4.5 Article

Neural/Bayes network predictor for inheritable cardiac disease pathogenicity and phenotype

Journal

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 119, Issue -, Pages 19-27

Publisher

ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2018.04.006

Keywords

Cardiac ventricular myosin; Cardiac atrial myosin; Cardiac myosin binding protein C; Inheritable heart disease mechanism; Machine learning; Autonomous motor; Hypertrophic cardiomyopathy; Dilated cardiomyopathy; Restrictive cardiomyopathy

Funding

  1. Mayo Foundation

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The cardiac muscle sarcomere contains multiple proteins contributing to contraction energy transduction and its regulation during a heartbeat. Inheritable heart disease mutants affect most of them but none more frequently than the ventricular myosin motor and cardiac myosin binding protein c (mybpc3). These co-localizing proteins have mybpc3 playing a regulatory role to the energy transducing motor. Residue substitution and functional domain assignment of each mutation in the protein sequence decides, under the direction of a sensible disease model, phenotype and pathogenicity. The unknown model mechanism is decided here using a method combing neural and Bayes networks. Missense single nucleotide polymorphisms (SNPs) are clues for the disease mechanism summarized in an extensive database collecting mutant sequence location and residue substitution as independent variables that imply the dependent disease phenotype and pathogenicity characteristics in 4 dimensional data points (4ddps). The SNP database contains entries with the majority having one or both dependent data entries unfulfilled. A neural network relating causes (mutant residue location and substitution) and effects (phenotype and pathogenicity) is trained, validated, and optimized using fulfilled 4ddps. It then predicts unfulfilled 4ddps providing the implicit disease model. A discrete Bayes network interprets fulfilled and predicted 4ddps with conditional probabilities for phenotype and pathogenicity given mutation location and residue substitution thus relating the neural network implicit model to explicit features of the motor and mybpc3 sequence and structural domains. Neural/Bayes network forecasting automates disease mechanism modeling by leveraging the world wide human missense SNP database that is in place and expanding.

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