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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 4 MAJOR COHORT STUDIES This chapter provides an overview of many of the major cohort studies of Gulf War veterans, discusses the general limitations of the studies, and summarizes the findings from each. Some of the cohorts were brought together in the first few years after the Gulf War; others were assembled more recently. Most of the studies compare sizable groups of deployed veterans with groups of nondeployed veterans or with veterans who were deployed to locations other than the Persian Gulf (for example, Bosnia). The major cohort studies are important for understanding the health of Gulf War veterans; those studies’ findings, on particular health outcomes, are evaluated thoroughly in Chapter 5 along with additional studies’ findings on smaller samples of Gulf War veterans. The largest studies of Gulf War veterans have been conducted in countries that were members of the Gulf War coalition including: the United States, Canada, Denmark, Australia, and the United Kingdom. Most major cohort studies address several fundamental questions about Gulf War veterans’ health: What are the nature and prevalence of veterans’ symptoms and diagnoses? Do symptoms that do not fit conventional medical diagnoses, and are therefore unexplained, warrant classification as a new syndrome? Are exposures to specific biologic, chemical, and radiologic agents during the Gulf War associated with veterans’ symptoms and illnesses? Those questions are designed to guide the reader through a complex body of research. Most major cohorts, once established, led to numerous studies that examined more detailed questions about Gulf War veterans’ health; the committee refers to those studies as derivatives. Table 4.1, at the end of this chapter, provides information about each original cohort—for example, method of assembly, the eligible population, the specific study methods, the study population, and the percentage of subjects who were enrolled—and includes the derivative studies. The table lists a derivative study under the original cohort from which it drew its study population and provides additional information, including its purpose, design, enrollment of its subjects, sample size, response rates,1 and other cohort characteristics. The table was vital in guiding the committee through its analysis and evaluation of the studies discussed in Chapter 5. The information helped the committee to identify the populations that have been studied and enabled the committee to understand which studies were independent of each other; 1 Table 4.1 contains the figures given in each study publication, except response rates. For uniformity, the committee calculated response rates with this formula: response rate = number of study participants who responded divided by the number of people who were located (rather than the number of eligible people).
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 that is important because the committee did not want to factor in the health outcomes occurring in the same people repeatedly. GENERAL LIMITATIONS OF GULF WAR COHORT STUDIES AND DERIVATIVE STUDIES The 24 major cohort studies of Gulf War veterans and their derivative studies have contributed greatly to our understanding of veterans’ health, but they are beset by limitations that are commonly encountered in epidemiologic studies, including lack of representativeness, selection bias, lack of control for potential confounding factors, self-reports of health outcomes, outcome misclassification, and self-reports of exposure. The committee members read each study carefully and noted the findings and limitations of each study. The foremost limitation is lack of representativeness, which limits one’s ability to generalize results to the entire population of interest; for example, about half the cohorts focus on groups of veterans that are selected for study according to where they served in the military (a military-unit-based study). Military-unit studies are not representative of all Gulf War veterans with respect to their duties and location during deployment, their military status during the war (active duty, reserves, or National Guard), their military status after the war (active duty, reserves, or discharged), their branch of service (Army, Navy, Air Force, or Marines), or ease of ascertainment (IOM 1999b). The most representative studies are population-based: the cohorts are selected on the basis of where their members reside. In population-based studies of Gulf War veterans, the cohort might be the entire deployed population, as in studies of Canadian and Australian veterans, or a random selection from the population of interest, as in several studies of US and British veterans. The committee, in evaluating major cohort studies, gave greater weight to Gulf War studies that were population-based. A study’s representativeness, even if it is population-based, can be compromised by low participation rates. Low participation rates can introduce selection bias, for example, when Gulf War veterans who are symptomatic choose to participate more frequently than those who are not symptomatic. Nondeployed veterans, who might be healthier, might be less inclined to participate. In some studies, researchers not only try to measure selection bias by comparing participants with nonparticipants from both deployed and nondeployed populations, but also make adjustments to overcome it, for example, by oversampling nondeployed populations as in the study by Eisen and colleagues (2005). Selection bias might also occur through the so-called healthy-warrior effect. That form of bias has the potential to occur in most of the major cohorts that compare deployed veterans with nondeployed personnel. The healthy-warrior effect is a form of selection bias insofar as chronically ill or less fit members of the armed forces might be less likely to have been deployed than more fit members. That is, there might have been nonrandom assignment of those selected and not selected for deployment. Some of the best studies attempt to measure the potential for selection bias and adjust for it in the analysis. A recurrent limitation is that most cohort studies rely on self-reporting of symptoms on questionnaires. Symptom self-reporting potentially introduces reporting bias, which occurs when the group being studied (such as deployed veterans) reports more frequently what it remembers than a comparison group (such as nondeployed veterans). Reporting bias, in this example, would lead to an overestimation of the prevalence of symptoms or diagnoses in the deployed population.
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 Symptom self-reporting might sometimes introduce another type of bias known as outcome misclassification, in which there are errors in how symptoms are classified into outcomes and analyzed. One Gulf War study sought to document outcome misclassification by comparing veterans’ symptom reporting on questionnaires with clinical examination about 3 months later (McCauley et al. 1999b). The study found that the extent of misclassification depended on the type of symptom being reported; agreement between questionnaire and clinical examination ranged from 4-79%. The overall problem led the investigators to caution that questionnaire data, in the absence of clinical evaluation or adjustment, might lead to outcome misclassification. Another study also found poor reliability and validity of self-reported diagnoses when compared with medical records (Gray et al. 1999a). In contrast, a study by the Department of Veterans Affairs (VA) (Kang et al. 2000), which verified a random subset of self-reported conditions (n = 4,200) against medical records, found a strong correlation between the two (above 93%). Those data, however, were available only for the 45.2% who signed consent forms that allowed researchers to verify records. The problem of symptom self-reporting is best addressed through medical evaluations, as was done by VA researchers (e.g., Eisen et al. 2005) and by several other investigators with the resources to conduct medical evaluations. Nevertheless, medical evaluations do not surmount the problem that some outcome measures being studied, such as chronic fatigue syndrome (CFS), are symptom-based syndromes that by definition lack a biologic “gold standard” with which symptoms can be validated. The lack of a diagnostic gold standard or other objective biologic markers poses a particular problem for veterans with fibromyalgia, CFS, and multiple chemical sensitivity (MCS) (IOM 1999a). Another limitation of most major cohort studies is self-reporting of exposures. Self-reporting of exposures, like self-reporting of symptoms, introduces the possibility of recall bias, the tendency for participants who are symptomatic to overestimate (or underestimate) their exposures compared with those who are not symptomatic. Indeed, a major study from the UK found that Gulf War veterans with more symptoms were likely to report more exposures than those not deployed to the gulf (Unwin et al. 1999). Other complicating factors are exposures often cannot be validated by objective means, often occurred years earlier, and might have been perceived rather than actual. For example, because of the sensitivity of the chemical-warfare monitors, many false alarms might have been perceived by veterans as actual exposures. Enhanced recordkeeping and monitoring of the environment during and after the Gulf War would have averted that problem. Indeed, many expert panels have recommended efforts to improve recordkeeping and environmental monitoring in future deployments (e.g., IOM 1999b; NRC 2000a; NRC 2000b; NRC 2000c). Other limitations of the body of evidence are that studies might be too narrow in their assessment of health status, the measurement instruments might have been too insensitive to detect abnormalities that affect deployed veterans, and the period of investigation has been too brief to detect health outcomes that have a long latency or require many years to progress to the point where disability, hospitalization, or death occurs. Virtually all US studies are cross-sectional, and this limits the opportunity to learn about symptom duration and chronicity, latency of onset (especially for health conditions with a long latency, such as cancer), and prognosis.
