title: False discovery rate control in two-stage designs.
abstract: BACKGROUND
  For gene expression or gene association studies with a large number of hypotheses the number of measurements per marker in a conventional single-stage design is often low due to limited resources. Two-stage designs have been proposed where in a first stage promising hypotheses are identified and further investigated in the second stage with larger sample sizes. For two types of two-stage designs proposed in the literature we derive multiple testing procedures controlling the False Discovery Rate (FDR) demonstrating FDR control by simulations: designs where a fixed number of top-ranked hypotheses are selected and designs where the selection in the interim analysis is based on an FDR threshold. In contrast to earlier approaches which use only the second-stage data in the hypothesis tests (pilot approach), the proposed testing procedures are based on the pooled data from both stages (integrated approach).
  
  
  RESULTS
  For both selection rules the multiple testing procedures control the FDR in the considered simulation scenarios. This holds for the case of independent observations across hypotheses as well as for certain correlation structures. Additionally, we show that in scenarios with small effect sizes the testing procedures based on the pooled data from both stages can give a considerable improvement in power compared to tests based on the second-stage data only.
  
  
  CONCLUSIONS
  The proposed hypothesis tests provide a tool for FDR control for the considered two-stage designs. Comparing the integrated approaches for both selection rules with the corresponding pilot approaches showed an advantage of the integrated approach in many simulation scenarios.
authors.affiliation: Center for Medical Statistics, Informatics, and Complex Systems, Medical University of Vienna, Austria. sonja.zehetmayer@meduniwien.ac.at
authors.forename: Sonja
authors.initials: S
authors.lastname: Zehetmayer
authors.forename: Martin
authors.initials: M
authors.lastname: Posch
mesh_terms: D003627:Data Interpretation, Statistical; D005189:False Positive Reactions; D012107:Research Design / Q000706:statistics & numerical data*; D018401:Sample Size