 
Summary: Genetic Epidemiology (2007)
Optimal Designs for TwoStage GenomeWide Association Studies
Andrew D. Skol,1,2Ã Laura J. Scott,1
Goncalo R. Abecasis,1
and Michael Boehnke1
1
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan
2
Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, Illinois
Genomewide association (GWA) studies require genotyping hundreds of thousands of markers on thousands of subjects,
and are expensive at current genotyping costs. To conserve resources, many GWA studies are adopting a staged design in
which a proportion of the available samples are genotyped on all markers in stage 1, and a proportion of these markers are
genotyped on the remaining samples in stage 2. We describe a strategy for designing costeffective twostage GWA studies.
Our strategy preserves much of the power of the corresponding onestage design and minimizes the genotyping cost of the
study while allowing for differences in per genotyping cost between stages 1 and 2. We show that the ratio of stage 2 to
stage 1 per genotype cost can strongly influence both the optimal design and the genotyping cost of the study. Increasing the
stage 2 per genotype cost shifts more of the genotyping and study cost to stage 1, and increases the cost of the study. This
higher cost can be partially mitigated by adopting a design with reduced power while preserving the false positive rate or
by increasing the false positive rate while preserving power. For example, reducing the power preserved in the twostage
design from 99 to 95% that of the onestage design decreases the twostage study cost by $15%. Alternatively, the same cost
