For investigators that have collected a well-matched group of cases and controls who wish to preserve many of the benefits of their sample collection design, we describe a replication-based two-stage case-control genetic association study design that uses free genotype data from public controls in stage 1, well-matched study controls in stage 2, and study cases distributed over stages 1 and 2. We compare the power and relative cost of our two-stage approach to single-stage approaches that strictly use either free public control genotype data or genotype data from study controls and to the single-stage approach that combines public and study controls. We discuss the advantages and limitations of each of the four sampling designs while considering the impact of ancestrally poorly-matched public controls and batch genotype effects. We show that the proposed replication-based two-stage design controls the overall type I error rate and has increased power over studies that exclude public controls.
