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

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.

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.

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.

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.