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Heterogeneity of Treatment Effects: Strategies & Methods - - PowerPoint PPT Presentation
Heterogeneity of Treatment Effects: Strategies & Methods - - PowerPoint PPT Presentation
Heterogeneity of Treatment Effects: Strategies & Methods University of Cincinnati Sheldon Greenfield, MD Sherrie H. Kaplan, PhD, MPH Health Policy Research Institute University of California, Irvine May 20, 2012 Definition of
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Definition of Heterogeneity of Treatment Effects
- Variation in outcomes within clinically
defined populations
- Disjunction between the overall (
summary, average ) effects of a treatment vs. effects in individuals or subsets
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Urgency
- Evolving disease epidemiology: the
failure of chronic disease nosology
- Quality, CPGs, coverage
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3 Overarching Causes
- Genetic/biologic
- Clinical stage/severity/outcome risk
- Beyond the disease: comorbidity,
passivity, burden, “resiliency”
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Understudied Sources of Individual Patient Variation
Heterogeneity of treatment effects can be due to variables that include:
- Biologic causes (e.g. biomarkers, stages
detected by imaging, differences in metabolism, etc.).
- Disease severity (i.e. those sicker at
baseline respond more favorably)
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Understudied Sources of Individual Patient Variation (cont’)
- Comorbidity, as a determinant of response
due to:
- Competing risk for mortality or other
- utcomes
- Disease-disease interactions
- Drug-drug interactions
- Burden of polypharmacy
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Understudied Sources of Individual Patient Variation (cont’)
- Functional status, quality of life,
resilience
- Social support
- Depression or other mental health
problems
- Medical context, e.g.
- Willingness and ability to work with
providers to optimize/tailor treatments
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Understudied Sources of Individual Patient Variation (cont’)
- Personal, cultural
- Adherence to treatment
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Recent Trials With Misleading Results
- Prostate cancer
- Carotid endarterectomy
- Healthy
- ASA for peripheral vascular disease
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- ACCORD
- ADVANCE
- DVT
- CATIE
Recent Trials With Misleading Results
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The Diabetes Story
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Reduction in Risk for Cardiovascular Events Associated With HbA1c Level 6.5% or Less or 7.0% or Less, by TIBI Subgroup
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Solutions
- Don’t do studies with mixed
populations: use prior data
- Stratified studies/ matching
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Multivariable Models
- CHADS
- GRACE
- Atrial fibrillation
- Endarterectomy
- TIBI
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Hypothetical Example
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The Total Illness Burden Index: Scoring and Validation
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Dimensions of the TIBI
Hearing Problems Gastro- Intestinal Disease Pulmonary Disease Arthritis Stroke and Neurological Disease Atherosclerotic Heart Disease Foot Disease Congestive Heart Failure Eye and Vision Conditions Total Illness Burden (TIBI)
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Scoring Shortness of Breath
1. During the past 4 weeks, how often have you felt short of breath… (circle one number on each line) ALL of the Time MOST
- f the
Time SOME of the Time A LITTLE
- f the
Time NONE
- f the
Time
- a. When lying down flat?…………………………………………..
1 2 3 4 5
- b. When sitting, resting?…………………………………………...
1 2 3 4 5
- c. When walking less than one block?…………………………...
1 2 3 4 5
- d. When climbing one flight of stairs?…………….……………...
1 2 3 4 5
- e. When climbing several flights of stairs?……….……………..
1 2 3 4 5
- If any in orange zone are circled, add 5
- If any in yellow zone are circled, add 3
- If any in green zone are circled, add 1
- Note: Risk factors from other questions (swelling in ankles, Hx of heart
disease, etc) may result in addition of 1 more.
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Scoring COPD
If one tablespoon or more, add 2 to total. If less than a teaspoon add 1 to total. If none, add 0 to total.
1. Do you have a regular or daily cough? (check one) NO YES
1 2
- 8a. When you cough, how much phlegm or sputum do you cough up?
(circle one) None………………………………………………………………. 1 Less than a teaspoonful a day…………………………………. 2 About a tablespoonful a day…………………………………… 3 Several tablespoonfuls a day………………………………….. 4 About a cup or more a day……………………………………... 5
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Scoring COPD
Have you ever been told by a physician that you have any
- f the following problems with your breathing?
NO YES Emphysema…………………………………………………………..
1 2
Chronic bronchitis………………………………….….……………..
1 2
Asthma…………………………………………………………………
1 2
If “yes” to any of these, add 1 to total.
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Steps in Constructing Subdimensions
- Transformed variables to uniform metric
- Tested reliability of clinically defined scale
(Cronbach’s alpha > .80)
- Created composite of each subdimension using
simple algebraic sum, mean
- Items in each subdimension varied
- Validated each subdimension as scale using
SF-36, etc.
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Summing the Scales
- A total score for TIBI is computed by
transforming and summing all of the scales.
- Validation of composite score robust across
scoring methods.
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Table 4. Domain scores for each disease cohort: outcome category discrimination by ENSEMBLE MDS domains
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Table 4. Domain scores for each disease cohort: outcome category discrimination by ENSEMBLE MDS domains
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Conclusions
- With CER, heterogeneity cannot be
ignored
- Need to collect data on causes
- Need solutions such as stratification