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 ORGANIZATION OF THIS CHAPTER This chapter organizes numerous major cohort studies by a key feature of study design—how the cohort was assembled. Roughly half the chapter covers cohorts that are population-based, and the rest includes cohorts that are military-unit based. For each major cohort, we use a uniform format. The cohort methods and major findings regarding symptoms and diagnoses are described first. Then we turn to how symptoms, if unexplained, cluster together (under the heading “Symptom Clustering”). The next section reviews findings of the medical evaluation, if one was conducted. The final section describes what symptom-exposure relationships were found. This chapter does not cover studies whose sample population is drawn from any of the Gulf War registries, because they lack comparison groups. Registries have been set up in the United States, by the Department of Defense (DOD) and VA, and in the UK by the Ministry of Defence for UK Gulf War. Registries are self-selected case series of veterans who presented for care, so they cannot be and were not intended to be representative of the symptoms and diagnoses of the entire group of Gulf War veterans. Nor were registries designed with control groups or with diagnostic standardization across the multiple sites at which examinations took place (Joseph 1997; Roy et al. 1998). Finally, registries relied on standard diagnostic classifications and were not designed to probe for novel diagnoses2 or to search for biologic correlates. Thus, because of their methodologic limitations, registry studies cannot stand alone as a basis of conclusions or of the conduct of research. But they do provide a glimpse into veterans’ symptoms and the difficulties of fitting those symptoms into standard diagnoses. Registry programs have been a valuable source of information for generating hypotheses that have been tested in rigorous epidemiologic studies with control groups to estimate the health status of Gulf War veterans. POPULATION-BASED STUDIES The Iowa Study The “Iowa study”, a major population-based study of US Gulf War veterans, was a cross-sectional survey of a representative sample of 4,886 military personnel who listed Iowa as their home of record at the time of enlistment (Iowa Persian Gulf Study Group 1997). The study examined the health of military personnel in all branches of service who were still serving or had left service. The sample was randomly selected from and representative of 28,968 military personnel. Of the study subjects who were contacted, 3,695 (90.7%) completed a telephone interview. Study subjects were divided into four groups: Gulf War-deployed regular military, Gulf War-deployed National Guard or Reserve, non-Gulf War-deployed regular military, and non-Gulf War-deployed National Guard or Reserve. Trained examiners using standardized questions, instruments, and scales interviewed the subjects.3 When compared with the groups not 2 Registries rely on the ICD-9-CM (Joseph 1997; Murphy et al. 1999). 3 Sources of questions included the National Health Interview Survey, the Behavioral Risk Factor Surveillance Survey, the National Medical Expenditures Survey, the Primary Care Evaluation of Mental Disorders, the Brief Symptom Inventory, the CAGE questionnaire (for alcoholism), the PTSD (Posttraumatic Stress Disorder)
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 deployed to the Persian Gulf, the two groups of Gulf War military personnel reported roughly twice the prevalence of symptoms suggestive of fibromyalgia, cognitive dysfunction, depression, alcohol abuse, asthma, posttraumatic stress disorder (PTSD), sexual discomfort, and chronic fatigue.4 In a separate analysis, the prevalence of MCS symptoms was about twice the prevalence in the comparison population (Black et al. 2000). Furthermore, in the main cohort study, which used a standardized instrument for assessing functioning (the Medical Outcome Study’s 36-item questionnaire known as the Short Form-36, or SF-36), Gulf War veterans displayed significantly lower scores on all eight subscales for physical and mental health. The subscales profile aspects of quality of life. The subscales for bodily pain, general health, and vitality showed the greatest absolute differences between deployed and nondeployed veterans. In short, this large, well-controlled study demonstrated that some sets of symptoms were more frequent and quality of life poorer among Gulf War veterans than among nondeployed military controls. Symptom Clustering The Iowa study was the first major population-based study to group sets of symptoms into categories suggestive of known syndromes or disorders, such as fibromyalgia or depression. Its finding of considerably higher prevalence of symptom groups suggestive of fibromyalgia, depression, and cognitive dysfunction among Gulf War veterans motivated other researchers to examine, through factor analysis, the potential for a new syndrome that would group and classify veterans’ symptoms. Several years later, the Iowa investigators performed a factor analysis on their cohort (Doebbeling et al. 2000). They identified three symptom factors in deployed veterans—somatic distress, psychologic distress, and panic—but the factors were not exclusive to deployed veterans. Thus, the study did not support the existence of a new syndrome (see Chapter 3 for a discussion of factor analysis). Exposure-Symptom Relationships The Iowa study assessed exposure-symptom relationships by asking veterans to report on their exposures in the Gulf War. Researchers found that many of the self-reported exposures were significantly associated with health conditions. For example, symptoms of cognitive dysfunction were found to have been associated with self-reports of exposure to solvents or petrochemicals, smoke or combustion products, lead from fuels, pesticides, ionizing or nonionizing radiation, chemical-warfare agents, use of pyridostigmine bromide (PB), infectious agents, and physical trauma. A similar set of exposures were associated with symptoms of depression or fibromyalgia. The study concluded that no exposure to any single agent was related to the conditions that the authors found to be more prevalent in Gulf War veterans (Iowa Persian Gulf Study Group 1997). Women’s Health The Gulf War was among the first wars to see a sizable fraction of women in the military. About 7% of military personnel serving in the Persian Gulf were women (Joseph 1997). The Iowa study was one of the few population-based US studies that investigated the health of Checklist—Military, the Centers for Disease Control and Prevention Chronic Fatigue Syndrome Questionnaire, the Chalder Fatigue Scale, the American Thoracic Society questionnaire, and the Sickness Impact Profile. 4 The conditions listed were not diagnosed, because no clinical examinations were performed. Rather, before conducting their telephone survey, researchers grouped sets of symptoms from their symptom checklists into a priori categories of diseases or disorders. After a veteran identified himself or herself as having the requisite set of symptoms, researchers analyzing responses considered the veteran as having symptoms “suggestive” of or consistent with a particular disorder but not as having a formal diagnosis of the disorder.
