Developing a Case Definition for Gulf War Illness

Input from the RAC-GWVI and VA Gulf War Research Strategic Planning Group

Lea Steele, Ph.D. Institute of Biomedical Studies Baylor University June 26, 2013

Developing a Case Definition for Gulf War Illness

Overview: After 22 years, the urgent need for an evidence-based, widely accepted case definition for Gulf War Illness
RAC-GWVI Literature Review and Findings re: GWI Case Definition

VA Gulf War Research Strategic Plan: Case Definition Process

What Makes a Good Case Def? Methodology Matters DOD CDMRP-supported Case Definition Efforts Case Definition Issues Raised at recent RAC-GWVI meeting

Overview:
Defining Gulf War Illness in 1990-91 Gulf War Veterans

Overview: Post War Illness in 1990-1991 Gulf War Veterans What is It? What is it Called?
Gulf War Syndrome, Undiagnosed Illness, Gulf War Veterans Illnesses, Chronic Multisymptom Illness, Gulf War Illness

In general terms, refer to the same thing: well-documented pattern of symptoms found at significantly elevated rates in 1990-91 Gulf War veterans Not explained by standard lab tests or by well-established medical or psych diagnoses; not explained by combat, war stressors Widespread problem in 1990-91 vets; longitudinal studies indicate few veterans have recovered or substantially improved in the 22 years since the war

Overview: Illness in 1990-1991 Gulf War Veterans

Important time in GWI research

Very limited research evidence in early years; in past decade--improved quality and focus of research Enhanced evidence base gives more cohesive picture re: GWI patterns of occurrence, etiology, pathobiology (CNS, ANS, immune/inflammatory, neuroendocrine) Parallel insights from animal models of persistent, delayed CNS and ANS effects of low-level GW neurotoxicants Growing number of treatment studies, research to identify biomarkers 2 multi-institutional GWI research consortia bring together many of most prominent GWI researchers; focus on detailed understanding of GWI pathophys, identifying specific treatment targets

Illness in 1990-1991 Gulf War Veterans

Problem: Still no generally accepted case definition for GWI
After 22 years, hundreds of millions of dollars of research

Studies use different case definitions, sometimes no case definition

Research results difficult to interpret, impossible to integrate Has slowed progress for understanding, addressing this problem Important that case def be established, and done well

RAC-GWVI Review and Findings re: GWI Case Definition

GWI--umbrella term for complex of chronic symptoms associated with service in 1991 Gulf War
Consistent profile of symptoms in statistically-defined domains Currently can only define by symptoms; 2008 Report describes six different case definitions, 4 other approaches for defining cases Since 2008, limited additional research re: case definition, literature to be updated in 2013 RAC report

RAC-GWVI Literature Review and Findings re: GWI Case Definition

2008 Report describes six different case definitions, 4 other approaches for defining cases (e.g. Haley syndromes, Fukuda/CDC CMI case def, VA-factor analysis syndrome, Kansas GWI)

Reflect similar symptom domains, different methods used for quantifying and combining those symptoms Produce case defs ranging from very broad to very narrow Examined use of factor analysis in defining GWIinsights for establishing symptom domains, but factors are not syndromes; approach has been misleading in relation to unique syndrome debate

Studies Identify Consistent Symptom Pattern

RAC-GWVI Review and Findings re: GWI Case Definition

GWI prevalence differs with different case definitions and modifications used by different studies
Prevalence also assessed in nondeployed, era veterans

provides sense of specificity of case definition approach represents background level of symptomatic illness expected in absence of GW service

Excess burden of GWI (prevalence difference) consistently 26-32% across studies

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RAC-GWVI Literature Review and Findings re: GWI Case Definition

Evidence demonstrating the importance of defining GWI as the pattern of symptoms specifically associated with military service in the 1990-1991 Gulf War GWI symptom profile and distribution are distinct: not the same as happens after every war; studies show marked differences from Vietnam, Bosnia, Iraq War veterans Studies also show GWI is distinct from multisymptom illnesses in general population (e.g. CFS, fibromyalgia); overall differences in symptom profile, biological parameters, distribution Only fraction of veterans with GWI meet criteria for CFS, FM, MCS

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VA Gulf War Research Strategic Plan: Case Definition Process

Recently released VA Gulf War Research Strategic Plan: 2013 2017 Major undertaking: initiated in April 2011

Led by Dr. Max Buja: 10 working groups, >45 participants (included members of 3 different VA research advisory panels and VA researchers, administrators)

5.3: Establish an Evidence-Based Case Definition of Chronic Multisymptom Illness in Gulf War Veterans

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VA Gulf War Research Strategic Plan:

5.3: Establish an Evidence-Based Case Definition of Chronic Multisymptom Illness in Gulf War Veterans

