control groups, and then testing the two groups for frequency differences. This strategy forms the basis for most of the statistical models described in this review and variations of it have been considered in many studies involving rare variants (Table 1). To make this collapsing strategy more biologically appealing, elaborate ways of leveraging functional elements and annotations in a genomic region to collapse the variants together can be exploited (see below and Box 2). The effect of collapsing variants and testing their collective frequency differences on power can be substantial, as depicted in Figure 1B.