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 women separately (Carney et al. 2003). Women were less likely to participate in combat than men, but 71% of women had at least one combat exposure. Women also reported similar rates of exposure to environmental agents, such as diesel fuel and smoke from oil-well fires. Their patterns of health-care use varied from that of men: they had significantly more outpatient, as well as inpatient, health care 5 years after the war. They were also more likely than men to receive VA compensation (17% vs 7%), although their level of disability was similar. Department of Veterans Affairs Study A major population-based study of US veterans was mandated by Public Law 103-446. The study is a retrospective cohort design conducted by VA. Its purpose is to estimate the prevalence of symptoms and other health outcomes (including reproductive outcomes in spouses and birth defects in children) in Gulf War veterans vs non-Gulf War veterans. This population-based survey had three phases. In the first, a questionnaire was mailed to 30,000 veterans. The second phase validated self-reported data with medical-record review and analyzed characteristics of those who did not respond to the mailed survey. The third phase was a comprehensive medical examination and laboratory testing of a random sample of 2,000 veterans drawn from the Gulf War population and a comparison group. The study was designed to be representative of the nearly 700,000 US veterans sent to the Persian Gulf and 800,680 non-Gulf War veterans of the same era. Questionnaires were mailed to a stratified random sample of 15,000 Gulf War and 15,000 non-Gulf War veterans identified by DOD and representing various units and branches of the military. The questionnaires contained a list of 48 symptoms and questions about chronic medical conditions, functional limitations, and other items from the National Health Interview Survey. A questionnaire about exposures was also included. The overall response rate was about 70%. Survey Findings (Phases I and II) The investigation found significantly higher symptom prevalence of all 48 symptoms among Gulf War veterans (Kang et al. 2000). Four of the most frequently reported symptoms were runny nose, headache, unrefreshing sleep, and anxiety (Table 4.2). Numerous chronic medical conditions—such as sinusitis, gastritis, and dermatitis—were reported more frequently among Gulf War veterans; many were reported twice as often. Ten symptoms and 12 medical conditions were remarkably similar in prevalence to those in a UK cohort (Unwin et al. 1999). Gulf War veterans reported significantly higher rates of functional impairment (27.8% vs 14.2%), limitations of employment (17.2% vs 11.6%), and health-care use as assessed by clinic visits (50.8% vs 40.5%) or hospitalizations (7.8% vs 6.4%) compared with nondeployed veterans. In a randomly selected subset of veterans, medical-record reviews verified more than 90% of self-reported reasons for clinic visits or hospitalizations. A separate analysis of the VA cohort found that 10% of them, compared with 4% of controls, met symptom-based criteria for PTSD, and 4.9% (vs 1.2%) met symptom-based criteria for CFS (Kang et al. 2003). Symptom Clustering The VA study searched for potentially new syndromes through factor analysis. A separate article by Kang and colleagues (2002) found that 47 symptoms reported by veterans yielded six factors, only one of which contained a cluster of neurologic symptoms that did not load on any factors in the non-Gulf War deployed veterans. The symptoms in the cluster were loss of balance or dizziness, speech difficulty, blurred vision, and tremors or shaking. A group of
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 277 deployed veterans (2.4%) vs 43 nondeployed veterans (0.45%) met a case definition subsuming all four symptoms. The authors interpreted their findings as suggesting a possible unique neurologic syndrome related to Gulf War deployment that requires objective supporting clinical evidence. TABLE 4.2 Results of VA Study Most Common Self-Reported Symptomsa Prevalence in Gulf War Veterans (%) Prevalence in Non-Gulf War Veterans (%) Runny nose 56 43 Headache 54 37 Unrefreshing sleep 47 24 Anxiety 45 28 Joint pain 45 27 Back pain 44 30 Fatigue 38 15 Ringing in ears 37 23 Heartburn 37 25 Difficulty in sleeping 37 21 Depression 36 22 Difficulty in concentrating 35 13 5 Most Common Self-Reported Chronic Medical Conditionsa Prevalence in Guld War Veterans (%) Prevalence in Non-Gulf War Veterans (%) Sinusitis 38.6 28.1 Gastritis 25.2 11.7 Dermatitis 25.1 12.0 Arthritis 22.5 16.7 Frequent diarrhea 21.2 5.9 a Subjects were asked whether symptoms were recurring or persistent during previous 12 months. Differences in prevalence are all statistically significant (p < 0.05). SOURCE: Kang et al. 2000. Exposure-Symptom Relationships A nested case-control analysis (see Chapter 3) was performed on those who met the case definition for the possible neurologic syndrome to determine which of 23 self-reported exposures were more common among cases than among controls (not deployed to the Gulf War) (Kang et al. 2002). Exposures to a variety of chemical agents were reported to be higher among cases than controls; the exposures noted were to chemical-agent-resistant compound paint, depleted uranium, nerve gas, food contaminated with oil or smoke, and bathing in or drinking water contaminated with oil or smoke. Dose-response relationships were not studied because of the nature of the dataset regarding self-reported exposure. Another cohort study (Kang et al. 2000) did not assess exposure-symptom relationships. It reported on exposures only by compiling the percentages of veterans who reported each of 23 environmental exposures and nine vaccine or prophylactic exposures (such as to PB). The five most common environmental exposures reported by more than 60% of survey participants were
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 to diesel, kerosene, or other petrochemical fumes; to local food other than that provided by the armed forces; to chemical protective gear; to smoke from oil-well fires; and to burning trash or feces. Medical Evaluation Findings (Phase III) Three studies have reported on physical examinations of a subsample of the cohort that assayed for general medical status (Eisen et al. 2005), distal symmetric polyneuropathy (Davis et al. 2004), and pulmonary function (Karlinsky et al. 2004). The examinations were conducted in 2001, about 10 years after the Gulf War. Eisen and colleagues (2005) examined 12 primary health outcome-measures and physical functioning on SF-36. Outcome measures were chosen by the authors to cover the most common symptoms reported by veterans, such as musculoskeletal pain, fatigue, rashes, and neuropathy (as noted in Kang et al 2000). The study evaluated 1,061 Gulf War and 1,128 non-Gulf War veterans who had been randomly selected from 11,441 Gulf War-deployed and 9,476 non-Gulf War-deployed veterans who previously had participated in a 1995 questionnaire survey (Kang et al. 2000). Researchers were blind to deployment status. Despite three waves of recruitment into the study, the participation rate in the 2005 study was low: only 60.9% of Gulf War veterans and 46.2% of non-Gulf War veterans participated. To determine nonparticipation bias, the study authors obtained previously collected findings from participants and nonparticipants from the DOD Manpower Data Center and gathered sociodemographic and self-reported health findings from the 1995 VA study (Kang et al. 2000). Four of 12 conditions were more prevalent among GW veterans: fibromyalgia (2.0% vs 1.2%; odds ratio [OR] 2.32, 95% confidence interval [CI] 1.02-5.27), CFS (1.6% vs 0.1%; OR 40.6, 95% CI 10.2-161.15), dermatologic conditions (34.6% vs 26.8 %; OR 1.38, 95% CI 1.06-1.80), and dyspepsia (9.1% vs 6.0%; OR 1.87, 95% CI 1.16-2.99). Fibromyalgia was diagnosed according to the 1990 criteria developed by the American College of Rheumatology (Wolfe et al. 1990). CFS was diagnosed according to the case definition developed by the International Chronic Fatigue Syndrome Study Group (Fukuda et al. 1994). The rate of CFS in the nondeployed veterans was similar to that of the US population. For dermatologic diagnoses, the study created two categories, one of which had a higher OR (see discussion in Chapter 5). A dyspepsia diagnosis required a history or symptoms of frequent heartburn and recurrent abdominal pain, and the use of antacids or other medications. Gulf War veterans reported worse physical health on the SF-36 (49.3 vs 50.8; p < 0.001), but the magnitude of the difference, although statistically significant, was not clinically significant. The analyses adjusted for age, sex, race, years of education, cigarette smoking history, duty type (active vs reserves or National Guard), service branch (Army or Marines vs Navy or Air Force), and rank (enlisted vs officer). The limitations of the study were its performance 10 years after the 1991 Gulf War, which precludes diagnoses that have already resolved, and low participation rates (60.9% Gulf War and 46.2% non-Gulf War), which introduce the possibility of participation bias. In the study by Davis et al. (2004), the presence of distal symmetric polyneuropathy was evaluated with a history, physical examination, and standardized electrophysiologic assessment of motor and sensory nerves in 1,061 deployed veterans and 1,128 nondeployed veterans. Spouses of deployed and nondeployed veterans were also used as controls. A population of 244