Calls for establishment of case definition for CMI in Gulf War veterans, and guidelines for its use Specifies that case definition be evidence-based, and developed by consensus of experts

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VA Gulf War Research Strategic Plan:

5.3: Establish an Evidence-Based Case Definition of Chronic Multisymptom Illness in Gulf War Veterans

Specifies the need for a comprehensive analytic effort, using extensive amount of available data

Analytic assessment of existing case definitionsstrengths and weaknesses in relation to priorities of interest Assessment of different algorithms, strategies for optimizing case def

Outlines major issues to be considered in optimizing case definition

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VA Gulf War Research Strategic Plan:

5.3: Establish an Evidence-Based Case Definition of Chronic Multisymptom Illness in Gulf War Veterans
Identifies, describes major considertions in optimizing case definition

Specificity Sensitivity Reliability Portability Strategy for considering other medical/psych conditions to be exclusionary for CMI (vs. comorbid) Subgroup identification Use in clinical practice, and special considerations

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Conceptual, Analytic Considerations:

What Makes a Good Case Definition?

Discussion of Sensitivity, Specificity, Use of Exclusionary Conditions Evaluating Impact of Different Case Def Algorithms

What Makes a Good GWI Case Definition?

True Gulf War Illness Target Condition

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What Makes a Good GWI Case Definition?

Gulf War Illness Case Definition

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What Makes a Good Case Definition?

Ideal Case Definition Case Definition Lacks Specificity

Case Definition Lacks Sensitivity

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Available GWI Case Definitions: From Very Broad to Very Narrow

Oregon GWUI: 1 unexplained symptom required (prev: unknown) CDC CMI: 1 symptom required in 2 of 3 symptom domains (prev: ~ 50% of GW veterans)

Kansas GWI: Moderately severe symptoms required in 3 of 6 symptom domains (prev: ~ 34% of GW veterans)
Haley: 3 syndromescomplex algorithm to determine symptom scores (combined prev: ~ 14 % of GW veterans) Kang/VA: 4 neurological symptoms (prev: ~2% of GW veterans)
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How Many Veterans Affected? Multisymptom illness affects excess of 25-32% of Gulf War Veterans

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What Makes a Good Case Definition?

Depends on purpose Should distinguish individuals with the

condition from those who dont have it

GWI Target

- Identify consistent group(s) of patients for research studies

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Analytic Considerations in Developing Algorithm to Define GWI

Illustrating examples using data from Kansas Veterans

Kansas study (1998-1999): Survey, symptom inventory modeled on large population-based studies through 1998 (CDC Air Force, Iowa, UK study, NHRC, VA National Survey)
1998 Goals: to determine if Kansas veterans had health problem associated with service in 1990-1991 war If so, to describe the problem(s) Kansas study: 1,548 GW veterans, 482 nondeployed era veterans 6 statistically -defined symptom domains significantly higher in GW veterans

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Considerations in Developing Algorithm for Defining GWI: Example using data from Kansas Veterans

6 statistically -defined symptom domains sign. higher in GW vets: Fatigue/sleep problems Somatic pain symptoms Neuro/cognitive/mood symptoms Gastrointestinal symptoms Respiratory symptoms Skin symptoms Roughly same proportion (29-30%) of Gulf War and nondeployed veterans had some symptoms in 1 or 2 symptom domains Roughly same proportion reported dx with many medical conditions (e.g., diabetes, heart disease, cancers) but several dx (e.g. migraines, CFS, PTSD) were sign. higher in GW veterans
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Burden of Symptoms in Kansas Gulf War Era Veterans

40%
Nondeployed Veterans Gulf War Veterans

30%

20%

10%

0%
1-2 Symptom Groups 3+ Symptom Groups

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Prevalence of Exclusionary Conditions and Symptom Groups Among Kansas Gulf War-Era Veterans
40%
Nondeployed Veterans Gulf War veterans

30%

20%

10%

0%
Any Exclusionary Condition No Exclusionary Conditions, 1-2 Symptom Groups No Exclusionary Conditions, 3+ Symptom Groups

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Raises Issues re: Specificity

Consideration of Exclusionary Criteria in Defining GWI

Issue: Can (or should) GW veterans with diagnosed conditions also be considered GWI cases?

