Workshop: Coverage tradeoffs and power estimation in the design of whole-genome sequencing experiments for detecting association

Whole-genome sequencing (WGS) allows direct interrogation of previously undetected uncommon or rare variants, which potentially contribute to the missing heritability of human diseases. However, cost of sequencing large numbers of samples limits its application in case control association studies. Here, theoretical and empirical design considerations for such sequencing studies, aimed at maximizing the power of detecting association under the constraint of study-wide cost are presented. Firstly, assuming cost is proportional to the total amount of base pairs to be sequenced across all samples, tradeoff in terms of study power between increasing the number of subjects and increasing depth-of-coverage was explored. It is demonstrated that under a wide range of realistic conditions for case-only sequencing designs, the optimal power of detecting association is achieved at medium depth-of-coverage, where the power of calling variants is suboptimal but approaching diminishing returns from increasing depth. Secondly, assuming cost is fixed per sample, which is approximately the case in exome sequencing, it is shown that the optimal design for sequencing both cases and controls includes cases totaling 1/e of all subjects.