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 Khamisiyah-exposed deployed veterans was also tested. Blood studies were performed to rule out metabolic causes of neuropathy. The diagnosis of peripheral neuropathy was defined as a distal sensory or motor neuropathy identified on the basis of the neurologic examination, nerve conduction study, or both. No difference in adjusted population prevalence of distal symmetric polyneuropathy between deployed and nondeployed veterans was found with electrophysiology (3.7% vs 6.3%; p = 0.07), neurologic examination (3.1% vs 2.6%; p = 0.60), or the two methods combined (6.3% vs 7.3%; p = 0.47). The prevalence of distal symmetric polyneuropathy in the spouses of deployed and nondeployed veterans did not differ (2.7% vs 3.2 %; p = 0.64). Veterans exposed to the Khamisiyah ammunition-depot explosion did not differ significantly from nonexposed deployed veterans in prevalence of polyneuropathy. Karlinsky and colleagues (2004) reported results of pulmonary-function tests (PFTs) on the same VA population as Eisen and colleagues. PFT results were classified into five categories: normal pulmonary function, nonreversible airway obstruction, reversible airway obstruction, restrictive lung physiology, and small-airway obstruction. The pattern of PFT results was similar in deployed and nondeployed veterans, with no statistically significant differences. The pattern of PFT results was also reported to be similar in those exposed and not exposed (according to DOD exposure estimates developed in 2002) to nerve agents from destruction of munitions at the storage site at Khamisiyah in 1991. Prevalences of self-reported pulmonary symptoms were higher in deployed veterans; however, self-reported diagnoses, use of asthma medications, and self-reported physician visits and hospitalizations for pulmonary conditions were similar in deployed and nondeployed. Although no adjustments were made for covariates, demographic variables were similar in the two groups, and a history of tobacco-smoking was more common in deployed than in nondeployed (51.1% vs 44.4%; p = 0.03). Oregon and Washington Veteran Studies Veterans from Oregon or Washington were studied in a series of analyses by investigators of the Portland Environmental Hazards Research Center (McCauley et al. 1999b). A questionnaire was sent to a random sample (n = 2,343) of 8,603 Gulf War veterans who listed Oregon or Washington as their home state of record at the time of deployment, according to data provided by the DOD Manpower Data Center. The response rate was 48.4%. The study found high rates (21-60%) of self-reported symptoms, including cognitive-psychologic symptoms, unexplained fatigue, musculoskeletal pain, gastrointestinal complaints, and rashes. However, in the next phase of the study, the clinical-examination component, the first 225 participants displayed differences between the symptoms they reported on questionnaires and the symptoms they reported at clinical examination. The greatest differences were in rash or lesions (4% agreement between questionnaire and clinical examination), gastrointestinal complaints (20% agreement), and musculoskeletal pain (35% agreement). The authors interpreted those findings as suggesting the likelihood of outcome misclassification when self-administered questionnaires were relied on. Symptom Clustering Investigators studied clusters of unexplained symptoms by creating a new case definition for unexplained illness (Storzbach et al. 2000). Using questionnaire data, potential cases were identified as those reporting at least one of the following symptoms: musculoskeletal pain; cognitive-psychological changes, gastrointestinal complaints; skin or mucous membrane lesions; or unexplained fatigue. Veterans whose symptom clusters remained unexplained at clinical
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 examination (after exclusion of established diagnoses) were defined as constituting cases. Controls were those who at the time of clinical examination had no history of case-defining symptoms during or after their service in the Gulf War. In an analysis of the 241 cases vs 113 controls, investigators found, at medical evaluation, small but statistically significant deficits in cases on some neurobehavioral tests of memory, attention, and response speed. Cases also were significantly more likely to report increased distress and psychiatric symptoms (Storzbach et al. 2000). Finally, more than half the veterans with unexplained musculoskeletal pain met symptom-based criteria for fibromyalgia, and a large proportion met symptom-based criteria for CFS (Bourdette et al. 2001). Bourdette and colleagues also undertook a factor analysis, which yielded three symptom-based factors: cognitive-psychologic, mixed somatic, and musculoskeletal. These case-control studies and others from this cohort are reviewed further in Chapter 5. Exposure-Symptom Relationships Another nested case-control analysis of the population-based cohort examined exposures that might account for cases of unexplained illness (Spencer et al. 2001). The sample consisted of 241 veterans with unexplained illness and 113 healthy controls. In multivariate analysis, exposures most highly associated with unexplained illness were combat conditions, heat stress, and having sought medical attention during the Gulf War. Exposure to PB, insecticides and repellents, and stress was not statistically significantly associated with unexplained illness when multiple simultaneous exposures were controlled for. Those findings led investigators to conclude that unexplained illnesses were not associated with cholinesterase-inhibiting neurotoxic chemicals. One strength of this study was its elimination of numerous self-reported exposures (such as anthrax and botulinum toxoid vaccines) with questionable validity as determined by lack of test-retest reliability or time-dependent information (for example, chemical weapon exposure reported by precombat veterans or postcombat veterans who could not have been so exposed) (McCauley et al. 1999a). Kansas Veteran Study The state of Kansas established the Kansas Persian Gulf War Veterans Health Initiative to determine the patterns of veterans’ health problems in the state. Using lists of eligible veterans from DOD, Steele and colleagues (2000) conducted a population-based survey of veterans who listed Kansas as their home state of record. A stratified random sample of 3,138 was selected, from which 2,396 were located with instate contact information. The survey, mailed out in 1998, asked about 16 specific medical or psychiatric conditions, 37 symptoms, service branch, locations during the Gulf War (including whether the veterans were notified about the Khamisiyah demolitions), and vaccinations. Kansas Gulf War veterans, in comparison with Kansas nondeployed veterans, reported greater prevalence of 10 physician-diagnosed conditions: skin conditions, stomach or intestinal conditions, depression, arthritis, migraine headaches, CFS, bronchitis, PTSD, asthma, and thyroid condition. Using their own definition of Gulf War illness, which was similar to that used by the Centers for Disease Control and Prevention (CDC) (Fukuda et al. 1998), the investigators found that its prevalence was most associated with the period and location in the gulf in which veterans served. It was least prevalent in the period before the war, for example. Overall, the multisymptom illness was found in 34% of deployed, 12% of nondeployed who had received vaccines, and 4% of nondeployed who did not receive vaccines. The study concluded that excess morbidity is tied to characteristics of Gulf War service and that vaccine exposure might contribute to onset of multisymptom illness.
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 Canadian Veteran Study The findings of a 1997 survey (Goss Gilroy Inc. 1998)5 mailed to the entire cohort of Canadian Gulf War veterans were similar to those of the Iowa study. Respondents from Canada who had been deployed to the Gulf War (n = 3,113) were compared with respondents deployed elsewhere (n = 3,439) during the same period. Of the Gulf War veterans responding, 2,924 were male, 189 female. Deployed forces had higher rates of self-reported chronic conditions and symptoms of a variety of clinical outcomes than controls. Those outcomes and symptoms include chronic fatigue, cognitive dysfunction, MCS, major depression, PTSD, chronic dysphoria, anxiety, and respiratory diseases. The greatest differences between deployed and nondeployed forces were in the first three. The symptom grouping with the highest overall prevalence was cognitive dysfunction, which occurred in 34-40% of Gulf War veterans and 10-15% of control veterans. Gulf War veterans also reported significantly more visits to health-care practitioners, greater dissatisfaction with their health status, and greater health-related reductions in recent activity. Symptom Clustering The Canadian study did not search for potentially new syndromes. Exposure-Symptom Relationships In Canadian Gulf War veterans, the greatest number of symptom groupings was associated with self-reported exposures to psychologic stressors and physical trauma. Several symptom groupings also were associated with exposure to chemical-warfare agents, absence of routine immunizations, sources of infectious diseases, and ionizing or nonionizing radiation. Nevertheless, a subset of Canadian veterans who, because they were based at sea, could not have been exposed to many of the agents reported symptoms as frequently as did land-based veterans. United Kingdom Veteran Studies The UK sent over 53,000 personnel to the Gulf War. From the pool of veterans, two teams of researchers each studied a separate, nonoverlapping, stratified random sample of Gulf War veterans. The first team was from the University of London (Guy’s, King’s, and St. Thomas’s Medical Schools), the second team from the University of Manchester. A third team of researchers from the London School of Hygiene and Tropical Medicine surveyed the entire cohort of 53,000 veterans for a more narrowly focused study of birth defects and other reproductive outcomes. University of London Veteran Studies Unwin and collaborators (1999) at the University of London investigated the health of servicemen from the UK in a population-based study. The study used a random sample of the entire UK contingent deployed to the Gulf War6 and two comparison groups. One of the comparison groups was deployed to the conflict in Bosnia (n = 2,620); this made the study the only one to use a comparison population with combat experience during the time of the Gulf War. 5 In January 1997, Goss Gilroy Inc. was contracted by the Canadian Department of National Defence to carry out an epidemiologic survey of Canadians who served in the Gulf War to establish the overall health status of Gulf War personnel. 6 UK military personnel in the Gulf War were somewhat different from US personnel in demographics, combat experience, and exposures to particular agents (UK Ministry of Defence, 2000).
