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Point estimation following two-stage adaptive threshold enrichment clinical trials

Kimani, P. K., Todd, S., Renfro, L. A. and Stallard, N. (2018) Point estimation following two-stage adaptive threshold enrichment clinical trials. Statistics in Medicine, 37 (22). pp. 3179-3196. ISSN 0277-6715

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To link to this item DOI: 10.1002/sim.7831

Abstract/Summary

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.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Science > School of Mathematical, Physical and Computational Sciences > Department of Mathematics and Statistics
Faculty of Science > School of Mathematical, Physical and Computational Sciences > Department of Mathematics and Statistics > Applied Statistics
ID Code:76977
Publisher:Wiley

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