Fast permutation tests and related methods,for association between rare variants and binary outcomes

In large‐scale genetic studies, a primary aim is to test for an association between genetic variants and a disease outcome. The variants of interest are often rare and appear with low frequency among subjects. In this situation, statistical tests based on standard asymptotic results do not adequately control the type I error rate, especially if the case : control ratio is unbalanced. In this article, we propose the use of permutation and approximate unconditional tests for testing association with rare variants. We use novel analytical calculations to efficiently approximate the true type I error rate under common study designs, and in numerical studies show that the proposed classes of tests significantly improve upon standard testing methods. We also illustrate our methods in data from a recent case–control study for genetic causes of a severe side effect of a common drug treatment.