSHPD California Office of Statewide Health Planning and Development CRP C-reactive protein CVLT California Verbal Learning Test CWP chronic widespread pain DASA Defence Analytical Services Agency (United Kingdom) DMDC Defense Manpower Data Center DNA deoxyribonucleic acid DND Department of National Defence (Canada) DoD Department of Defense DSM Diagnostic and Statistical Manual of Mental Disorders DSP distal symmetric polyneuropathy DU depleted uranium EBV Epstein-Barr virus EEG electroencephalography ESR erythrocyte sedimentation rate FARS Fatality Analysis Reporting System FEV1 forced expiratory volume in 1 second
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War FGID functional gastrointestinal disorder FSH follicle stimulating hormone FVC forced vital capacity GAD generalized anxiety disorder GAO Government Accountability Office GHQ-12 12-item General Health Questionnaire GI gastrointestinal GW Gulf War GWV Gulf War deployed veterans HIV human immunodeficiency virus HPA hypothalamic-pituitary-adrenal axis HR hazard ratio HSC Health Symptoms Checklist IBS irritable bowel syndrome ICD International Statistical Classification of Diseases and Related Health Problems IOM Institute of Medicine LH luteinizing hormone MANOVA multivariate analysis of variance MCH mean corpuscular hemoglobin MCS multiple chemical sensitivity MCV mean corpuscular volume MDD major depressive disorder MRR mortality rate ratio MS multiple sclerosis NART National Adults Reading Test NAS National Academy of Sciences NDI National Death Index NDV nondeployed veterans NIH National Institutes of Health NIS neuropathy impairment score NOAA National Oceanic and Atmospheric Administration NTE neuropathy target esterase ODTP Oregon Dual Task Procedure OPIDP organophosphate-induced delayed polyneuropathy OR odds ratio PASAT Paced Auditory Serial Addition Test PB pyridostigmine bromide PCL patient checklist PCL-C Patient Checklist-Civilian PCL-M Patient Checklist-Military PFT pulmonary function test PHQ Patient Health Questionnaire PIR proportional incidence ratio PMR proportional morbidity ratio PON1 paraoxonase-1 POW prisoner of war
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War PR prevalence ratio PRIME-MD Primary Care Evaluation of Mental Disorders PTSD posttraumatic stress disorder QoLI quality of life index RAC VA Research Advisory Committee on Gulf War Veterans’ Illnesses RoM ratio of means RR relative risk (or risk ratio as indicated in text) SCAN Schedule for Clinical Assessment and Diagnosis SCID Structured Clinical Interview for DSM-III-R Sd standard deviation SF-12 12-Item Short Form Health Survey SF-36 36-Item Short Form Health Survey SMR standardized mortality ratio SNAP Schedule for Nonadaptive and Adaptive Personality SSA Social Security Administration TBI traumatic brain injury TOMM Test of Memory Malingering UK United Kingdom VA Department of Veterans Affairs WAIS Wechsler Adult Intelligence Scale WCST Wisconsin Card Sorting Test WHO World Health Organization WMS Wechsler Memory Scale
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