A predictive enrichment procedure to identify potential responders to a new therapy for randomized, comparative controlled clinical studies

Junlong Li, Lihui Zhao, Lu Tian, Tianxi Cai, Brian Claggett, Andrea Callegaro, Benjamin Dizier, Bart Spiessens, Fernando Ulloa-Montoya, Lee Jen Wei

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


To evaluate a new therapy versus a control via a randomized, comparative clinical study or a series of trials, due to heterogeneity of the study patient population, a pre-specified, predictive enrichment procedure may be implemented to identify an "enrichable" subpopulation. For patients in this subpopulation, the therapy is expected to have a desirable overall risk-benefit profile. To develop and validate such a "therapy-diagnostic co-development" strategy, a three-step procedure may be conducted with three independent data sets from a series of similar studies or a single trial. At the first stage, we create various candidate scoring systems based on the baseline information of the patients via, for example, parametric models using the first data set. Each individual score reflects an anticipated average treatment difference for future patients who share similar baseline profiles. A large score indicates that these patients tend to benefit from the new therapy. At the second step, a potentially promising, enrichable subgroup is identified using the totality of evidence from these scoring systems. At the final stage, we validate such a selection via two-sample inference procedures for assessing the treatment effectiveness statistically and clinically with the third data set, the so-called holdout sample. When the study size is not large, one may combine the first two steps using a "cross-training-evaluation" process. Comprehensive numerical studies are conducted to investigate the operational characteristics of the proposed method. The entire enrichment procedure is illustrated with the data from a cardiovascular trial to evaluate a beta-blocker versus a placebo for treating chronic heart failure patients.

Original languageEnglish (US)
Pages (from-to)877-887
Number of pages11
Issue number3
StatePublished - Sep 1 2016


  • Cox model
  • Cross-validation
  • Stratified medicine
  • Survival analysis
  • Therapy-diagnostic co-development

ASJC Scopus subject areas

  • Statistics and Probability
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)
  • Applied Mathematics

Fingerprint Dive into the research topics of 'A predictive enrichment procedure to identify potential responders to a new therapy for randomized, comparative controlled clinical studies'. Together they form a unique fingerprint.

Cite this