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bioRxiv · 10.1101/2021.10.12.464134

netCRS: Network-based comorbidity risk score for prediction of myocardial infarction using biobank-scaled PheWAS data

Nam, Y.·Jung, S.-H.·Verma, A.·Sriram, V.·Won, H.-H.·Yun, J.-S.·Regeneron Genetics Center,·Kim, D.
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Abstract

The polygenic risk score (PRS) can help to identify individuals genetic susceptibility for various diseases by combining patient genetic profiles and identified single-nucleotide polymorphisms (SNPs) from genome-wide association studies. Although multiple diseases will usually afflict patients at once or in succession, conventional PRSs fail to consider genetic relationships across multiple diseases. Even multi-trait PRSs, which take into account genetic effects for more than one disease at a time, fail to consider a sufficient number of phenotypes to accurately reflect the state of disease comorbidity in a patient, or are biased in terms of the traits that are selected. Thus, we developed novel network-based comorbidity risk scores to quantify associations among multiple phenotypes from phenome-wide association studies (PheWAS). We first constructed a disease-SNP heterogeneous multi-layered network (DS-Net), which consists of a disease network (disease-layer) and SNP network (SNP-layer). The disease-layer describes the population-level interactome from PheWAS data. The SNP-layer was constructed according to linkage disequilibrium. Both layers were attached to transform the information from a population-level interactome to individual-level inferences. Then, graph-based semi-supervised learning was applied to predict possible comorbidity scores on disease-layer for each subject. The SNP-layer serves as receiving individual genotyping data in the scoring process, and the disease-layer serves as the propagated output for an individuals multiple disease comorbidity scores. The possible comorbidity scores were combined by logistic regression, and it is denoted as netCRS. The DS-Net was constructed from UK Biobank PheWAS data, and the individual genetic profiles were collected from the Penn Medicine Biobank. As a proof-of-concept study, myocardial infarction (MI) was selected to compare netCRS with the PRS with pruning and thresholding (PRS-PT). The combined model (netCRS + PRS-PT + covariates) achieved an AUC improvement of 6.26% compared to the (PRS-PT + covariates) model. In terms of risk stratification, the combined model was able to capture the risk of MI up to approximately eight-fold higher than that of the low-risk group. The netCRS and PRS-PT complement each other in predicting high-risk groups of patients with MI. We expect that using these risk prediction models will allow for the development of prevention strategies and reduction of MI morbidity and mortality.

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Nam, Y., Jung, S.-H., Verma, A., Sriram, V., Won, H.-H., Yun, J.-S., Regeneron Genetics Center,, Kim, D.. 2021-10-14. netCRS: Network-based comorbidity risk score for prediction of myocardial infarction using biobank-scaled PheWAS data. https://doi.org/10.1101/2021.10.12.464134

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