Free Access
Neuroepidemiology 2011;37:129–140

Validation of a Research Case Definition of Gulf War Illness in the 1991 US Military Population

Iannacchione V.G.a · Dever J.A.a · Bann C.M.a · Considine K.A.a · Creel D.a · Carson C.P.a · Best H.a · Haley R.W.b
aRTI International, Research Triangle Park, N.C., and bDivision of Epidemiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Tex., USA
email Corresponding Author

 goto top of outline Key Words

  • Epidemiological methods
  • Case definition
  • Diagnostic criteria
  • Confirmatory factor analysis
  • Health surveys
  • Persian Gulf syndrome
  • Validation studies

 goto top of outline Abstract

Background: A case definition of Gulf War illness with 3 primary variants, previously developed by factor analysis of symptoms in a US Navy construction battalion and validated in clinic veterans, identified ill veterans with objective abnormalities of brain function. This study tests prestated hypotheses of its external validity. Methods: A stratified probability sample (n = 8,020), selected from a sampling frame of the 3.5 million Gulf War era US military veterans, completed a computer-assisted telephone interview survey. Application of the prior factor weights to the subjects’ responses generated the case definition. Results: The structural equation model of the case definition fit both random halves of the population sample well (root mean-square error of approximation = 0.015). The overall case definition was 3.87 times (95% confidence interval, 2.61–5.74) more prevalent in the deployed than the deployable nondeployed veterans: 3.33 (1.10–10.10) for syndrome variant 1; 5.11 (2.43–10.75) for variant 2, and 4.25 (2.33–7.74) for variant 3. Functional status on SF-12 was greatly reduced (effect sizes, 1.0–2.0) in veterans meeting the overall and variant case definitions. Conclusions: The factor case definition applies to the full Gulf War veteran population and has good characteristics for research.

