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Bayesian Subgroup Analysis

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### Bayesian Subgroup Analysis

Gene Pennello, Ph.D. Division of Biostatistics, CDRH, FDA

Disclaimer: No official support or endorsement of this presentation by the Food & Drug Administration is intended or should be inferred.

FIW 2006 September 28, 2006

Outline

Frequentist Approaches

Bayesian Hierarchical Model Approach

Bayesian Critical Boundaries

Directional Error Rate

Power

Summary

Frequentist Approaches

Strong control of FWE

Weak control of FWE

Gatekeeper: test subgroups (controlling FWE) only if overall effect is significant

Confirmatory Study: confirm with a new study in which only patients in the subgroup are enrolled.

Concerns with Frequentist Approaches

Limited power of FWE procedures

Powerlessness of gatekeeper if overall effect is insignificant

Discourages multiple hypothesis testing, thereby impeding progress.

Confirmation of findings, one at a time, impedes progress.

“No aphorism is more frequently repeated in connection with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Fisher RA, 1926, The arrangement of field experiments, Journal of the Ministry of Agriculture, 33, 503-513.

A Bayesian Approach with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Adjust subgroup inference for its consistency with related results.

Choices Build prior on subgroup relationships.

Invoke relatedness by modeling a priori exchangeability of effects.

Prior Exchangeability Model with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Subgroups: Labels do not inform on magnitude or direction of main subgroup effects.

Treatments: Labels do not inform for main treatment effects.

Subgroup by Treatment Interactions: Labels do not inform for treatment effects within subgroups.

Prior Exchangeability Model with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Exchangeability modeled with random effects models.

Key Result: Result for a subgroup is related to results in other subgroups because effects are iid draws from random effect distribution.

Bayesian Two-Way Normal Random Effects Model with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Bayesian Two-Way Normal Random Effects Model with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Note: In prior distribution, Pr(zero effect) = 0

That is, only directional (Type III) errors can be made here.

Known Variances Inference with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Subgroup Problem:

Posterior

Note: In prior distribution, Pr(zero effect) = 0

That is, only directional (Type III) errors can be made here.

Bayes Decision Rule with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Declare difference > 0 if

Let

Note: In prior distribution, Pr(zero effect) = 0

That is, only directional (Type III) errors can be made here.

if with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Bayes Critical z ValueLinear dependence on standardized marginal treatment effect

↑ with ↓interaction (↑ ) ↓with ↑ # subgroups b.

Full Interaction Case with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”:

Critical z value

↑ with ↓ true F ratio measuring heterogeneity of interaction effects.

Bayes Critical z ValueNo Interaction Case with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”:

Critical z value

Power can be > than for unadjusted 5% level z test for subgroup if true F ratio measuring heterogeneity of treatment effects is large.

Bayes Critical z ValueFull Bayes Critical t Boundaries with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Directional Error Control with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Directional FDR controlled at A under 0-1-A loss function for correct decision, incorrect decision, and no decision (Lewis and Thayer, 2004).

Weak control of FW directional error rate, loosely speaking, because of dependence on F ratio for interaction.

Comparisons of Sample Size to Achieve Same Power with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

ULSD = 5% level unadjusted z test Bonf = Bonferonni 5% level z test HM = EB hierarchical model test

EX. Beta-blocker for Hypertension with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Losartan versus atenolol randomized trial

Endpoint: composite of Stroke/ MI/ CV Death

N=9193 losartan (4605), atenolol (4588)

# Events losartan (508), atenolol (588)

80% European Caucasians 55-80 years old.

http://www.fda.gov/cder/foi/label/2003/020386s032lbl.pdf

EX. Beta-blocker for Hypertension with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Cox Analysis

N logHR SE HR (95% CI) p val

Overall9193 .87 ( .77, .98) 0.021

Race SubgroupsNon-Black 8660 -.19 .06 .83 ( .73, .94) 0.003Black 533 .51 .24 1.67 (1.04,2.66) 0.033

Is Finding Among Blacks Real or a Directional Error?

EX. Beta-blocker for Hypertension with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Bayesian HM Analysis

logHR se/sd HR (95%CI) p val Pr>0non-blackfrequentist -.19 .06 0.83 ( .73 .94) 0.003 0.001Bayesian -.18 .06 0.84 ( .74, .95) 0.003

blackfrequentist .51 .24 1.67 (1.04, 2.67) 0.033 0.983Bayesian .38 .27 1.47 (0.87, 2.44) 0.914Bayesian analysis cast doubt on finding, but is predicated on not expecting a smaller effect in blacks a priori.

Suggested Strategy with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Planned subgroup analysis

Bayesian adjustment using above HM or similar model

Pennello,1997, JASASimon, 2002, Stat. Med. Dixon and Simon, 1991, Biometrics

Suggested Strategy with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Unplanned subgroup analysis

Ask for confirmatory trial of subgroup.

Posterior for treatment effect in the subgroup given by HM is prior for confirmatory trial.

Prior information could reduce size of confirmatory trial.

Summary with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Bayesian approach presented here considers trial as a whole, adjusts for consistency in finding over subgroups.

Error rate is not rigidly pre-assigned Can vary from conservative to liberal depending on interaction F ratio and marginal treatment effect.

Power gain can be substantial.Control for directional error rate is made only when warranted.

References with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Dixon DO and Simon R (1991), Bayesian subset analysis, Biometrics, 47, 871-881.

Lewis C and Thayer DT (2004), A loss function related to the FDR for random effects multiple comparisons, Journal of Statistical Planning and Inference125, 49-58.

Pennello GA (1997), The k-ratio multiple comparisons Bayes rule for the balanced two-way design, J. Amer. Stat. Assoc.,92, 675-684

Simon R (2002), Bayesian subset analysis: appliation to studying treatment-by-gender interactions, Statist. Med., 21, 2909-2916.

Sleight P (2000), Subgroup analyses in clinical trials: fun to look at but don’t believe them!, Curr Control Trials Cardiovasc Med, 1, 25-27.

Other Notable References with field trials, than that we must ask Nature few questions, or, ideally, one question at a time. The writer is convinced that this view is wholly mistaken. Nature, he suggests, will best respond to a logical and carefully thought out questionnaire …”

Berry DA, 1990, Subgroup Analysis (correspondence) Biometrics, 46, 1227-1230.

Gonen M, Westfall P, Johnson WO (2003), Bayesian multiple testing for two-sample multivariate endpoints, Biometrics, 59, 76-82.

Westfall PH, Johnson WO, and Utts JM (1997), A Bayesian perspective on the Bonferroni adjustment, 84, 419-427

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