Flexible design for following up positive findings

Kai Yu, Nilanjan Chatterjee, William Wheeler, Qizhai Li, Sophia Wang, Nathaniel Rothman, Sholom Wacholder

Research output: Contribution to journalArticle


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.

Original languageEnglish (US)
Pages (from-to)540-551
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number3
Publication statusPublished - Sep 2007
Externally publishedYes


ASJC Scopus subject areas

  • Genetics

Cite this

Yu, K., Chatterjee, N., Wheeler, W., Li, Q., Wang, S., Rothman, N., & Wacholder, S. (2007). Flexible design for following up positive findings. American Journal of Human Genetics, 81(3), 540-551. https://doi.org/10.1086/520678