The binomial exact test has been used in many whole exome sequencing studies to assess the burden of de novo variants in cases versus controls (e.g., Iossifov et al., 2012, 2014; Sanders et al., 2012). We therefore performed this test as a comparison to the rate ratio test conducted in the main text. We utilized the R function binom.test, and conducted a one-sided test with ‘hypothesis = “greater”’. We set the test up to compare the number of observed de novo variants of a particular class in probands versus siblings, accounting for the number of samples in each cohort by estimating the “probability of success” based on the proportion of samples that were TD probands versus controls. Hence, we used this general format in R: binom.test(x,n,p,alternative="greater")