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 GWS = Gulf War syndrome; GWV = Gulf War veteran; HSC = Health Symptom Checklist; ICF = idiopathic chronic fatigue; MCS = multiple chemical sensitivity; MOD = Ministry of Defence (UK); NDV = nondeployed veteran; NGV = non-Gulf War veteran; ODSS = Operation Desert Shield / Operation Desert Storm; ODTP = Oregon Dual Task Procedures; PG = Persian Gulf; PTSD = posttraumatic stress disorder; PTSS = posttraumatic stress symptomatology; SF-12 = Medical Outcome Study Short Form 12; SF-36 = Medical Outcome Study Short Form 36; SF36-PF = Medical Outcome Study Short Form 36 Physical Functioning; UN = United Nations.
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 REFERENCES Amato AA, McVey A, Cha C, Matthews EC, Jackson CE, Kleingunther R, Worley L, Cornman E, Kagan-Hallet K. 1997. Evaluation of neuromuscular symptoms in veterans of the Persian Gulf War. Neurology 48(1):4-12. Anger WK, Storzbach D, Binder LM, et al. 1999. Neurobehavioral deficits in Persian Gulf veterans: Evidence from a population-based study. Journal of the International Neuropsychological Society 5(3):203-212. Axelrod BN, Milner IB. 1997. Neuropsychological findings in a sample of Operation Desert Storm veterans. Journal of Neuropsychiatry and Clinical Neurosciences 9(1):23-28. Barrett DH, Doebbeling CC, Schwartz DA, Voelker MD, Falter KH, Woolson RF, Doebbeling BN. 2002. Posttraumatic stress disorder and self-reported physical health status among U.S. Military personnel serving during the Gulf War period: A population-based study. Psychosomatics 43(3):195-205. Benotsch EG, Brailey K, Vasterling JJ, Uddo M, Constans JI, Sutker PB. 2000. War zone stress, personal and environmental resources, and PTSD symptoms in Gulf War veterans: A longitudinal perspective. Journal of Abnormal Psychology 109(2):205-213. Binder LM, Storzbach D, Anger WK, Campbell KA, Rohlman DS. 1999. Subjective cognitive complaints, affective distress, and objective cognitive performance in Persian Gulf War veterans. Archives of Clinical Neuropsychology 14(6):531-536. Binder LM, Storzbach D, Campbell KA, Rohlman DS, Anger WK, Members of the Portland Environmental Hazards Research Center. 2001. Neurobehavioral deficits associated with chronic fatigue syndrome in veterans with Gulf War unexplained illnesses. Journal of the International Neuropsychological Society 7(7):835-839. Black DW, Doebbeling BN, Voelker MD, Clarke WR, Woolson RF, Barrett DH, Schwartz DA. 1999. Quality of life and health-services utilization in a population-based sample of military personnel reporting multiple chemical sensitivities. Journal of Occupational and Environmental Medicine 41(10):928-933. Black DW, Doebbeling BN, Voelker MD, Clarke WR, Woolson RF, Barrett DH, Schwartz DA. 2000. Multiple chemical sensitivity syndrome: Symptom prevalence and risk factors in a military population. Archives of Internal Medicine 160(8):1169-1176. Black DW, Carney CP, Forman-Hoffman VL, Letuchy E, Peloso P, Woolson RF, Doebbeling BN. 2004a. Depression in veterans of the first gulf war and comparable military controls. Annals of Clinical Psychiatry 16(2):53-61. Black DW, Carney CP, Peloso PM, Woolson RF, Schwartz DA, Voelker MD, Barrett DH, Doebbeling BN. 2004b. Gulf War veterans with anxiety: Prevalence, comorbidity, and risk factor. Epidemiology 15(2):135-142. Bourdette DN, McCauley LA, Barkhuizen A, Johnston W, Wynn M, Joos SK, Storzbach D, Shuell T, Sticker D. 2001. Symptom factor analysis, clinical findings, and functional status in a population-based case control study of Gulf War unexplained illness. Journal of Occupational and Environmental Medicine 43(12):1026-1040.
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 Brailey K, Vasterling JJ, Sutker PB. 1998. Psychological Aftermath of Participation in the Persian Gulf War. Lundberg A, Editor. The Environment and Mental Health: A Guide for Clinicians. London: Lawrence Erlbaum Associates. Pp. 83-101. Bullman TA, Mahan CM, Kang HK, Page WF. 2005. Mortality in US Army Gulf War Veterans Exposed to 1991 Khamisiyah Chemical Munitions Destruction. American Journal of Public Health 95(8):1382-1388. Carney CP, Sampson TR, Voelker M, Woolson R, Thorne P, Doebbeling BN. 2003. Women in the Gulf War: Combat experience, exposures, and subsequent health care use. Military Medicine 168(8):654-661. Chalder T, Hotopf M, Unwin C, Hull L, Ismail K, David A, Wessely S. 2001. Prevalence of Gulf war veterans who believe they have Gulf war syndrome: Questionnaire study. British Medical Journal 323(7311):473-476. Cherry N, Creed F, Silman A, Dunn G, Baxter D, Smedley J, Taylor S, Macfarlane GJ. 2001a. Health and exposures of United Kingdom Gulf war veterans. Part I: The pattern and extent of ill health. Occupational and Environmental Medicine 58(5):291-298. Cherry N, Creed F, Silman A, Dunn G, Baxter D, Smedley J, Taylor S, Macfarlane GJ. 2001b. Health and exposures of United Kingdom Gulf war veterans. Part II: The relation of health to exposure. Occupational and Environmental Medicine 58(5):299-306. David AS, Farrin L, Hull L, Unwin C, Wessely S, Wykes T. 2002. Cognitive functioning and disturbances of mood in UK veterans of the Persian Gulf War: A comparative study. Psychological Medicine 32(8):1357-1370. Davis LE, Eisen SA, Murphy FM, Alpern R, Parks BJ, Blanchard M, Reda DJ, King MK, Mithen FA, Kang HK. 2004. Clinical and laboratory assessment of distal peripheral nerves in Gulf War veterans and spouses. Neurology 63(6):1070-1077. Dlugosz LJ, Hocter WJ, Kaiser KS, Knoke JD, Heller JM, Hamid NA, Reed RJ, Kendler KS, Gray GC. 1999. Risk factors for mental disorder hospitalization after the Persian Gulf War: U.S. Armed Forces, June 1, 1991-September 30, 1993. Journal of Clinical Epidemiology 52(12):1267-1278. Doebbeling BN, Clarke WR, Watson D, Torner JC, Woolson RF, Voelker MD, Barrett DH, Schwartz DA. 2000. Is there a Persian Gulf War syndrome? Evidence from a large population-based survey of veterans and nondeployed controls. American Journal of Medicine 108(9):695-704. Doyle P, Maconochie N, Davies G, Maconochie I, Pelerin M, Prior S, Lewis S. 2004. Miscarriage, stillbirth and congenital malformation in the offspring of UK veterans of the first Gulf war. International Journal of Epidemiology 33(1):74-86. Eisen SA, Kang HK, Murphy FM, Blanchard MS, Reda DJ, Henderson WG, Toomey R, Jackson LW, Alpern R, Parks BJ, Klimas N, Hall C, Pak HS, Hunter J, Karlinsky J, Battistone MJ, Lyons MJ. 2005. Gulf War veterans' health: Medical evaluation of a US cohort. Annals of Internal Medicine 142(11):881-890. Everitt B, Ismail K, David AS, Wessely S. 2002. Searching for a Gulf War syndrome using cluster analysis. Psychological Medicine 32(8):1371-1378. Forbes AB, McKenzie DP, Mackinnon AJ, Kelsall HL, McFarlane AC, Ikin JF, Glass DC, Sim MR. 2004. The health of Australian veterans of the 1991 Gulf War: Factor analysis of self-reported symptoms. Occupational and Environmental Medicine 61(12):1014-1020.
