P-KNN: joint calibration of multiple pathogenicity prediction tools streamlines variant classification

Clinical guidelines for interpreting genetic variants in the context of Mendelian disease require converting the outputs of pathogenicity prediction tools into well-calibrated probabilities. However, the existing calibration method is only valid when pre-committing to one tool, preventing clinical laboratories from using multiple tools with complementary strengths. To lift this restriction, we introduce Pathogenicity K-Nearest Neighbors (P-KNN), a flexible method that jointly calibrates any set of tools.