title: Flexible design for following up positive findings.
abstract: As more population-based studies suggest associations between genetic variants and disease risk, there is a need to improve the design of follow-up studies (stage II) in independent samples to confirm evidence of association observed at the initial stage (stage I). We propose to use flexible designs developed for randomized clinical trials in the calculation of sample size for follow-up studies. We apply a bootstrap procedure to correct the effect of regression to the mean, also called "winner's curse," resulting from choosing to follow up the markers with the strongest associations. We show how the results from stage I can improve sample size calculations for stage II adaptively. Despite the adaptive use of stage I data, the proposed method maintains the nominal global type I error for final analyses on the basis of either pure replication with the stage II data only or a joint analysis using information from both stages. Simulation studies show that sample-size calculations accounting for the impact of regression to the mean with the bootstrap procedure are more appropriate than is the conventional method. We also find that, in the context of flexible design, the joint analysis is generally more powerful than the replication analysis.
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. yuka@mail.nih.gov
authors: Kai
authors: K
authors: Yu
authors: Nilanjan
authors: N
authors: Chatterjee
authors: William
authors: W
authors: Wheeler
authors: Qizhai
authors: Q
authors: Li
authors: Sophia
authors: S
authors: Wang
authors: Nathaniel
authors: N
authors: Rothman
authors: Sholom
authors: S
authors: Wacholder
mesh_terms: D005500:Follow-Up Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics; D012107:Research Design; D018401:Sample Size
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