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Predicting Drug-Induced Liver Injury Using Machine Learning on a Diverse Set of Predictors.

作者信息

Adeluwa Temidayo, McGregor Brett A, Guo Kai, Hur Junguk

机构信息

Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND, United States.

Department of Neurology, University of Michigan, Ann Arbor, MI, United States.

出版信息

Front Pharmacol. 2021 Aug 18;12:648805. doi: 10.3389/fphar.2021.648805. eCollection 2021.


DOI:10.3389/fphar.2021.648805
PMID:34483896
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8416433/
Abstract

A major challenge in drug development is safety and toxicity concerns due to drug side effects. One such side effect, drug-induced liver injury (DILI), is considered a primary factor in regulatory clearance. The Critical Assessment of Massive Data Analysis (CAMDA) 2020 CMap Drug Safety Challenge goal was to develop prediction models based on gene perturbation of six preselected cell-lines (CMap L1000), extended structural information (MOLD2), toxicity data (TOX21), and FDA reporting of adverse events (FAERS). Four types of DILI classes were targeted, including two clinically relevant scores and two control classifications, designed by the CAMDA organizers. The L1000 gene expression data had variable drug coverage across cell lines with only 247 out of 617 drugs in the study measured in all six cell types. We addressed this coverage issue by using Kru-Bor ranked merging to generate a singular drug expression signature across all six cell lines. These merged signatures were then narrowed down to the top and bottom 100, 250, 500, or 1,000 genes most perturbed by drug treatment. These signatures were subject to feature selection using Fisher's exact test to identify genes predictive of DILI status. Models based solely on expression signatures had varying results for clinical DILI subtypes with an accuracy ranging from 0.49 to 0.67 and Matthews Correlation Coefficient (MCC) values ranging from -0.03 to 0.1. Models built using FAERS, MOLD2, and TOX21 also had similar results in predicting clinical DILI scores with accuracy ranging from 0.56 to 0.67 with MCC scores ranging from 0.12 to 0.36. To incorporate these various data types with expression-based models, we utilized soft, hard, and weighted ensemble voting methods using the top three performing models for each DILI classification. These voting models achieved a balanced accuracy up to 0.54 and 0.60 for the clinically relevant DILI subtypes. Overall, from our experiment, traditional machine learning approaches may not be optimal as a classification method for the current data.

摘要
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/383ea38e41f3/fphar-12-648805-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/e08159d16c5e/fphar-12-648805-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/59e74947115c/fphar-12-648805-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/d9717d4cd770/fphar-12-648805-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/5641b9c7d00c/fphar-12-648805-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/d48da11abfff/fphar-12-648805-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/de88c9c0da94/fphar-12-648805-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/383ea38e41f3/fphar-12-648805-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/e08159d16c5e/fphar-12-648805-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/59e74947115c/fphar-12-648805-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/d9717d4cd770/fphar-12-648805-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/5641b9c7d00c/fphar-12-648805-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/d48da11abfff/fphar-12-648805-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/de88c9c0da94/fphar-12-648805-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf9f/8416433/383ea38e41f3/fphar-12-648805-g007.jpg

相似文献

[1]
Predicting Drug-Induced Liver Injury Using Machine Learning on a Diverse Set of Predictors.

Front Pharmacol. 2021-8-18

[2]
Predictability of drug-induced liver injury by machine learning.

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[3]
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[4]
Prediction and mechanistic analysis of drug-induced liver injury (DILI) based on chemical structure.

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[5]
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[7]
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Comprehensive analysis of high-throughput transcriptomics to distinguish drug-induced liver injury (DILI) phenotypes.

Arch Toxicol. 2025-6-4

[2]
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[5]
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[6]
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[7]
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本文引用的文献

[1]
Prediction and mechanistic analysis of drug-induced liver injury (DILI) based on chemical structure.

Biol Direct. 2021-1-18

[2]
An ensemble learning approach for modeling the systems biology of drug-induced injury.

Biol Direct. 2021-1-12

[3]
Integration of human cell lines gene expression and chemical properties of drugs for Drug Induced Liver Injury prediction.

Biol Direct. 2021-1-9

[4]
Machine-Learning Prediction of Oral Drug-Induced Liver Injury (DILI) via Multiple Features and Endpoints.

Biomed Res Int. 2020

[5]
Development of Prediction Models for Drug-Induced Cholestasis, Cirrhosis, Hepatitis, and Steatosis Based on Drug and Drug Metabolite Structures.

Front Pharmacol. 2020-2-14

[6]
Predictability of drug-induced liver injury by machine learning.

Biol Direct. 2020-2-13

[7]
Diverse approaches to predicting drug-induced liver injury using gene-expression profiles.

Biol Direct. 2020-1-15

[8]
Direct Detection of miR-122 in Hepatotoxicity Using Dynamic Chemical Labeling Overcomes Stability and isomiR Challenges.

Anal Chem. 2020-1-27

[9]
Drug-induced liver injury.

Nat Rev Dis Primers. 2019-8-22

[10]
Drug-induced liver injury: a safety review.

Expert Opin Drug Saf. 2018-8

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