Group sequential study designs in genetic-epidemiological case-control studies

Objective: In past years, the focus of genetic-epidemiological studies has shifted to analyzing complex diseases. Here, single genes often contribute only little to the manifestation of traits so that many probands have to be included in a study to reliably detect small effects. To reduce the number of required phenotypings and genotypings and thus facilitate analyzing complex traits, sequential study designs can be applied. Methods: For sequential analyses of complex diseases in association studies, we compare the procedure by Sobell et al. (Am J Med Genet 1993;48:28-35) with the adaptation of formal group sequential study designs by Pampallona and Tsiatis (J Stat Plan Inf 1994;42:19-35). Error rates and average sample sizes are investigated by Monte-Carlo simulations. Results: Formal sequential designs have a higher power regardless of underlying genetic effects. In addition, compared with conventional designs with fixed samples, average sample sizes are reduced considerably; under the null hypothesis of no association, up to 50% of the required sample size can be spared. Conclusions: To increase the efficiency of genetic-epidemiological case-control studies, we recommend using formal group sequential study designs. The tremendous savings in average sample sizes are expected to affect both cost and time spent on large-scale studies.