Copyright © 2011 S. Karger AG, Basel

 goto top of outline References
  1. Research Advisory Committee on Gulf War Veterans’ Illnesses: Gulf War illness and the health of Gulf War veterans. Washington, Department of Veterans Affairs, 2008.
  2. DeFraites RF, Wanat RR, Norwood AE, William S, Cowan D, Callahan T: Investigation of a suspected outbreak of an unknown disease among veterans of Operation Desert Shield/Storm, 123rd Army Reserve Command, Fort Benjamin Harrison, Indiana, April 1992. Washington, Walter Reed Army Institute of Research, 1992.
  3. Berg SW: Post-Persian Gulf medical findings in military reservists. Presentation to the NIH Technology Assessment Conference on the Persian Gulf experience and health, 27–29 April 1994, Bethesda, MD, 1994.
  4. Joseph SC: A comprehensive clinical evaluation of 20,000 Persian Gulf War veterans: Comprehensive Clinical Evaluation Program evaluation team. Milit Med 1997;162:149–155.
  5. Haley RW, Kurt TL, Hom J: Is there a Gulf War syndrome? Searching for syndromes by factor analysis of symptoms. JAMA 1997;277:215–222.
  6. Haley RW, Kurt TL: Self-reported exposure to neurotoxic chemical combinations in the Gulf War: a cross-sectional epidemiologic study. JAMA 1997;277:231–237.
  7. Haley RW, Spence JS, Carmack PS, Gunst RF, Schucany WR, Petty F, Devous MD Sr, Bonte FJ, Trivedi MH: Abnormal brain response to cholinergic challenge in chronic encephalopathy from the 1991 Gulf War. Psych Res Neuroimag 2009;171:207–220.
  8. Haley RW, Luk GD, Petty F: 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. Psychiatr Res 2001;102:175–200.
  9. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4 (DSM-IV). Washington, American Psychiatric Association, 1994.
  10. 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: Evaluation of neurologic function in Gulf War veterans: a blinded case-control study. JAMA 1997;277:223–230.
  11. Hom J, Haley RW, Kurt TL: Neuropsychological correlates of Gulf War syndrome. Arch Clin Neuropsychol 1997;12:531–544.
  12. Roland PS, Haley RW, Yellin W, Owens K: Vestibular dysfunction in Gulf War syndrome. Otolaryngol Head Neck Surg 2000;122:319–329.
  13. Haley RW, Vongpatanasin W, Wolfe GI, Bryan WW, Armitage R, Hoffmann RF, Petty F, Callahan TS, Charuvastra E, Shell WE, Marshall WW, Victor RG: Blunted circadian variation in autonomic regulation of sinus node function in veterans with Gulf War syndrome. Am J Med 2004;117:469–478.
  14. Haley RW, Marshall WW, McDonald GG, Daugherty M, Petty F, Fleckenstein JL: Brain abnormalities in Gulf War syndrome: evaluation by 1H magnetic resonance spectroscopy. Radiology 2000;215:807–817.
  15. Briggs RW, Cheshkov S, Lu H, Li X, McColl RW, Buhner D, Ferree T, Haley RW: Objective brain abnormalities by 3T MRI and EEG in Gulf War illness. 49th Annual Meeting of the Society of Toxicology, Salt Lake City, March 2010, Biomarkers Session, abstract No 2293.
  16. Ringe W, Briggs RW, Gopinath K, Kraut M, Rypma B, Odegard T, Bartlett J, Crosson B, Hart J, Haley RW: Functional neuroimaging shows abnormalities in brain function underlying symptoms of Gulf War illness. 49th Annual Meeting of the Society of Toxicology, Salt Lake City, March 2010, Biomarkers Session, abstract No 2294.
  17. Haley RW, Maddrey AM, Gershenfeld HK: Severely reduced functional status in veterans fitting a case definition of Gulf War syndrome. Am J Publ Health 2002;92:46–47.
  18. Steele L: Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with characteristics of person, place, and time of military service. Am J Epidemiol 2000;152:992–1002.
  19. Poblete PP, Araneta MRG, Sato PA, Hiliopoulos KM, Kamens DR, Morn CB, Zau AC, Gray GC: National study on reproductive outcomes: a reliability study of self-administered survey vs telephone interview. Conference of Federally Sponsored Gulf War Veterans’ Illnesses Research, Washington, June 1998, p 46.
  20. 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;148:315–323.
  21. Larson GE, Highfill-McRoy RM, Booth-Kewley S: Psychiatric diagnoses in historic and contemporary military cohorts: combat deployment and the healthy warrior effect. Am J Epidemiol 2008;167:1269–1276.
  22. McLaughlin R, Nielsen L, Waller M: An evaluation of the effect of military service on mortality: quantifying the healthy soldier effect. Ann Epidemiol 2008;18:928–936.
  23. Wilson J, Jones M, Fear NT, Hull L, Hotopf M, Wessely S, Rona RJ: Is previous psychological health associated with the likelihood of Iraq War deployment? An investigation of the ‘healthy warrior effect’. Am J Epidemiol 2009;169:1362–1369.
  24. Defense Science Board: Report of the Defense Science Board Task Force on Persian Gulf War health effects. Washington, Office of the Under Secretary of Defense for Acquisition and Technology, 1994.
  25. 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;157:227–233.
  26. Kang HK, Mahan CM, Lee KY, Murphy FM, Simmens SJ, Young HA, Levine PH: Evidence for a deployment-related Gulf War syndrome by factor analysis. Arch Environ Health 2002;57:61–68.
  27. Cherry N, Creed F, Silman A, Dunn G, Baxter D, Smedley J, Taylor S, Macfarlane GJ: Health and exposures of United Kingdom Gulf war veterans. I. The pattern and extent of ill health. Occup Environ Med 2001;58:291–298.
  28. Blanchard MS, Eisen SA, Alpern R, Karlinsky J, Toomey R, Reda DJ, Murphy FM, Jackson LW, Kang HK: Chronic multisymptom illness complex in Gulf War I veterans 10 years later. Am J Epidemiol 2006;163:66–75.
  29. Horner RD, Kamins KG, Feussner JR, Grambow SD, Hoff-Lindquist J, Mitsumoto H, Pascuzzi R, Spencer P, Tim R, Howard D, Smith TC, Ryan MA, Coffman CJ, Kasarskis EJ: Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology 2003;61:742–749.
  30. Institute of Medicine: Gulf War and Health. Washington, National Academies Press, 2004, vol 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines; vol 2: Insecticides and Solvents – Updated Literature Review on Sarin; vol 3: Fuels, Combustion Products, and Propellants.
  31. Araneta MR, Moore CA, Olney RS, Edmonds LD, Karcher JA, McDonough C, Hiliopoulos KM, Schlangen KM, Gray GC: Goldenhar syndrome among infants born in military hospitals to Gulf War veterans. Teratology 1997;56:244–251.
  32. Iowa Persian Gulf Study Group: Self-reported illness and health status among Gulf War veterans: a population-based study. The Iowa Persian Gulf Study Group. JAMA 1997;277:238–245.
  33. Nagelkerke NJD: A note on a general definition of the coefficient of determination. Biometrika 1991;78:691–692.

