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Identification and inference for subgroups with differential treatment efficacy from randomized controlled trials
Yue Wei1, Jason C Hsu2, Wei Chen3
1Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Statistics in Medicine
|September 20, 2021
Summary
This study introduces a new statistical method to find patient subgroups that benefit most from targeted therapies in clinical trials. The approach successfully identified subgroups with differential treatment efficacy for age-related macular degeneration (AMD).
Area of Science:
- Biostatistics
- Genetics
- Ophthalmology
Background:
- Modern clinical trials increasingly focus on targeted therapies for specific patient subgroups, moving away from a one-size-fits-all approach.
- Identifying these subgroups is crucial for developing personalized medicine and optimizing treatment efficacy.
- Time-to-event outcomes are common in clinical trials, particularly for diseases like age-related macular degeneration (AMD).
Purpose of the Study:
- To develop a simultaneous inference procedure for identifying and inferring subgroups with differential treatment efficacy in randomized controlled trials (RCTs) with time-to-event outcomes.
- To apply this method to the Age-Related Eye Disease Study (AREDS) data to assess the efficacy of nutritional supplements in delaying AMD progression.
- To validate the findings in an independent RCT, AREDS2.
Main Methods:
- Formulation of a multiple testing problem through contrasts.
- Construction of simultaneous confidence intervals to control within- and across-marker multiplicity.
- Application of the method to AREDS and AREDS2 data, using realistic simulations with real genotype data for performance evaluation.
Main Results:
- The developed method successfully identified patient subgroups with differential treatment efficacy in the AREDS trial.
- Specific gene regions, including ESRRB-VASH1 on chromosome 14, were associated with subgroups showing varied responses to antioxidants and zinc combination therapy for AMD.
- Consistent differential treatment responses were observed in targeted and non-targeted subgroups when validating findings in the AREDS2 trial.
Conclusions:
- The multiple-testing-based simultaneous inference approach provides a robust framework for confidently identifying and inferring patient subgroups with differential treatment effects.
- This methodology represents a significant advancement for modern drug development, enabling more precise targeting of therapies.
- The findings highlight the potential for personalized nutritional interventions in managing age-related macular degeneration.
Keywords:
AMD progressionCE4cross-talk plotmultiple testingratio of quantile survivalsubgroup identificationMore Related Videos
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