RE: "FACTOR ANALYSIS OF SELF-REPORTED SYMPTOMS: DOES IT IDENTIFY A GULF WAR SYNDROME?"

Robert W. Haley

Division of Epidemiology Department of Internal Medicine University of Texas Southwestern Medical Center Dallas, TX 75390-8874


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In a recent article, Knoke et al. (1Go) from the US Naval Health Research Center in San Diego joined other skeptics (2GoGo–4Go) in attacking our use of factor analysis to identify Gulf War syndromes (5Go) by attempting to show that symptom complexes identified by factor analysis can be found in both the deployed and nondeployed Gulf War-era veteran populations. In past letters I have countered these attacks by pointing to serious design flaws, most notably inadvertent exclusion of most veterans with the illness, use of questionnaires that measure psychiatric illnesses rather than the new illness in question, failure to include the defining symptoms, wording of questions that blur the veterans' unique symptoms with common functional symptoms, performing factor analysis on data ill-suited for that purpose, and testing factor structures with incorrect statistical procedures (6GoGo–8Go). Knoke et al. have repeated these mistakes.

First, Knoke et al. (1Go) incorrectly reported 65 percent and 46 percent participation rates in their deployed and nondeployed groups, respectively. In truth, the participation rates among those who served in those battalions during the war were 11 percent (524/4,700) and 9 percent (935/10,700), respectively. By automatically excluding the 45 percent who separated from the service between 1990 and 1995–a time of intense military downsizing when most ill Gulf War veterans were discharged for impaired performance–Knoke et al. excluded virtually all of the types of seriously ill patients we have been seeing (5Go, 9Go). Basically, they studied a group systematically purged of the illness they purported to study.

Second, their questionnaire was heavily weighted toward symptom questions taken directly from the Hopkins Symptom Checklist, developed to measure psychiatric illnesses. To choose among alternative factor analysis models, Knoke et al. deliberately searched the data for symptom profiles resembling the common psychiatric conditions measured by the Hopkins Symptom Checklist (1Go). Since psychiatric conditions and subsyndromal psychiatric symptoms are common in most populations apart from the Gulf War syndrome, it is not surprising that their factor analysis identified common psychiatric conditions in both deployed and nondeployed groups. Any resemblance to the conditions we have studied is purely superficial.

Third, although Knoke et al. (1Go) attempted to include a set of symptoms more characteristic of the illness seen in Gulf War veterans, the wording of their questions was too nonspecific to be useful, and questions on key defining symptoms were not asked. For example, questions on sensory disturbances did not distinguish paresthesias of extremities from nonspecific "numbness/tingling" anywhere, and there were no questions to detect vertigo attacks, issues we found to be central (5Go, 10Go).

Fourth, Knoke et al. (1Go) did not adequately support their conclusion that the same exploratory factor structure was present in both deployed and nondeployed groups. The accepted method is to express the factor model as a set of structural equations with equality constraints and to test its goodness-of-fit across the groups (11Go). Knoke's intuitive approach of comparing standardized factor scores (1Go) is highly insensitive for detecting ill-fitting models. The fact that many symptoms loaded on the factors in the deployed but not in the nondeployed group is a clear sign that the model is not invariant.

In contrast, our research suggests that there is a unique Gulf War neurologic syndrome with several reproducible variants (5Go). A series of small clinical case-control studies has demonstrated an association of our factor analysis-derived case definition with objective and sensitive measures of brain dysfunction (10Go, 12Go), neuronal injury in the brainstem and basal ganglia (13Go), abnormal brain dopamine production (14Go), neurotoxic chemical risk factors (15Go), and genetic predisposition (16Go). After 6 years of thoroughly characterizing the disease clinically, we are proposing a large sample survey to test our theory by measuring the prevalence of our case definition in deployed and nondeployed populations, followed by confirmatory case-control tests of our neurophysiologic, brain-imaging, and genetic findings (10Go, 12GoGo–14Go, 16Go). Time will tell which approach was more insightful. For now, I conclude that the factor analytical efforts of the US Naval Health Research Center (1Go) and the others (2GoGo–4Go) have added little to our understanding of Gulf War syndrome.