    External Resources

  34. Dever JA, Mason RE: DMDC Sampling Planning Tool (Version 2.1). Arlington, Defense Manpower Data Center, 2003.
  35. Kuhn WW, Tucker AW: Nonlinear Programming. Proceedings of the Second Berkeley Symposium on Mathematical Statistics and Probability. Berkeley, University of California Press, 1951, pp 481–492.
  36. Mason RE, Wheeless SC, George BJ, Dever JA, Riemer RA, Elig TW: Sample Allocation for the Status of the Armed Forces Surveys. Proceedings of the Section on Survey Research. Alexandria, American Statistical Association, 1995, pp 769–774.
  37. Hillier FS, Lieberman GJ: Operations Research, ed 2. San Francisco, Holden-Day, 1974.
  38. Fukuda K, Nisenbaum R, Stewart G, Thompson WW, Robin L, Washko RM, Noah DL, Barrett DH, Randall B, Herwaldt BL, Mawle AC, Reeves WC: Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA 1998;280:981–988.
  39. American Association for Public Opinion Research: Standard Definitions: Final Dispositions of Case Codes and Outcome Rates for Surveys, ed 5. Lenexa, AAPOR, 2008.
  40. Groves R, Couper M: Nonresponse in Household Interview Surveys. New York, Wiley & Sons, 1998.
  41. Iannacchione V: Sequential weight adjustments for location and cooperation propensity for the 1995 National Survey of Family Growth. J Offic Statist 2010;19:31–43.
  42. Breiman L, Friedman J, Stone C, Olshen R: Classification and Regression Trees. New York, CRC Press, 1984.
  43. Muthen LK, Muthen BO: Mplus User’s Guide, ed 5. Los Angeles, Muthen & Muthen, 2007.
  44. Ware J Jr, Kosinski M, Keller SD: SF-12: How to Score the SF-12 Physical and Mental Health Summary Scales. Boston, New England Medical Center, 1995.
  45. SUDAAN Language Manual, Release 10.0. Research Triangle Park, Research Triangle Institute, 2008.
  46. Ware J Jr, Kosinski M, Keller SD: A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996;34:220–233.
  47. Hays RD, Farivar SS, Liu H: Approaches and recommendations for estimating minimally important differences for health-related quality of life measures. COPD J Chron Obstruct Pulm Dis 2005;2:63–67.

    External Resources

  48. Hu L-T, Bentler PM: Fit indices in covariance structure modeling: sensitivity to underparameterized model misspecification. Psychol Methods 1998;3:424–453.

    External Resources

  49. Hu L-T, Bentler PM: Cutoff criteria for fit indexes in covariance structure analysis: conventional criteria versus new alternatives. Struct Equat Modeling 1999;6:1–55.

    External Resources

  50. Byrne BM: Structural Equation Modeling with EQS and EQS/Windows: Basic Concepts, Applications, and Programming. Thousand Oaks, Sage Publications, 1994.
  51. Ware JE, Snow KK, Kosinski M, Gandek B: SF-36 Health Survey Manual and Interpretation Guide. Boston, Health Institute, 1997.
  52. Haley RW, Kramer GL, Xiao J, Teiber JF: Nerve agent exposure associated with Gulf War encephalopathy through gene-environment interaction with the Q192R polymorphism of paraoxonase 1 (PON1). 49th Annual Meeting of the Society of Toxicology, Salt Lake City, March 2010, Neurotoxicity and Neurodegenerative Disease Session, abstract No 2242.
  53. Hays RD, Sherbourne CD, Spritzer KL, Dixon WJ: A microcomputer program (sf36.exe) that generates SAS code for scoring the SF-36 health survey. Proceedings of the 22nd Annual SAS Users Group International Conference, 1996, pp 1128–1132.

 goto top of outline Author Contacts

Prof. Robert W. Haley, MD
Division of Epidemiology, Department of Internal Medicine
University of Texas Southwestern Medical Center
5323 Harry Hines Blvd, Dallas, TX 75390-8874 (USA)
Tel. +1 214 648 3075, E-Mail

 goto top of outline Article Information

Received: June 7, 2011
Accepted: August 3, 2011
Published online: October 7, 2011
Number of Print Pages : 12
Number of Figures : 3, Number of Tables : 5, Number of References : 53

 goto top of outline Publication Details


Vol. 37, No. 2, Year 2011 (Cover Date: October 2011)

Journal Editor: Feigin V.L. (Auckland)
ISSN: 0251-5350 (Print), eISSN: 1423-0208 (Online)

For additional information:

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.