Data adaptive interim modification of sample sizes for candidate-gene association studies

Objectives: The use of conventional Transmission/Disequilibrium tests in the analysis of candidate-gene association studies requires the precise and complete pre-specification of the total number of trios to be sampled to obtain sufficient power at a certain significance level (type I error risk). In most of these studies, very little information about the genetic effect size will be available beforehand and thus it will be difficult to calculate a reasonable sample size. One would therefore wish to reassess the sample size during the course of a study. Method: We propose an adaptive group sequential procedure which allows for both early stopping of the study with rejection of the null hypothesis (H₀) and for recalculation of the sample size based on interim effect size estimates when H₀ cannot be rejected. The applicability of the method which was developed by Müller and Schäfer [Biometrics 2001;57:886–891] in a clinical context is demonstrated by a numerical example. Monte Carlo simulations are performed comparing the adaptive procedure with a fixed sample and a conventional group sequential design. Results: The main advantage of the adaptive procedure is its flexibility to allow for design changes in order to achieve a stabilized power characteristic while controlling the overall type I error and using the information already collected. Conclusions: Given these advantages, the procedure is a promising alternative to traditional designs.