When considering which study design to use when including public controls, investigators should consider the trade-offs between increased power and increased false positives when choosing how to include public control genotype data in their study. Investigators should also consider that reporting a large number of false positives could impact the power of future replication studies due to the increased multiple test burden from following up a larger number of variants. Study designs that include public controls in a single-stage or joint-analysis two-stage design have more power than the proposed replication-based two-stage design, however, these designs are also more susceptible to increased type I error rates. The recent report by Sebastiani et al. (Sebastiani et al., 2010), that found evidence for associations between 150 genetic variants and longevity based on a case-control sample where cases and controls were disproportionately genotyped on different genotyping platforms, highlights the potential severe impact of batch genotype effects. Our proposed replication-based two-stage design is designed to protect the overall type I error of the experiment while still increasing power and decreasing study costs compared to studies that exclude public controls.
