Exemplar case-control scenarios generating exponent points (EPs) towards pathogenicity when using PS4-LRCalc
| Scenario number | Case number with variant/total cases | Control number with variant/total controls | Observed effect size | ACMG 2015 Framework (OR≥5, LCI≥1) | Likelihood of OR≥5 versus likelihood of OR≤1 | ||
| OR (95% CI) | p-value (Fisher’s exact test) | LR | EPs | ||||
| 1 | 10/10 000 | 2/10 000 | 5.0 (1.10 to 22.84) | 0.04 | Strong | 33.28 | 4.8 |
| 2 | 100/10 000 | 20/10 000 | 5.0 (3.12 to 8.15) | 4.69×10–14 | Strong | 3.97×1013 | 42.8 |
| 3 | 20/10 000 | 2/10 000 | 10.0 (2.34 to 42.87) | 1.20×10–4 | Strong | 2.35×104 | 13.7 |
| 4 | 5/10 000 | 1/10 000 | 5.0 (0.58 to 42.82) | 0.22 | None/? | 5.29 | 2.3 |
| 5 | 4/10 000 | 1/10 000 | 4.0 (0.45 to 35.80) | 0.37 | None/? | 2.41 | 1.2 |
| 6 | 9/10 000 | 2/10 000 | 4.5 (0.97 to 20.85) | 0.07 | None/? | 16.79 | 3.9 |
Shown are illustrative sets of variant observations in case and control data sets of equal size (10 000 individuals each) and the respective likelihood ratio (LR) and exponent points (EPs) generated for each using PS4-LRCalc. In scenarios 1–3, assignation of PS4 at ‘strong’ would have been possible under the 2015 ACMG/AMP framework; integration of PS4-LRCalc allows more refined quantification of evidence strength, such that the equivalent of ‘very strong’ evidence can be applied for scenarios 2 and 3. The variants depicted in scenarios 4–6 fail to fulfil the 2015 ACMG/AMP criteria of OR≥5 and p<0.05 for application of PS4; thus any evidence allocation would be on the basis of professional judgement. Scenarios 1, 3 and 6 are further illustrated in figure 2A–C.
ACMG, American College of Medical Genetics; AMP, Association of Molecular Pathology; EP, exponent point; LR, likelihood ratio; OR, odds ratio; PS4-LRCalc, PS4-likelihood ratio calculator.