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Article

Machine Learning to Identify Interaction of Single-Nucleotide Polymorphisms as a Risk Factor for Chronic Drug-Induced Liver Injury

Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR 72079, USA
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Academic Editor: Matteo Goldoni
Int. J. Environ. Res. Public Health 2021, 18(20), 10603; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph182010603
Received: 9 August 2021 / Revised: 28 September 2021 / Accepted: 5 October 2021 / Published: 10 October 2021
(This article belongs to the Collection Predictive Toxicology)
Drug-induced liver injury (DILI) is a major cause of drug development failure and drug withdrawal from the market after approval. The identification of human risk factors associated with susceptibility to DILI is of paramount importance. Increasing evidence suggests that genetic variants may lead to inter-individual differences in drug response; however, individual single-nucleotide polymorphisms (SNPs) usually have limited power to predict human phenotypes such as DILI. In this study, we aim to identify appropriate statistical methods to investigate gene–gene and/or gene–environment interactions that impact DILI susceptibility. Three machine learning approaches, including Multivariate Adaptive Regression Splines (MARS), Multifactor Dimensionality Reduction (MDR), and logistic regression, were used. The simulation study suggested that all three methods were robust and could identify the known SNP–SNP interaction when up to 4% of genotypes were randomly permutated. When applied to a real-life DILI chronicity dataset, both MARS and MDR, but not logistic regression, identified combined genetic variants having better associations with DILI chronicity in comparison to the use of individual SNPs. Furthermore, a simple decision tree model using the SNPs identified by MARS and MDR was developed to predict DILI chronicity, with fair performance. Our study suggests that machine learning approaches may help identify gene–gene interactions as potential risk factors for better assessing complicated diseases such as DILI chronicity. View Full-Text
Keywords: drug-induced liver injury; chronicity; machine learning; SNP; genotype; gene–gene interactions; epistasis; splines drug-induced liver injury; chronicity; machine learning; SNP; genotype; gene–gene interactions; epistasis; splines
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MDPI and ACS Style

Moore, R.; Ashby, K.; Liao, T.-J.; Chen, M. Machine Learning to Identify Interaction of Single-Nucleotide Polymorphisms as a Risk Factor for Chronic Drug-Induced Liver Injury. Int. J. Environ. Res. Public Health 2021, 18, 10603. https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph182010603

AMA Style

Moore R, Ashby K, Liao T-J, Chen M. Machine Learning to Identify Interaction of Single-Nucleotide Polymorphisms as a Risk Factor for Chronic Drug-Induced Liver Injury. International Journal of Environmental Research and Public Health. 2021; 18(20):10603. https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph182010603

Chicago/Turabian Style

Moore, Roland, Kristin Ashby, Tsung-Jen Liao, and Minjun Chen. 2021. "Machine Learning to Identify Interaction of Single-Nucleotide Polymorphisms as a Risk Factor for Chronic Drug-Induced Liver Injury" International Journal of Environmental Research and Public Health 18, no. 20: 10603. https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph182010603

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