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Hum Mutat. 2019 Sep;40(9):1579-1592. doi: 10.1002/humu.23826. Epub 2019 Aug 7.

Predicting pathogenicity of missense variants with weakly supervised regression.

Author information

1
Department of Electrical and Computer Engineering, Texas A&M University, College Station, Texas.

Abstract

Quickly growing genetic variation data of unknown clinical significance demand computational methods that can reliably predict clinical phenotypes and deeply unravel molecular mechanisms. On the platform enabled by the Critical Assessment of Genome Interpretation (CAGI), we develop a novel "weakly supervised" regression (WSR) model that not only predicts precise clinical significance (probability of pathogenicity) from inexact training annotations (class of pathogenicity) but also infers underlying molecular mechanisms in a variant-specific manner. Compared to multiclass logistic regression, a representative multiclass classifier, our kernelized WSR improves the performance for the ENIGMA Challenge set from 0.72 to 0.97 in binary area under the receiver operating characteristic curve (AUC) and from 0.64 to 0.80 in ordinal multiclass AUC. WSR model interpretation and protein structural interpretation reach consensus in corroborating the most probable molecular mechanisms by which some pathogenic BRCA1 variants confer clinical significance, namely metal-binding disruption for p.C44F and p.C47Y, protein-binding disruption for p.M18T, and structure destabilization for p.S1715N.

KEYWORDS:

clinical significance; genetic variation; genome medicine; machine learning; model interpretability; molecular mechanism; weak supervision

PMID:
31144781
PMCID:
PMC6744350
[Available on 2020-09-01]
DOI:
10.1002/humu.23826

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