Presentation – Dr. Lea Steele - IOM Gulf War Illness "CMI" Panel.
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Transcript of Presentation – Dr. Lea Steele - IOM Gulf War Illness "CMI" Panel.
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
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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
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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
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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 patternsof 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
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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
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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
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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 GWI—insights for establishing symptom domains, but “factors are not syndromes”; approach has been misleading in relation to “unique syndrome” debate
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Studies Identify Consistent Symptom Pattern
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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 definitions—strengths 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
Conceptual, Analytic Considerations:
What Makes a Good Case Definition?
Discussion of Sensitivity, Specificity, Use of Exclusionary Conditions
Evaluating Impact of Different Case Def Algorithms
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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 DefinitionLacks Specificity
Case DefinitionLacks Sensitivity
1 2 3
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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 syndromes—complex 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 don’t have it
- Identify consistent group(s) of patients for research studies
GWI Target
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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
1-2 Symptom Groups 3+ Symptom Groups0%
10%
20%
30%
40%Nondeployed Veterans
Gulf War Veterans
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Prevalence of Exclusionary Conditions and Symptom GroupsAmong Kansas Gulf War-Era Veterans
Any Exclusionary Condition No Exclusionary Conditions, 1-2 Symptom Groups
No Exclusionary Conditions, 3+ Symptom Groups
0%
10%
20%
30%
40%Nondeployed Veterans
Gulf War veterans
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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)
Diagnosis/Condition dx by PhysicianNumber of Veterans Percent
Chronic problems due to serious injury 27 4%
Heart disease 21 3%
Cancer 18 3%
Diabetes 18 3%
Liver disease 12 2%
Dx schizophrenia 3 < 1%
Excluded for any medical diagnoses 102 16%
Excluded for any psych diagnoses 12 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
OR: CDC Case Def
OR:KS Case Def
Wore pesticide-treated uniforms 1.88 3.72*
Used pesticides on skin 2.30* 2.89*
Used PB pills 1.99* 3.21*
Participated in ground combat 1.43 1.42
Heard chemical alarms 1.09 1.31
Living area fogged with pesticides 1.03 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 CDMRP’s 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 MeetingDiscussions 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
“ 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, I’ve 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