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Learning high-order interactions for polygenic risk prediction
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-orde...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9916647/ https://www.ncbi.nlm.nih.gov/pubmed/36763605 http://dx.doi.org/10.1371/journal.pone.0281618 |
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author | Massi, Michela C. Franco, Nicola R. Manzoni, Andrea Paganoni, Anna Maria Park, Hanla A. Hoffmeister, Michael Brenner, Hermann Chang-Claude, Jenny Ieva, Francesca Zunino, Paolo |
author_facet | Massi, Michela C. Franco, Nicola R. Manzoni, Andrea Paganoni, Anna Maria Park, Hanla A. Hoffmeister, Michael Brenner, Hermann Chang-Claude, Jenny Ieva, Francesca Zunino, Paolo |
author_sort | Massi, Michela C. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9916647 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-99166472023-02-11 Learning high-order interactions for polygenic risk prediction Massi, Michela C. Franco, Nicola R. Manzoni, Andrea Paganoni, Anna Maria Park, Hanla A. Hoffmeister, Michael Brenner, Hermann Chang-Claude, Jenny Ieva, Francesca Zunino, Paolo PLoS One Research Article 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. Public Library of Science 2023-02-10 /pmc/articles/PMC9916647/ /pubmed/36763605 http://dx.doi.org/10.1371/journal.pone.0281618 Text en © 2023 Massi et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Massi, Michela C. Franco, Nicola R. Manzoni, Andrea Paganoni, Anna Maria Park, Hanla A. Hoffmeister, Michael Brenner, Hermann Chang-Claude, Jenny Ieva, Francesca Zunino, Paolo Learning high-order interactions for polygenic risk prediction |
title | Learning high-order interactions for polygenic risk prediction |
title_full | Learning high-order interactions for polygenic risk prediction |
title_fullStr | Learning high-order interactions for polygenic risk prediction |
title_full_unstemmed | Learning high-order interactions for polygenic risk prediction |
title_short | Learning high-order interactions for polygenic risk prediction |
title_sort | learning high-order interactions for polygenic risk prediction |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9916647/ https://www.ncbi.nlm.nih.gov/pubmed/36763605 http://dx.doi.org/10.1371/journal.pone.0281618 |
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