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

Drug discovery is a costly process which usually takes more than 10 years and billions of dollars for one successful drug to enter the market. Despite all the safety tests, drugs may still cause adverse reactions and be restricted in use or even withdrawn from the market. Drug-induced liver injury (DILI) is one of the major adverse drug reactions, and computational models may be used to predict and reduce it. To assess the computational prediction performance of DILI, we curated DILI endpoints from three databases and prepared drug features including chemical descriptors, therapeutic classifications, gene expressions, and binding proteins. We trained machine-learning models to predict the various DILI endpoints using different drug features. Using the optimal feature sets, the top-performing models obtained areas under the receiver operating characteristic curve (AUC) around 0.8 for some DILI endpoints. We found that some features, including therapeutic classifications and proteins, have good prediction performance towards DILI. We also discovered that the severity of DILI endpoints as well as the selection of negative samples may significantly affect the prediction results. Overall, our study provided a comprehensive collection, curation, and prediction of DILI endpoints using various drug features, which may help the drug researchers to better understand and prevent DILI during the drug discovery process.

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Computational Models Using Multiple Machine Learning Algorithms for Predicting Drug Hepatotoxicity with the DILIrank Dataset

10.20944/preprints202002.0178.v1 ◽

2020 ◽

Author(s):

Robert Ancuceanu ◽

Marilena Viorica Hovanet ◽

Adriana Iuliana Anghel ◽

Florentina Furtunescu ◽

Monica Neagu ◽

...

Keyword(s):

Machine Learning ◽

Liver Injury ◽

Computational Models ◽

Liver Toxicity ◽

Learning Algorithms ◽

Machine Learning Algorithms ◽

Drug Induced ◽

Reference Drug ◽

Drug Induced Liver Injury

Drug induced liver injury (DILI) remains one of the challenges in the safety profile of both authorized drugs and candidate drugs and predicting hepatotoxicity from the chemical structure of a substance remains a challenge worth pursuing, being also coherent with the current tendency for replacing non-clinical tests with in vitro or in silico alternatives. In 2016 a group of researchers from FDA published an improved annotated list of drugs with respect to their DILI risk, constituting “the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans”, DILIrank. This paper is one of the few attempting to predict liver toxicity using the DILIrank dataset. Molecular descriptors were computed with the Dragon 7.0 software, and a variety of feature selection and machine learning algorithms were implemented in the R computing environment. Nested (double) cross-validation was used to externally validate the models selected. A number of 78 models with reasonable performance have been selected and stacked through several approaches, including the building of multiple meta-models. The performance of the stacked models was slightly superior to other models published. The models were applied in a virtual screening exercise on over 100,000 compounds from the ZINC database and about 20% of them were predicted to be non-hepatotoxic.

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Computational Models Using Multiple Machine Learning Algorithms for Predicting Drug Hepatotoxicity with the DILIrank Dataset

International Journal of Molecular Sciences ◽

10.3390/ijms21062114 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2114

Author(s):

Robert Ancuceanu ◽

Marilena Viorica Hovanet ◽

Adriana Iuliana Anghel ◽

Florentina Furtunescu ◽

Monica Neagu ◽

...

Keyword(s):

Machine Learning ◽

Liver Injury ◽

Computational Models ◽

Liver Toxicity ◽

Learning Algorithms ◽

Machine Learning Algorithms ◽

Drug Induced ◽

Reference Drug ◽

Drug Induced Liver Injury

Drug-induced liver injury (DILI) remains one of the challenges in the safety profile of both authorized and candidate drugs, and predicting hepatotoxicity from the chemical structure of a substance remains a task worth pursuing. Such an approach is coherent with the current tendency for replacing non-clinical tests with in vitro or in silico alternatives. In 2016, a group of researchers from the FDA published an improved annotated list of drugs with respect to their DILI risk, constituting “the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans” (DILIrank). This paper is one of the few attempting to predict liver toxicity using the DILIrank dataset. Molecular descriptors were computed with the Dragon 7.0 software, and a variety of feature selection and machine learning algorithms were implemented in the R computing environment. Nested (double) cross-validation was used to externally validate the models selected. A total of 78 models with reasonable performance were selected and stacked through several approaches, including the building of multiple meta-models. The performance of the stacked models was slightly superior to other models published. The models were applied in a virtual screening exercise on over 100,000 compounds from the ZINC database and about 20% of them were predicted to be non-hepatotoxic.

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Predicting Antituberculosis Drug–Induced Liver Injury Using an Interpretable Machine Learning Method: Model Development and Validation Study (Preprint)

10.2196/preprints.29226 ◽

2021 ◽

Author(s):

Tao Zhong ◽

Zian Zhuang ◽

Xiaoli Dong ◽

Ka Hing Wong ◽

Wing Tak Wong ◽

...