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  1. Knoke JD, Smith TC, Gray GC, et al. Factor analysis of self-reported symptoms: does it identify a Gulf War syndrome? Am J Epidemiol 2000;152:379–88.[Abstract/Free Full Text]
  2. Fukuda K, Nisenbaum R, Stewart G, et al. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA 1998;280:981–8.[Abstract/Free Full Text]
  3. Ismail K, Everitt B, Blatchley N, et al. Is there a Gulf War syndrome? Lancet 1999;353:179–82.[ISI][Medline]
  4. Doebbeling BN, Clarke WR, Watson D, et al. Is there a Persian Gulf War syndrome? Evidence from a large population-based survey of veterans and nondeployed controls. Am J Med 2000;108:695–704.[ISI][Medline]
  5. Haley RW, Kurt TM, Hom J. Is there a Gulf War syndrome? Searching for syndromes by factor analysis of symptoms. JAMA 1997;277:215–22.[Abstract]
  6. Haley RW. Chronic multisystem illness among Gulf War veterans (with discussion). (Letter). JAMA 1999;282:327–9.[Free Full Text]
  7. Haley RW. Is there a Gulf War syndrome? (Letter). Lancet 1999;354:1645–6.[Medline]
  8. Haley RW. Will we solve the Gulf War syndrome puzzle by population surveys or clinical research? Am J Med (in press).
  9. Haley RW. Point: bias from the "healthy-warrior effect" and unequal follow-up in three government studies of health effects of the Gulf War. Am J Epidemiol 1998;148:315–23.[ISI][Medline]
  10. Roland PS, Haley RW, Yellin W, et al. Vestibular dysfunction in Gulf War syndrome. Otolaryngol Head Neck Surg 2000;122:319–29.[ISI][Medline]
  11. Jöreskog KG. Structural analysis of covariance and correlation matrices. Psychometrika 1978;43:443–7.[ISI]
  12. Haley RW, Hom J, Roland PS, et al. Evaluation of neurologic function in Gulf War veterans: a blinded case-control study. JAMA 1997;277:223–30.[Abstract]
  13. Haley RW, Marshall WW, McDonald GG, et al. Brain abnormalities in Gulf War syndrome: evaluation by 1H magnetic resonance spectroscopy. Radiology 2000;215:807–17.[Abstract/Free Full Text]
  14. Haley RW, Fleckenstein JL, Marshall WW, et al. Effect of basal ganglia injury on central dopamine activity in Gulf War syndrome: correlation of proton magnetic resonance spectroscopy and plasma homovanillic acid levels. Arch Neurol 2000;57:1280–5.[Abstract/Free Full Text]
  15. Haley RW, Kurt TL. Self-reported exposure to neurotoxic chemical combinations in the Gulf War: a cross-sectional epidemiologic study. JAMA 1997;277:231–7.[Abstract]
  16. Haley RW, Billecke S, La Du BN. Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicol Appl Pharmacol 1999;157:227–33.[ISI][Medline]

 

FOUR OF THE AUTHORS REPLY

Gregory C. Gray, Tyler C. Smith, Anthony W. Hawksworth and James D. Knoke

DoD Center for Deployment Health Research Naval Health Research Center San Diego, CA 92186-5122
Division of Epidemiology Department of Family and Preventive Medicine University of California, San Diego La Jolla, CA 92093


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We understand Dr. Haley's reluctance (1Go) to embrace our recently published paper (2Go). We are the fourth independent research team (2GoGoGo–5Go) to attempt replication of Dr. Haley's factor analysis report (6Go) and the fourth to reject his assertions of unique Gulf War syndromes. We respond to his criticisms.

Participation. Our study population was described in the Population subsection of the Materials and Methods section (2Go, p. 379) and in the original study report (7Go). The participation percentages reported in the Ascertainment and Demographics subsection of the Results section (2Go, pp. 380–1) refer to this population and are correct. Although Department of Defense separation data demonstrated a reduction in forces after the war, Gulf War veterans did not separate from service for medical reasons at higher rates than did their nondeployed peers (8Go, 9Go). Gulf War-related illnesses serious enough to cause separation should be apparent in health care utilization data. Analyses of hospital data, however, have not demonstrated evidence for such unexplained illnesses after the war (8Go, 10Go, 11Go).

Questionnaire. We agree that many of our symptom questions were taken from the Hopkins Symptom Checklist. This is described in the Data subsection of the Materials and Methods section (2Go, pp. 379–80). We agree with some of Dr. Haley's points in this paragraph. However, we never referred to our factors as "identifying psychiatric conditions," and we do not think the similarity in factors between the studies is a coincidence.

Wording of questions. Haley states that the wording of our symptom questions, those not taken from the Hopkins Symptom Checklist, "was too nonspecific to be useful" (1Go, p. 1204). Our unique symptom questions loaded on two factors, depression and malaise, which resembled Haley's factors "confusion-ataxia" and "fever-adenopathy," respectively. We believe our two sets of unique symptom questions were indeed specific and useful.

Comparison of factors between groups of veterans. Haley states that our method of comparing standardized factor scores is "highly insensitive for detecting ill-fitting models" (1Go, p. 1204) but presents no reference for this assertion. He does, however, present a citation (1Go, **reference 11Go) for an "accepted method" for comparing groups, which is a primary reference for latent structure analysis. Latent structure analysis is a methodological alternative to factor analysis, which may be more appropriate if the manifest variables (symptom questions) are categorical, as opposed to continuous. This was pointed out to us by a reviewer, which we acknowledged in the Discussion. As we noted, "we used classical factor analysis to be consistent with previous work" (2Go, p. 388). We agree that latent structure analysis would be preferable in this context and would have used it for this report had Haley not used factor analysis in his 1997 report. Finally, we never said that the factor structure in the deployed and nondeployed veteran groups was the "same," or "invariant." Rather, we said that it was "similar" and stand by that assertion.

