CardioClassifier – demonstrating the power of disease- and gene-specific computational decision support for clinical genome interpretation
Whiffin N., Walsh R., Govind R., Edwards M., Ahmad M., Zhang X., Tayal U., Buchan R., Midwinter W., Wilk A., Najgebauer H., Francis C., Wilkinson S., Monk T., Brett L., O'Regan D., Prasad S., Morris-Rosendahl D., Barton PJR., Edwards E., Ware J., Cook S.
ABSTRACT Purpose Internationally-adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier ( www.cardioclassifier.org ), a semi-automated decision-support tool for inherited cardiac conditions (ICCs). Methods CardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support varian interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules. Results We benchmarked CardioClassifier on 57 expertly-curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically-actionable variants (64/219 vs 156/219, Fisher’s P =1.1x10-18), with important false positives; illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually-curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data. Conclusion CardioClassifier is an ICC-specific decision-support tool that integrates expertly curated computational annotations with case-specific data to generate fast, reproducible and interactive variant pathogenicity reports, according to best practice guidelines.