Keyword(s):

Machine Learning ◽

Liver Injury ◽

Receiver Operating Characteristic Curve ◽

Receiver Operating Characteristic ◽

Operating Characteristic ◽

Characteristic Curve ◽

Alanine Transaminase ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Operating Characteristic Curve

BACKGROUND Tuberculosis (TB) is a pandemic, being one of the top 10 causes of death and the main cause of death from a single source of infection. Drug-induced liver injury (DILI) is the most common and serious side effect during the treatment of TB. OBJECTIVE We aim to predict the status of liver injury in patients with TB at the clinical treatment stage. METHODS We designed an interpretable prediction model based on the XGBoost algorithm and identified the most robust and meaningful predictors of the risk of TB-DILI on the basis of clinical data extracted from the Hospital Information System of Shenzhen Nanshan Center for Chronic Disease Control from 2014 to 2019. RESULTS In total, 757 patients were included, and 287 (38%) had developed TB-DILI. Based on values of relative importance and area under the receiver operating characteristic curve, machine learning tools selected patients’ most recent alanine transaminase levels, average rate of change of patients’ last 2 measures of alanine transaminase levels, cumulative dose of pyrazinamide, and cumulative dose of ethambutol as the best predictors for assessing the risk of TB-DILI. In the validation data set, the model had a precision of 90%, recall of 74%, classification accuracy of 76%, and balanced error rate of 77% in predicting cases of TB-DILI. The area under the receiver operating characteristic curve score upon 10-fold cross-validation was 0.912 (95% CI 0.890-0.935). In addition, the model provided warnings of high risk for patients in advance of DILI onset for a median of 15 (IQR 7.3-27.5) days. CONCLUSIONS Our model shows high accuracy and interpretability in predicting cases of TB-DILI, which can provide useful information to clinicians to adjust the medication regimen and avoid more serious liver injury in patients.

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Predicting Antituberculosis Drug–Induced Liver Injury Using an Interpretable Machine Learning Method: Model Development and Validation Study

JMIR Medical Informatics ◽

10.2196/29226 ◽

2021 ◽

Vol 9 (7) ◽

pp. e29226

Author(s):

Tao Zhong ◽

Zian Zhuang ◽

Xiaoli Dong ◽

Ka Hing Wong ◽

Wing Tak Wong ◽

...

Keyword(s):

Machine Learning ◽

Liver Injury ◽

Receiver Operating Characteristic Curve ◽

Receiver Operating Characteristic ◽

Operating Characteristic ◽

Characteristic Curve ◽

Alanine Transaminase ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Operating Characteristic Curve

Background Tuberculosis (TB) is a pandemic, being one of the top 10 causes of death and the main cause of death from a single source of infection. Drug-induced liver injury (DILI) is the most common and serious side effect during the treatment of TB. Objective We aim to predict the status of liver injury in patients with TB at the clinical treatment stage. Methods We designed an interpretable prediction model based on the XGBoost algorithm and identified the most robust and meaningful predictors of the risk of TB-DILI on the basis of clinical data extracted from the Hospital Information System of Shenzhen Nanshan Center for Chronic Disease Control from 2014 to 2019. Results In total, 757 patients were included, and 287 (38%) had developed TB-DILI. Based on values of relative importance and area under the receiver operating characteristic curve, machine learning tools selected patients’ most recent alanine transaminase levels, average rate of change of patients’ last 2 measures of alanine transaminase levels, cumulative dose of pyrazinamide, and cumulative dose of ethambutol as the best predictors for assessing the risk of TB-DILI. In the validation data set, the model had a precision of 90%, recall of 74%, classification accuracy of 76%, and balanced error rate of 77% in predicting cases of TB-DILI. The area under the receiver operating characteristic curve score upon 10-fold cross-validation was 0.912 (95% CI 0.890-0.935). In addition, the model provided warnings of high risk for patients in advance of DILI onset for a median of 15 (IQR 7.3-27.5) days. Conclusions Our model shows high accuracy and interpretability in predicting cases of TB-DILI, which can provide useful information to clinicians to adjust the medication regimen and avoid more serious liver injury in patients.