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 Ford JD, Campbell KA, Storzbach D, Binder LM, Anger WK, Rohlman DS. 2001. Posttraumatic stress symptomatology is associated with unexplained illness attributed to Persian Gulf War military service. Psychosomatic Medicine 63(5):842-849. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. 1994. The chronic fatigue syndrome: A comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Annals of Internal Medicine 121(12):953-959. Fukuda K, Nisenbaum R, Stewart G, Thompson WW, Robin L, Washko RM, Noah DL, Barrett DH, Randall B, Herwaldt BL, Mawle AC, Reeves WC. 1998. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. Journal of the American Medical Association 280(11):981-988. Goldstein G, Beers SR, Morrow LA, Shemansky WJ, Steinhauer SR. 1996. A preliminary neuropsychological study of Persian Gulf veterans. Journal of the International Neuropsychological Society 2(4):368-371. Goss Gilroy Inc. 1998. Health Study of Canadian Forces Personnel Involved in the 1991 Conflict in the Persian Gulf. Ottawa, Canada: Goss Gilroy Inc. Department of National Defence. Gray GC, Coate BD, Anderson CM, Kang HK, Berg SW, Wignall FS, Knoke JD, Barrett-Connor E. 1996. The postwar hospitalization experience of US veterans of the Persian Gulf War. New England Journal of Medicine 335(20):1505-1513. Gray GC, Kaiser KS, Hawksworth AW, Hall FW, Barrett-Connor E. 1999a. Increased postwar symptoms and psychological morbidity among US Navy Gulf War veterans. American Journal of Tropical Medicine and Hygiene 60(5):758-766. Gray GC, Smith TC, Knoke JD, Heller JM. 1999b. The postwar hospitalization experience of Gulf War Veterans possibly exposed to chemical munitions destruction at Khamisiyah, Iraq. American Journal of Epidemiology 150(5):532-540. Gray GC, Reed RJ, Kaiser KS, Smith TC, Gastanaga VM. 2002. Self-reported symptoms and medical conditions among 11,868 Gulf War-era veterans: The Seabee Health Study. American Journal of Epidemiology 155(11):1033-1044. Haley RW, Kurt TL. 1997. Self-reported exposure to neurotoxic chemical combinations in the Gulf War. A cross-sectional epidemiologic study. Journal of the American Medical Association 277(3):231-237. Haley RW, Hom J, Roland PS, Bryan WW, Van Ness PC, Bonte FJ, Devous MD Sr, Mathews D, Fleckenstein JL, Wians FH Jr, Wolfe GI, Kurt TL. 1997a. Evaluation of neurologic function in Gulf War veterans. A blinded case-control study. Journal of the American Medical Association 277(3):223-230. Haley RW, Kurt TL, Hom J. 1997b. Is there a Gulf War Syndrome? Searching for syndromes by factor analysis of symptoms. Journal of the American Medical Association 277(3):215-222. Haley RW, Billecke S, La Du BN. 1999. Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicology and Applied Pharmacology 157(3):227-233. Haley RW, Marshall WW, McDonald GG, Daugherty MA, Petty F, Fleckenstein JL. 2000a. Brain abnormalities in Gulf War syndrome: Evaluation with 1H MR spectroscopy. Radiology 215(3):807-817.
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 Haley RW, Fleckenstein JL, Marshall WW, McDonald GG, Kramer GL, Petty F. 2000b. Effect of basal ganglia injury on central dopamine activity in Gulf War syndrome: Correlation of proton magnetic resonance spectroscopy and plasma homovanillic acid levels. Archives of Neurology 57(9):1280-1285. Haley RW, Luk GD, Petty F. 2001. Use of structural equation modeling to test the construct validity of a case definition of Gulf War syndrome: Invariance over developmental and validation samples, service branches and publicity. Psychiatry Research 102(2):175-200. Haley RW, Vongpatanasin W, Wolfe GI, Bryan WW, Armitage R, Hoffmann RF, Petty F, Callahan TS, Charuvastra E, Shell WE, Marshall WW, Victor RG. 2004. Blunted circadian variation in autonomic regulation of sinus node function in veterans with Gulf War syndrome. American Journal of Medicine 117(7):469-478. Hom J, Haley RW, Kurt TL. 1997. Neuropsychological correlates of Gulf War syndrome. Archives of Clinical Neuropsychology 12(6):531-544. Hotopf M, David A, Hull L, Ismail K, Unwin C, Wessely S. 2000. Role of vaccinations as risk factors for ill health in veterans of the Gulf war: Cross sectional study. British Medical Journal 320(7246):1363-1367. Hotopf M, David AS, Hull L, Nikalaou V, Unwin C, Wessely S. 2003a. Gulf war illness — Better, worse, or just the same? A cohort study. British Medical Journal 327(7428):1370-1372. Hotopf M, Mackness MI, Nikolaou V, Collier DA, Curtis C, David A, Durrington P, Hull L, Ismail K, Peakman M, Unwin C, Wessely S, Mackness B. 2003b. Paraoxonase in Persian Gulf War veterans. Journal of Occupational and Environmental Medicine 45(7):668-675. Ikin JF, Sim MR, Creamer MC, Forbes AB, McKenzie DP, Kelsall HL, Glass DC, McFarlane AC, Abramson MJ, Ittak P, Dwyer T, Blizzard L, Delaney KR, Horsley KWA, Harrex WK, Schwarz H. 2004. War-related psychological stressors and risk of psychological disorders in Australian veterans of the 1991 Gulf War. British Journal of Psychiatry 185:116-126. Ikin JF, McKenzie DP, Creamer MC, et al. 2005. War zone stress without direct combat: The Australian naval experience of the Gulf War. Journal of Traumatic Stress 18(3):193-204. IOM (Institute of Medicine). 1999a. Gulf War Veterans: Measuring Health. Washington, DC: National Academy Press. IOM. 1999b. Strategies to Protect the Health of Deployed US Forces: Medical Surveillance, Record Keeping, and Risk Reduction. Washington, DC: National Academy Press. Iowa Persian Gulf Study Group. 1997. Self-reported illness and health status among Gulf War veterans: A population-based study. Journal of the American Medical Association 277(3):238-245. Ishoy T, Suadicani P, Guldager B, Appleyard M, Gyntelberg F. 1999a. Risk factors for gastrointestinal symptoms. The Danish Gulf War Study. Danish Medical Bulletin 46(5):420-423. Ishoy T, Suadicani P, Guldager B, Appleyard M, Hein HO, Gyntelberg F. 1999b. State of health after deployment in the Persian Gulf. The Danish Gulf War Study. Danish Medical Bulletin 46(5):416-419.
