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Point estimation following two-stage adaptive threshold enrichment clinical trials
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Kimani, Peter K., Todd, Susan, Renfro, Lindsay A. and Stallard, Nigel (2018) Point estimation following two-stage adaptive threshold enrichment clinical trials. Statistics in Medicine, 37 (22). pp. 3179-3196. doi:10.1002/sim.7831
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Official URL: https://doi.org/10.1002/sim.7831
Abstract
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: | Journal Article | ||||||||
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| Subjects: | R Medicine > R Medicine (General) | ||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences > Statistics and Epidemiology Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Clinical trials -- Methodology, Biochemical markers | ||||||||
| Journal or Publication Title: | Statistics in Medicine | ||||||||
| Publisher: | John Wiley & Sons Ltd. | ||||||||
| ISSN: | 1097-0258 | ||||||||
| Official Date: | September 2018 | ||||||||
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| Volume: | 37 | ||||||||
| Number: | 22 | ||||||||
| Page Range: | pp. 3179-3196 | ||||||||
| DOI: | 10.1002/sim.7831 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Open Access | ||||||||
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