Mendelian

AI-MARRVEL (AIM) is a knowledge-driven AI system for diagnosing Mendelian disorders that uses a random-forest machine-learning classifier trained on over 3.5 million variants from thousands of diagnosed cases. It incorporates expert-engineered features to recapitulate the complex decision-making processes in molecular diagnosis. AIM doubled the rate of accurate genetic diagnosis across three independent real-world cohorts compared to benchmarked methods. Its confidence metric achieved 98% precision and identified 57% of diagnosable cases from 871 unsolved cases. AIM also demonstrated potential for novel disease gene discovery.

Diagnosing genetic disorders requires extensive manual curation and interpretation of candidate variants, a labor-intensive task even for trained geneticists. Although artificial intelligence (AI) shows promise in aiding these diagnoses, existing AI tools have only achieved moderate success for primary diagnosis. AI-MARRVEL (AIM) uses a random-forest machine-learning classifier trained on over 3.5 million variants from thousands of diagnosed cases. AIM additionally incorporates expert-engineered features into training to recapitulate the intricate decision-making processes in molecular diagnosis. AIM improved the rate of accurate genetic diagnosis, doubling the number of solved cases as compared with benchmarked methods, across three distinct real-world cohorts. AIM achieved a precision rate of 98% and identified 57% of diagnosable cases out of a collection of 871 cases. AIM demonstrated potential for novel disease gene discovery by correctly predicting two newly reported disease genes from the Undiagnosed Diseases Network.