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. Author manuscript; available in PMC: 2019 Jul 1.
Published in final edited form as: Nat Genet. 2018 Dec 10;51(1):88–95. doi: 10.1038/s41588-018-0294-6

Fig. 5. Evaluation of de novo mutations from a cohort with severe developmental delay, intellectual disability, and epileptic encephalopathy versus de novo variation from unaffected siblings of autism probands.

Fig. 5

a, Enrichment of pathogenic de novo mutations in the most constrained CCRs, excluding pathogenic variants present in gnomAD. The 95% CI error bars are 0.22–0.29 for the 0–20 percentile bin, 1.36–1.81 for the 20–80 percentile bin, 1.24–2.16 for the 80–90 percentile bin, 1.66–3.50 for the 90–95 percentile bin, and 4.96–10.2 for the 95–100 percentile bin. b, ROC analysis for the developmental disorder de novo variant evaluation set described for a, where true positives are the pathogenic mutations and true negatives are the set of benign mutations. Of the 3,400 pathogenic and 1,269 benign mutations, each tool scored (M pathogenic; N benign): CCR (3,108; 1,149), CADD (3,399; 1,269), GERP++ (3,400; 1,269), MPC (3,221; 1,205), REVEL (3,368; 1,251), pLI (3,283; 1,212), MTR (3,389; 1,260). The dots in b and d indicate the score cutoff with the maximal Youden J statistic for each tool. Values in parenthesis indicate the AUC and the maximal J, respectively. c, Enrichment of pathogenic de novo mutations in the most constrained CCRs, after excluding benign and pathogenic mutations on the basis of their presence in gnomAD. The 95% CI error bars are 0.59–0.85 for the 0–20 percentile bin, 0.60–0.84 for the 20–80 percentile bin, 0.72–1.28 for the 80–90 percentile bin, 1.13–2.56 for the 90–95 percentile bin, and 3.16–6.81 for the 95–100 percentile bin. d, ROC analysis for the developmental disorder de novo variant evaluation set from c. Of the 3,400 pathogenic and 731 benign mutations, each tool scored (M pathogenic; N benign): CCR (3,108; 670), CADD (3,399; 731), GERP++ (3,400; 731), MPC (3,221; 704), REVEL (3,368; 726), pLI (3,283; 709), MTR (3,389; 728). CIs for each metric’s ROC AUC in b: CCR (0.711–0.745), CADD (0.567–0.603), GERP++ (0.542–0.579), MPC (0.643–0.676), REVEL (0.612–0.646), pLI (0.586–0.622), MTR (0.608–0.642). CIs for the ROC AUCs in d: CCR (0.586–0.629), CADD (0.581–0.624), GERP++ (0.509–0.556), MPC 0.627–0.667), REVEL (0.593–0.635), pLI (0.576–0.621), MTR (0.598–0.639).