To increase statistical power, we used a collapsing method, in which the total number of rare nonsynonymous variants in cases and comparison subjects was compared using Fisher’s exact test (FET). The total number of chromosome sequenced was based on the assumption that each individual has two chromosomes (and two copies) of this gene. To account for the variable sample size sequenced for each rare variant, the sample size was adjusted using harmonic mean: N = n /(∑1/ Ni ) , where Ni is the sample size of the i th variant and n is the number of variants. The number of each rare variant was adjusted as ∑ pi * N , where pi is the frequency of the i th variant. In addition to the collapsing method, we also used a weighted-sum method (36) (WSM) to test for the association of rare variants and ND.
