Learning high-order interactions for polygenic risk prediction.

Autor: Massi MC; MOX, Department of Mathematics, Politecnico di Milano, Milan, Italy.; HDSC - Health Data Science Centre, Human Technopole, Milan, Italy., Franco NR; MOX, Department of Mathematics, Politecnico di Milano, Milan, Italy., Manzoni A; MOX, Department of Mathematics, Politecnico di Milano, Milan, Italy., Paganoni AM; MOX, Department of Mathematics, Politecnico di Milano, Milan, Italy., Park HA; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Medical Faculty, University of Heidelberg, Heidelberg, Germany., Hoffmeister M; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany., Brenner H; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Chang-Claude J; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Ieva F; MOX, Department of Mathematics, Politecnico di Milano, Milan, Italy.; HDSC - Health Data Science Centre, Human Technopole, Milan, Italy., Zunino P; MOX, Department of Mathematics, Politecnico di Milano, Milan, Italy.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2023 Feb 10; Vol. 18 (2), pp. e0281618. Date of Electronic Publication: 2023 Feb 10 (Print Publication: 2023).
DOI: 10.1371/journal.pone.0281618
Abstrakt: Within the framework of precision medicine, the stratification of individual genetic susceptibility based on inherited DNA variation has paramount relevance. However, one of the most relevant pitfalls of traditional Polygenic Risk Scores (PRS) approaches is their inability to model complex high-order non-linear SNP-SNP interactions and their effect on the phenotype (e.g. epistasis). Indeed, they incur in a computational challenge as the number of possible interactions grows exponentially with the number of SNPs considered, affecting the statistical reliability of the model parameters as well. In this work, we address this issue by proposing a novel PRS approach, called High-order Interactions-aware Polygenic Risk Score (hiPRS), that incorporates high-order interactions in modeling polygenic risk. The latter combines an interaction search routine based on frequent itemsets mining and a novel interaction selection algorithm based on Mutual Information, to construct a simple and interpretable weighted model of user-specified dimensionality that can predict a given binary phenotype. Compared to traditional PRSs methods, hiPRS does not rely on GWAS summary statistics nor any external information. Moreover, hiPRS differs from Machine Learning-based approaches that can include complex interactions in that it provides a readable and interpretable model and it is able to control overfitting, even on small samples. In the present work we demonstrate through a comprehensive simulation study the superior performance of hiPRS w.r.t. state of the art methods, both in terms of scoring performance and interpretability of the resulting model. We also test hiPRS against small sample size, class imbalance and the presence of noise, showcasing its robustness to extreme experimental settings. Finally, we apply hiPRS to a case study on real data from DACHS cohort, defining an interaction-aware scoring model to predict mortality of stage II-III Colon-Rectal Cancer patients treated with oxaliplatin.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Massi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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