The collapsing strategy makes important assumptions. First, some formulations of collapsed tests assume that each subject is likely to have only a single rare variant. This may be true given the low frequency of the variants, but could in theory be untrue if the variants interact with one another or large genomic regions are tested.20, 33 Second, if one collapses variants by counting individuals possessing rare variants, then if either the frequency of those variants is large enough or if there are many of them, the percentage of individuals possessing any one of them could reach 100%. Therefore, ways of circumscribing the variants to be collapsed, such as leveraging functional information (Box 2), or weighting the variants in some way,34, 35 are important. Alternatively, one could employ statistics that do not rely on simple counting. For example, one could tally the number of variants within a collapsed set possessed by each individual.33
