Abstract
Rare disease patients often endure prolonged diagnostic odysseys and may still remain undiagnosed for years. Selecting the appropriate genetic tests is crucial to lead to timely diagnosis. Phenotypic features offer great potential for aiding genomic diagnosis in rare disease cases. We see great promise in effective integration of phenotypic information into genetic test selection workflow. In this study, we present a phenotype-driven molecular genetic test recommendation (Phen2Test) for pediatric rare disease diagnosis. Phen2Test was constructed using frequency matrix of phecodes and demographic data from the EHR before ordering genetic tests, with the objective to streamline the selection of molecular genetic tests (whole-exome / whole-genome sequencing, or gene panels) for clinicians with minimum genetic training expertise. We developed and evaluated binary classifiers based on 1,005 individuals referred to genetic counselors for potential genetic evaluation. In the evaluation using the gold standard cohort, the model achieved strong performance with an AUROC of 0.82 and an AUPRC of 0.92. Furthermore, we tested the model on another silver standard cohort (n=6,458), achieving an overall AUROC of 0.72 and an AUPRC of 0.671. Phen2Test was adjusted to align with current clinical guidelines, showing superior performance with more recent data, demonstrating its potential for use within a learning healthcare system as a genomic medicine intervention that adapts to guideline updates. This study showcases the practical utility of phenotypic features in recommending molecular genetic tests with performance comparable to clinical geneticists. Phen2Test could assist clinicians with limited genetic training and knowledge to order appropriate genetic tests.