The pathogenicity weights incorporated in FATHMM were not directly used to train for, or recognize, pathogenic sequences and/or mutations. We do nevertheless recognize the potential for bias in the performances observed. Therefore, to remove this bias, we performed a “leave-one-out” analysis on all benchmarking datasets. Here, we adjusted our pathogenicity weights, Wd and Wn, if and only when the AAS being evaluated was present in either the HGMD [Stenson et al., 2009] or UniProt [Apweiler et al., 2004] datasets. We observed no significant deviations in the performance measures reported above and hence concluded that the performances observed were not biased toward the pathogenicity weights employed (see Supp. Table S2).