Can be tricky: Pros and cons differ for different studies, in different situations (e.g., large/small, cohort/case-control, different study questions, etc. )
Evidence can inform this decision: can evaluate impact of incorporating different strategies for using exclusionary criteria

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Exclusionary Diagnoses (Kansas GWI case def)

Later sample of 646 KS and Missouri Gulf War Vets (2001)
Number of Veterans
27 21 18 18 12

Diagnosis/Condition dx by Physician
Chronic problems due to serious injury Heart disease Cancer Diabetes Liver disease

Percent 4% 3% 3% 3% 2%

Dx schizophrenia Excluded for any medical diagnoses

Excluded for any psych diagnoses

3 102
12

< 1% 16%
2%

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Impact of Use of Different GWI Case Definitions on Research Results

Issue: What are effects of using broader/narrower GWI case definitions on research findings? Can evaluate analytically in multiple ways, e.g. effects on direction and magnitude of association of GWI with different risk factors Example: Use of CDC, Kansas case defs generally identify same direction of association, but different magnitude

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Use of Different Case Definitions to Assess Risk Factors for Gulf War Illness in 304 Kansas and Missouri GW Veterans

Exposure/ Risk Factor

Wore pesticide-treated uniforms Used pesticides on skin Used PB pills Participated in ground combat Heard chemical alarms Living area fogged with pesticides

OR: CDC Case Def 1.88 2.30* 1.99* 1.43 1.09 1.03

OR: KS Case Def 3.72* 2.89* 3.21* 1.42 1.31 1.33

__________ *p< 0.05

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VA Strategic Planning Group

Rationale for Case Definition based on Expert Consensus and Evidence-driven Analytic Effort
Comprehensive analytic effort

GWI is complex, challenging to study. Essential that ambiguity be minimized to the extent possible Unlike other conditions, extensive amount of population-based symptom data available; suitable comparison group allows refinement Encourages buy-in for broader use of case definition

Expert Consensus

As with any health condition, case definition is best developed by those who are most experienced in conducting research and treating patients with that condition This expertise is needed to best identify and weigh pros/cons of different elements of the case definition Also encourages buy-in, for broader use of case definition

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DOD Office of Congressionally Directed Medical Research Programs (CDMRP) GWIRP

Major priorities of CDMRPs GWI Research Program include improvement of GWI case definition

CDMRP has funded 2 large projects, now underway:

Fort Devens cohort: longitudinal evaluation of symptom data to improve GWI case definition, based on current symptom profile

Baylor project (with Westat): National study of Gulf War and era veterans to characterize current symptoms, optimize case definition

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Recent RAC-GWVI Meeting Discussions re: IOM Case Definition Assignment

May 2013: VA contracts with IOM to produce consensus case definition for multisymptom illness in GW veterans Charge to IOM Panel: Comprehensive review of the literature Info sources: literature on CMI in 1990-1991 GW veterans, other military populations, other populations Discussions with researchers who have developed case defs in GWV, clinicians who treat GWV

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In Light of Process Outlined by VA Strategic Plan, Concerns raised re: IOM development of GWI case definition

Charge appears to center on a literature review; no analytic use of the extensive data available to develop case definition No consideration of the 2 major case definition projects currently funded by DOD/CDMRP

No GWI expert consensus; no broad representation of scientists, clinicians most experienced in GWI research and patient care; no representation of CDMRP
With notable exceptions, panel members have limited research experience specific to GWI, little background in developing symptom-based case definitions Historically, IOM has not undertaken this type of project
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Assignment of Case Definition to IOM

Historically, IOM has not undertaken this type of project; no previous examples of IOM developing case definition

Earlier this year, IOM treatments panel devised their own case definition for chronic multisymptom illness (for purposes of report): rationale and methods unclear, not specified Chronic symptoms in at least 2 of 6 categories: fatigue, mood/cognition, musculoskeletal, gastrointestinal, respiratory, neurologic

Did not appear to use available evidence or GWI expertise (no literature review, no input from GWI experts, no analytic use of data resources)

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Summary

Until diagnostic biomarkers become available, advances in GWI research can be greatly facilitated by establishing a strong, consistently used case definition Evidence-based, using comprehensive analytic effort to assess optimal algorithm and case definition parameters Developed by consensus of broad representation of researchers, clinicians most expert in GWI

Current IOM charge for developing case definition does not appear to address the benchmarks set by VA GW Strategic Plan Solutions ? RAC discussions included changing or withdrawing IOM charge, other creative solutions for modifying the process

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 My symptoms began in the Gulf with severe abdominal cramping and severe diarrhea. I also had terrible headaches and bouts of dizziness and tingling. Once I returned to the base in Germany, the headaches persisted, and I experienced the cramps and diarrhea on a cyclic basis. I also went through periods of night sweats. And there were periods where I would sleep a lot because I was so fatigued. My joints were stiff, and my knees would swell after I ran. It was harder for me to do things without feeling short of breath. These symptoms became worse as time passed. Ever since my return from the Gulf, Ive been plagued by multiple rashes and lesions on my face, neck, arms and back. They come and go.
SSgt BJ, Desert Storm veteran, U.S. Army