Point estimation following two-stage adaptive threshold enrichment clinical trials

Peter K. Kimani, Susan Todd, Lindsay A. Renfro, Nigel Stallard

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


Recently, several study designs incorporating treatment effect assessment in biomarker-based subpopulations have been proposed. Most statistical methodologies for such designs focus on the control of type I error rate and power. In this paper, we have developed point estimators for clinical trials that use the two-stage adaptive enrichment threshold design. The design consists of two stages, where in stage 1, patients are recruited in the full population. Stage 1 outcome data are then used to perform interim analysis to decide whether the trial continues to stage 2 with the full population or a subpopulation. The subpopulation is defined based on one of the candidate threshold values of a numerical predictive biomarker. To estimate treatment effect in the selected subpopulation, we have derived unbiased estimators, shrinkage estimators, and estimators that estimate bias and subtract it from the naive estimate. We have recommended one of the unbiased estimators. However, since none of the estimators dominated in all simulation scenarios based on both bias and mean squared error, an alternative strategy would be to use a hybrid estimator where the estimator used depends on the subpopulation selected. This would require a simulation study of plausible scenarios before the trial.

Original languageEnglish
Pages (from-to)3179-3196
Number of pages18
JournalStatistics in Medicine
Issue number22
Publication statusPublished - 30 Sept 2018
Externally publishedYes


  • biomarker
  • multistage
  • personalized medicine
  • subgroup or subpopulation selection
  • targeted therapy


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