We agree with numerous reviewers of Dr. Haley's work (12GoGoGoGo–16Go), and most recently the Institute of Medicine (17Go), that while hypothesis-generating, his studies of Gulf War veterans have had numerous shortcomings. His factor analysis report (6Go) involved a small group of servicemen from only one military unit, lacked a control group, suffered from low participation, and likely was influenced by recall bias and media events. Certainly, Dr. Haley's factor analysis report does not justify the Gulf War syndrome diagnoses he is ascribing to ill veterans nor does it justify enrolling them in his "shotgun therapy" trial of five pharmaceutical agents.


    NOTES
 
Editor's note: Interested readers can find more on this interesting and provocative topic in the transcripts of public hearings held by the Presidential Committee on Gulf War Veterans' Illnesses and the Presidential Special Oversight Board for Department of Defense Investigations of Gulf War Chemical and Biological Incidents at the following websites: http://www.oversight.ncr.gov/hal.htm/ and http://www.oversight.ncr.gov/xcript_hearing_13jul99.html/.


    REFERENCES 
 TOP
 INTRODUCTION
 REFERENCES
 INTRODUCTION 
 REFERENCES 
 

  1. Haley RW. Re: "Factor analysis of self-reported symptoms: does it identify a Gulf War syndrome?" (Letter). Am J Epidemiol 2000;152:1204–5.[Free Full Text]
  2. Knoke JD, Smith TC, Gray GC, et al. Factor analysis of self-reported symptoms: does it identify a Gulf War syndrome? Am J Epidemiol 2000;152:379–88.[Abstract/Free Full Text]
  3. Fukuda K, Nisenbaum R, Stewart G, et al. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA 1998;280:981–8.[Abstract/Free Full Text]
  4. Ismail K, Everitt B, Blatchley N, et al. Is there a Gulf War syndrome? Lancet 1999;353:179–82.[ISI][Medline]
  5. Doebbeling BN, Clarke WR, Watson D, et al. Is there a Persian Gulf War syndrome? Evidence from a large population-based survey of veterans and nondeployed controls. Am J Med 2000;108:695–704.[ISI][Medline]
  6. Haley RW, Kurt TL, Hom J. Is there a Gulf War syndrome? Searching for syndromes by factor analysis of symptoms. JAMA 1997;277:215–22.[Abstract]
  7. Gray GC, Kaiser KS, Hawksworth AW, et al. Increased postwar symptoms and psychological morbidity among U.S. Navy Gulf War veterans. Am J Trop Med Hyg 1999;60:758–66.[Abstract/Free Full Text]
  8. Gray GC, Coate BD, Anderson CM, et al. The postwar hospitalization experience of U.S. veterans of the Persian Gulf War. N Engl J Med 1996;335:1505–13.[Abstract/Free Full Text]
  9. Gray G, Knoke J, Berg S, et al. Counterpoint: responding to suppositions and misunderstandings. Am J Epidemiol 1998;148:328–33.[ISI][Medline]
  10. Gray GC, Smith TC, Kang HK, et al. Are Gulf War veterans suffering war-related illnesses? Federal and civilian hospitalizations examined, June 1991 to December 1994. Am J Epidemiol 2000;151:63–71.[Abstract]
  11. Knoke JD, Gray GC. Hospitalizations for unexplained illnesses among U.S. veterans of the Persian Gulf War. Emerg Infect Dis 1998;4:211–19.[ISI][Medline]
  12. Landrigan PJ. Illness in Gulf War veterans. Causes and consequences. JAMA 1997;277:259–61.[ISI][Medline]
  13. Engel CC Jr, Jing Z. Identification of Gulf War syndrome: methodological issues and medical illnesses. (Letter). JAMA 1997;278:383–4.
  14. Hyams KC, Wignall FS. Identification of Gulf War syndrome: methodological issues and medical illnesses. (Letter). JAMA 1997;278:384.
  15. Gots RE, Schwartz SL, Chaudhry V, et al. Identification of Gulf War syndrome: methodological issues and medical illnesses. (Letter). JAMA 1997;278:385.
  16. Albers J, Berent S. Controversies in neurotoxity. Current status. Clin Neurobehav Toxicity 2000;18:741–63.
  17. Committee on Health Effects Associated with Exposures during the Gulf War. Gulf War and health. Vol 1. Depleted uranium, sarin, pyridostigmine bromide, vaccines. Bethesda, MD: Division of Health Promotion and Disease Prevention, Institute of Medicine, 2000.