Combination of expert guidelines-based and machine learning-based approaches leads to superior accuracy of automated prediction of clinical effect of copy number variations

Abstract

Clinical interpretation of copy number variants (CNVs) is a complex process that requires skilled clinical professionals. General recommendations have been recently released to guide the CNV interpretation based on predefined criteria to uniform the decision process. Several semiautomatic computational methods have been proposed to recommend appropriate choices, relieving clinicians of tedious searching in vast genomic databases. We have developed and evaluated such a tool called MarCNV and tested it on CNV records collected from the ClinVar database. Alternatively, the emerging machine learning-based tools, such as the recently published ISV (Interpretation of Structural Variants), showed promising ways of even fully automated predictions using broader characterization of affected genomic elements. Such tools utilize features additional to ACMG criteria, thus providing supporting evidence and the potential to improve CNV classification. Since both approaches contribute to evaluation of CNVs clinical impact, we propose a combined solution in the form of a decision support tool based on automated ACMG guidelines (MarCNV) supplemented by a machine learning-based pathogenicity prediction (ISV) for the classification of CNVs. We provide evidence that such a combined approach is able to reduce the number of uncertain classifications and reveal potentially incorrect classifications using automated guidelines. CNV interpretation using MarCNV, ISV, and combined approach is available for non-commercial use at https://predict.genovisio.com/.

Predictive Modeling and Structure Analysis of Genetic Variants in Familial Hypercholesterolemia: Implications for Diagnosis and Protein Interaction Studies

“…The use of AI has drastically increased in clinical genomics. It has been applied in a wide range of conditions and approaches, such as patient photography analysis (facial analysis for disease identification, radiologic studies, microscopy data) [ 164 ], cardiology predictions (hypertension incident, atrial fibrillation, aortic stenosis) [ 165 ] blood biomarkers (mantle cell lymphoma [ 166 ], anemia [ 167 ]), interpretation of copy number variants [ 168 ], or classification of non-coding variants [ 169 ]. Regarding variant pathogenicity predictions, AI has revolutionized the field, providing advanced tools for accurate assessment.…”