Fig. 3

Evaluation and optimization of PS4 in the truth set. A Distribution of sample sizes among cases and the corresponding minimum allele frequencies in cases for variants that reached a p-value < 0.05. Based on this result, the truth set was divided into three subsets: subset 1, variants present in both cases and controls with AF in cases ≥ 0.0005; subset 2, variants present in both cases and controls with AF in cases < 0.0005; subset 3, variants present only in cases and absent in controls. Since odds ratio (OR) estimation requires a non-zero count of the tested variant in both the case and control groups, it was only calculated for subset 1 and subset 2 and AC was used for the optimization of cases in subset 3. B In truth subset 1, a variant was considered as enriched in cases if the OR was above the given cutoff, the lower bound of the 95% confidence intervals around the estimate of the OR was > 1. C Local posterior probability curves of different OR values in truth subset 2. The horizontal lines represent the posterior probability thresholds for supporting, moderate, strong, and very strong evidence. The black curves represent the posterior probability estimated from the truth subset 2. The grey curves represent one-sided 95% confidence intervals calculated from 10,000 bootstrap samples of this dataset. D In truth subset 3, variant enrichment in cases was assessed based on the case allele counts above the given cutoff. Numbers of true positive (TP, P/LP variants above a tested cutoff), false negative (FN, P/LP variants below a tested cutoff), true negative (TN, BL-VUS/LB/B variants below a tested cutoff), and false positive (FP, BL-VUS/LB/B variants above a tested cutoff) calls in truth subsets 1 and 3 are shown, along with evaluation metrics, including sensitivity (true positive rate), specificity (true negative rate), accuracy, positive predictive value (PPV, precision), negative predictive value (NPV), F1 score, and the lower boundary of the 95% confidence interval of the positive likelihood ratio (LR⁺_LB)