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 Ishoy T, Andersson AM, Suadicani P, Guldager B, Appleyard M, Gyntelberg F, Skakkebaek NE, Danish Gulf War Study. 2001a. Major reproductive health characteristics in male Gulf War Veterans. The Danish Gulf War Study. Danish Medical Bulletin 48(1):29-32. Ishoy T, Suadicani P, Andersson A-M, Guldager B, Appleyard M, Skakkebaek N, Gyntelberg F. 2001b. Prevalence of male sexual problems in the Danish Gulf War Study. Scandinavian Journal of Sexology 4(1):43-55. Ismail K, Everitt B, Blatchley N, Hull L, Unwin C, David A, Wessely S. 1999. Is there a Gulf War syndrome? Lancet 353(9148):179-182. Ismail K, Kent K, Brugha T, Hotopf M, Hull L, Seed P, Palmer I, Reid S, Unwin C, David AS, Wessely S. 2002. The mental health of UK Gulf war veterans: Phase 2 of a two phase cohort study. British Medical Journal 325(7364):576. Jamal GA, Hansen S, Apartopoulos F, Peden A. 1996. The "Gulf War syndrome". Is there evidence of dysfunction in the nervous system? Journal of Neurology, Neurosurgery and Psychiatry 60(4):449-451. Joseph SC. 1997. A comprehensive clinical evaluation of 20,000 Persian Gulf War veterans. Military Medicine 162(3):149-155. Kang HK, Bullman TA. 1996. Mortality among US veterans of the Persian Gulf War. New England Journal of Medicine 335(20):1498-1504. Kang HK, Mahan CM, Lee KY, Magee CA, Murphy FM. 2000. Illnesses among United States veterans of the Gulf War: A population-based survey of 30,000 veterans. Journal of Occupational and Environmental Medicine 42(5):491-501. Kang HK, Bullman TA. 2001. Mortality among US veterans of the Persian Gulf War: 7-year follow-up. American Journal of Epidemiology 154(5):399-405. Kang HK, Mahan CM, Lee KY, Murphy FM, Simmens SJ, Young HA, Levine PH. 2002. Evidence for a deployment-related Gulf War syndrome by factor analysis. Archives of Environmental Health 57(1):61-68. Kang HK, Natelson BH, Mahan CM, Lee KY, Murphy FM. 2003. Post-traumatic stress disorder and chronic fatigue syndrome-like illness among Gulf War veterans: A population-based survey of 30,000 veterans. American Journal of Epidemiology 157(2):141-148. Karlinsky JB, Blanchard M, Alpern R, Eisen SA, Kang H, Murphy FM, Reda DJ. 2004. Late prevalence of respiratory symptoms and pulmonary function abnormalities in Gulf War I Veterans. Archives of Internal Medicine 164(22):2488-2491. Kelsall HL, Sim MR, Forbes AB, Glass DC, McKenzie DP, Ikin JF, Abramson MJ, Blizzard L, Ittak P. 2004a. Symptoms and medical conditions in Australian veterans of the 1991 Gulf War: Relation to immunisations and other Gulf War exposures. Occupational and Environmental Medicine 61(12):1006-1013. Kelsall HL, Sim MR, Forbes AB, McKenzie DP, Glass DC, Ikin JF, Ittak P, Abramson MJ. 2004b. Respiratory health status of Australian veterans of the 1991 Gulf War and the effects of exposure to oil fire smoke and dust storms. Thorax 59(10):897-903. Knoke JD, Gray GC. 1998. Hospitalizations for unexplained illnesses among US veterans of the Persian Gulf War. Emerging Infectious Diseases 4(2):211-219. Knoke JD, Gray GC, Garland FC. 1998. Testicular cancer and Persian Gulf War service. Epidemiology 9(6):648-653.
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 Knoke JD, Smith TC, Gray GC, Kaiser KS, Hawksworth AW. 2000. Factor analysis of self-reported symptoms: Does it identify a Gulf War syndrome? American Journal of Epidemiology 152(4):379-388. Kurt TL. 1998. Epidemiological association in US veterans between Gulf War illness and exposures to anticholinesterases. Toxicology Letters 102-103:523-526. Lange JL, Schwartz DA, Doebbeling BN, Heller JM, Thorne PS. 2002. Exposures to the Kuwait oil fires and their association with asthma and bronchitis among gulf war veterans. Environmental Health Perspectives 110(11):1141-1146. Lindem K, Proctor SP, Heeren T, Krengel M, Vasterling J, Sutker PB, Wolfe J, Keane TM, White RF. 2003a. Neuropsychological performance in Gulf War era veterans: Neuropsychological symptom reporting. Journal of Psychopathology and Behavioral Assessment 25(2):121-127. Lindem K, Heeren T, White RF, Proctor SP, Krengel M, Vasterling J, Sutker PB, Wolfe J, Keane TM. 2003b. Neuropsychological performance in Gulf War era veterans: Traumatic stress symptomatology and exposure to chemical-biological warfare agents. Journal of Psychopathology and Behavioral Assessment 25(2):105-119. Maconochie N, Doyle P, Davies G, Lewis S, Pelerin M, Prior S, Sampson P. 2003. The study of reproductive outcome and the health of offspring of UK veterans of the Gulf war: Methods and description of the study population. BMC Public Health 3(1):4. McCauley LA, Joos SK, Spencer PS, Lasarev M, Shuell T. 1999a. Strategies to assess validity of self-reported exposures during the Persian Gulf War. Environmental Research 81(3):195-205. McCauley LA, Joos SK, Lasarev MR, Storzbach D, Bourdette DN. 1999b. Gulf War unexplained illnesses: Persistence and unexplained nature of self-reported symptoms. Environmental Research 81(3):215-223. McCauley LA, Joos SK, Barkhuizen A, Shuell T, Tyree WA, Bourdette DN. 2002a. Chronic fatigue in a population-based study of Gulf War veterans. Archives of Environmental Health 57(4):340-348. McCauley LA, Lasarev M, Sticker D, Rischitelli DG, Spencer PS. 2002b. Illness experience of Gulf War veterans possibly exposed to chemical warfare agents. American Journal of Preventive Medicine 23(3):200-206. McKenzie DP, Ikin JF, McFarlane AC, Creamer M, Forbes AB, Kelsall HL, Glass DC, Ittak P, Sim MR. 2004. Psychological health of Australian veterans of the 1991 Gulf War: An assessment using the SF-12, GHQ-12 and PCL-S. Psychological Medicine 34(8):1419-1430. Morgan CA 3rd, Hill S, Fox P, Kingham P, Southwick SM. 1999. Anniversary reactions in Gulf War veterans: A follow-up inquiry 6 years after the war. American Journal of Psychiatry 156(7):1075-1079. Murphy FM, Kang H, Dalager NA, Lee KY, Allen RE, Mather SH, Kizer KW. 1999. The health status of Gulf War veterans: Lessons learned from the Department of Veterans Affairs Health Registry. Military Medicine 164(5):327-331. Nisenbaum R, Reyes M, Mawle AC, Reeves WC. 1998. Factor analysis of unexplained severe fatigue and interrelated symptoms: Overlap with criteria for chronic fatigue syndrome. American Journal of Epidemiology 148(1):72-77.
