sum of alternate alleles weighted by the inverse of the binomial variance. A rank sum test is then performed on the genotype scores between phenotypic groups. The Kernel-Based Adaptive Cluster (KBAC) test60 also uses a weighting scheme that reflects apparent effect sizes of individual variants. An alternative approach to combine rare variants into a single test is to select an allele frequency threshold based on the observed data. This variable threshold (VT) approach61 was motivated by population genetic simulations that showed that there is no single optimal weighting scheme or allele frequency threshold. There are numerous other statistical tests for rare variants in complex traits (reviewed in refs.62–65).