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Deep Learning on High-Throughput Transcriptomics to Predict Drug-Induced Liver Injury

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2020.562677 ◽

2020 ◽

Vol 8 ◽

Author(s):

Ting Li ◽

Weida Tong ◽

Ruth Roberts ◽

Zhichao Liu ◽

Shraddha Thakkar

Keyword(s):

Deep Learning ◽

Liver Injury ◽

High Throughput ◽

Permutation Test ◽

Characteristic Curve ◽

Machine Learning Algorithms ◽

Attrition Rate ◽

Support Vector ◽

Drug Induced ◽

Drug Induced Liver Injury

Drug-induced liver injury (DILI) is one of the most cited reasons for the high drug attrition rate and drug withdrawal from the market. The accumulated large amount of high throughput transcriptomic profiles and advances in deep learning provide an unprecedented opportunity to improve the suboptimal performance of DILI prediction. In this study, we developed an eight-layer Deep Neural Network (DNN) model for DILI prediction using transcriptomic profiles of human cell lines (LINCS L1000 dataset) with the current largest binary DILI annotation data [i.e., DILI severity and toxicity (DILIst)]. The developed models were evaluated by Monte Carlo cross-validation (MCCV), permutation test, and an independent validation (IV) set. The developed DNN model achieved the area under the receiver operating characteristic curve (AUC) of 0.802 and 0.798, and balanced accuracy of 0.741 and 0.721 for training and an IV set, respectively, outperforming the conventional machine learning algorithms, including K-nearest neighbors (KNN), Support Vector Machine (SVM), and Random Forest (RF). Moreover, the developed DNN model provided a more balanced sensitivity of 0.839 and specificity of 0.603. Besides, we found the developed DNN model had a superior predictive performance for oncology drugs. Also, the functional and network analysis of genes driving the predictions revealed their relevance to the underlying mechanisms of DILI. The proposed DNN model could be a promising tool for early detection of DILI potential in the pre-clinical setting.

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The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development

Archives of Toxicology ◽

10.1007/s00204-020-02763-w ◽

2020 ◽

Vol 94 (8) ◽

pp. 2559-2585 ◽

Cited By ~ 3

Author(s):

Paul A. Walker ◽

Stephanie Ryder ◽

Andrea Lavado ◽

Clive Dilworth ◽

Robert J. Riley

Keyword(s):

Drug Discovery ◽

Liver Injury ◽

Drug Uptake ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

New Chemical Entities ◽

Preclinical Animal Models ◽

Uptake Transporters

Abstract Early identification of toxicity associated with new chemical entities (NCEs) is critical in preventing late-stage drug development attrition. Liver injury remains a leading cause of drug failures in clinical trials and post-approval withdrawals reflecting the poor translation between traditional preclinical animal models and human clinical outcomes. For this reason, preclinical strategies have evolved over recent years to incorporate more sophisticated human in vitro cell-based models with multi-parametric endpoints. This review aims to highlight the evolution of the strategies adopted to improve human hepatotoxicity prediction in drug discovery and compares/contrasts these with recent activities in our lab. The key role of human exposure and hepatic drug uptake transporters (e.g. OATPs, OAT2) is also elaborated.

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A high content screening assay to predict human drug-induced liver injury during drug discovery

Journal of Pharmacological and Toxicological Methods ◽

10.1016/j.vascn.2013.08.001 ◽

2013 ◽

Vol 68 (3) ◽

pp. 302-313 ◽

Cited By ~ 89

Author(s):

Mikael Persson ◽

Anni F. Løye ◽

Tomas Mow ◽

Jorrit J. Hornberg

Keyword(s):

Drug Discovery ◽

Liver Injury ◽

High Content Screening ◽

Screening Assay ◽

Drug Induced ◽

Drug Induced Liver Injury

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Prediction of Alternative Drug-Induced Liver Injury Classifications Using Molecular Descriptors, Gene Expression Perturbation, and Toxicology Reports

Frontiers in Genetics ◽

10.3389/fgene.2021.661075 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wojciech Lesiński ◽

Krzysztof Mnich ◽

Witold R. Rudnicki

Keyword(s):

Gene Expression ◽

Machine Learning ◽

Liver Injury ◽

Cell Lines ◽

Predictive Models ◽

Molecular Descriptors ◽

Chemical Properties ◽

Human Cell Lines ◽

Drug Induced ◽

Drug Induced Liver Injury

Motivation: Drug-induced liver injury (DILI) is one of the primary problems in drug development. Early prediction of DILI, based on the chemical properties of substances and experiments performed on cell lines, would bring a significant reduction in the cost of clinical trials and faster development of drugs. The current study aims to build predictive models of risk of DILI for chemical compounds using multiple sources of information.Methods: Using several supervised machine learning algorithms, we built predictive models for several alternative splits of compounds between DILI and non-DILI classes. To this end, we used chemical properties of the given compounds, their effects on gene expression levels in six human cell lines treated with them, as well as their toxicological profiles. First, we identified the most informative variables in all data sets. Then, these variables were used to build machine learning models. Finally, composite models were built with the Super Learner approach. All modeling was performed using multiple repeats of cross-validation for unbiased and precise estimates of performance.Results: With one exception, gene expression profiles of human cell lines were non-informative and resulted in random models. Toxicological reports were not useful for prediction of DILI. The best results were obtained for models discerning between harmless compounds and those for which any level of DILI was observed (AUC = 0.75). These models were built with Random Forest algorithm that used molecular descriptors.

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