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 Southwick SM, Morgan A, Nagy LM, Bremner D, Nicolaou AL, Johnson DR, Rosenheck R, Charney DS. 1993. Trauma-related symptoms in veterans of Operation Desert Storm: A preliminary report. American Journal of Psychiatry 150(10):1524-1528. Southwick SM, Morgan CA 3rd, Darnell A, Bremner D, Nicolaou AL, Nagy LM, Charney DS. 1995. Trauma-related symptoms in veterans of Operation Desert Storm: A 2-year follow-up. American Journal of Psychiatry 152(8):1150-1155. Spencer PS, McCauley LA, Joos SK, Lasarev MR, Schuell T, Bourdette D, Barkhuizen A, Johnston W, Storzbach D, Wynn M, Grewenow R. 1998. U.S. Gulf War Veterans: Service periods in theater, differential exposures, and persistent unexplained illness. Toxicology Letters 102-103:515-521. Spencer PS, McCauley LA, Lapidus JA, Lasarev M, Joos SK, Storzbach D. 2001. Self-reported exposures and their association with unexplained illness in a population-based case-control study of Gulf War veterans. Journal of Occupational and Environmental Medicine 43(12):1041-1056. Steele L. 2000. Prevalence and patterns of Gulf War illness in Kansas veterans: Association of symptoms with characteristics of person, place, and time of military service. American Journal of Epidemiology 152(10):992-1002. Storzbach D, Campbell KA, Binder LM, McCauley L, Anger WK, Rohlman DS, Kovera CA. 2000. Psychological differences between veterans with and without Gulf War unexplained symptoms. Psychosomatic Medicine 62(5):726-735. Storzbach D, Rohlman DS, Anger WK, Binder LM, Campbell KA. 2001. Neurobehavioral deficits in Persian Gulf veterans: Additional evidence from a population-based study. Environmental Research 85(1):1-13. Stretch RH, Bliese PD, Marlowe DH, Wright KM, Knudson KH, Hoover CH. 1995. Physical health symptomatology of Gulf War-era service personnel from the states of Pennsylvania and Hawaii. Military Medicine 160(3):131-136. Stretch RH, Bliese PD, Marlowe DH, Wright KM, Knudson KH, Hoover CH. 1996a. Psychological health of Gulf War-era military personnel. Military Medicine 161(5):257-261. Stretch RH, Marlowe DH, Wright KM, Bliese PD, Knudson KH, Hoover CH. 1996b. Post-traumatic stress disorder symptoms among Gulf War veterans. Military Medicine 161(7):407-410. Suadicani P, Ishoy T, Guldager B, Appleyard M, Gyntelberg F. 1999. Determinants of long-term neuropsychological symptoms. The Danish Gulf War Study. Danish Medical Bulletin 46(5):423-427. Sutker PB, Uddo M, Brailey K, Allain AN. 1993. War-zone trauma and stress-related symptoms in Operation Desert Shield/Storm (ODS) returnees. Journal of Social Issues 49(4):33-50. Sutker PB, Uddo M, Brailey K, Allain AN, Errera P. 1994a. Psychological symptoms and psychiatric diagnoses in Operation Desert Storm troops serving graves registration duty. Journal of Traumatic Stress 7(2):159-171. Sutker PB, Uddo M, Brailey K, Vasterling JJ, Errera P. 1994b. Psychopathology in war-zone deployed and nondeployed Operation Desert Storm troops assigned graves registration duties. Journal of Abnormal Psychology 103(2):383-390.
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 Sutker PB, Davis JM, Uddo M, Ditta SR. 1995a. Assessment of psychological distress in Persian Gulf troops: Ethnicity and gender comparisons. Journal of Personality Assessment 64(3):415-427. Sutker PB, Davis JM, Uddo M, Ditta SR. 1995b. War zone stress, personal resources, and PTSD in Persian Gulf War returnees. Journal of Abnormal Psychology 104(3):444-452. Sutker PB, Corrigan SA, Sundgaard-Riise K, Uddo M, Allain AN. 2002. Exposure to war trauma, war-related PTSD, and psychological impact of subsequent hurricane. Journal of Psychopathology and Behavioral Assessment 24(1):25-37. Thompson KE, Vasterling JJ, Benotsch EG, Brailey K, Constans J, Uddo M, Sutker PB. 2004. Early symptom predictors of chronic distress in Gulf War veterans. Journal of Nervous and Mental Disease 192(2):146-152. United Kingdom Ministry of Defence. 2000. Background to the Use of Medical Countermeasures to Protect British Forces During the Gulf War (Operation Granby). [Online]. Available: http://www.mod.uk/issues/gulfwar/info/medical/ukchemical.htm [accessed September 26, 2003]. Unwin C, Blatchley N, Coker W, Ferry S, Hotopf M, Hull L, Ismail K, Palmer I, David A, Wessely S. 1999. Health of UK servicemen who served in Persian Gulf War. Lancet 353(9148):169-178. Unwin C, Hotopf M, Hull L, Ismail K, David A, Wessely S. 2002. Women in the Persian Gulf: Lack of gender differences in long-term health effects of service in United Kingdom Armed Forces in the 1991 Persian Gulf War. Military Medicine 167(5):406-413. Vasterling JJ, Brailey K, Constans JI, Borges A, et al. 1997. Assessment of intellectual resources in Gulf War veterans: Relationship to PTSD. Assessment 4(1):51-59. Vasterling JJ, Brailey K, Constans JI, Sutker PB. 1998. Attention and memory dysfunction in posttraumatic stress disorder. Neuropsychology 12(1):125-133. Vasterling JJ, Brailey K, Tomlin H, Rice J, Sutker PB. 2003. Olfactory functioning in Gulf War-era veterans: Relationships to war-zone duty, self-reported hazards exposures, and psychological distress. Journal of the International Neuropsychological Society 9(3):407-418. Wagner AW, Wolfe J, Rotnitsky A, Proctor SP, Erickson DJ. 2000. An investigation of the impact of posttraumatic stress disorder on physical health. Journal of Traumatic Stress 13(1):41-55. White RF, Proctor SP, Heeren T, Wolfe J, Krengel M, Vasterling J, Lindem K, Heaton KJ, Sutker P, Ozonoff DM. 2001. Neuropsychological function in Gulf War veterans: Relationships to self-reported toxicant exposures. American Journal of Industrial Medicine 40(1):42-54. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, et al. 1990. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis and Rheumatism 33(2):160-172. Wolfe J, Proctor SP, Erickson DJ, Heeren T, Friedman MJ, Huang MT, Sutker PB, Vasterling JJ, White RF. 1999a. Relationship of psychiatric status to Gulf War veterans' health problems. Psychosomatic Medicine 61(4):532-540.
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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 Wolfe J, Erickson DJ, Sharkansky EJ, King DW, King LA. 1999b. Course and predictors of posttraumatic stress disorder among Gulf War veterans: A prospective analysis. Journal of Consulting and Clinical Psychology 67(4):520-528. Wolfe J, Proctor SP, Erickson DJ, Hu H. 2002. Risk factors for multisymptom illness in US Army veterans of the Gulf War. Journal of Occupational and Environmental Medicine 44(3):271-281. Zwerling C, Torner JC, Clarke WR, Voelker MD, Doebbeling BN, Barrett DH, Merchant JA, Woolson RF, Schwartz DA. 2000. Self-reported postwar injuries among Gulf War veterans. Public Health Reports 115(4):346-349.
Representative terms from entire chapter: