Figure 1. Overview of PS4-LRCalc framework for flexible PS4 application. (1) For a given set of case-control variant observations, the expected background odds of selecting a case among variant carriers are calculated using the equivalent observed odds among non-carriers. (2) The background odds are then scaled according to the ORs of association and non-association and converted to an expected probability of selecting a case among variant carriers under each hypothesis. (3) Variant observations in cases and controls are then modelled using a binomial likelihood function, which evaluates the likelihood that a given probability p of case selection would generate the observed data (k variant observations in cases across n total observations); note that these probabilities directly convert to odds values, which in turn generate a continuum of ORs across all possible values of p. (4) The likelihood ratio (LR) towards pathogenicity is determined by quantifying the total likelihood of association (L(Assoc); red area under curve) and dividing it by the total likelihood of non-association (L(NonAssoc); blue area under curve). The LR can then be converted to Tavtigian exponent points (EPs) by taking its log (to base 2.08). PS4-LRCalc, PS4-likelihood ratio calculator.