Dataset Information

In Silico Prediction of Drug-Induced Liver Injury Based on Ensemble Classifier Method.

ABSTRACT: Drug-induced liver injury (DILI) is a major factor in the development of drugs and the safety of drugs. If the DILI cannot be effectively predicted during the development of the drug, it will cause the drug to be withdrawn from markets. Therefore, DILI is crucial at the early stages of drug research. This work presents a 2-class ensemble classifier model for predicting DILI, with 2D molecular descriptors and fingerprints on a dataset of 450 compounds. The purpose of our study is to investigate which are the key molecular fingerprints that may cause DILI risk, and then to obtain a reliable ensemble model to predict DILI risk with these key factors. Experimental results suggested that 8 molecular fingerprints are very critical for predicting DILI, and also obtained the best ratio of molecular fingerprints to molecular descriptors. The result of the 5-fold cross-validation of the ensemble vote classifier method obtain an accuracy of 77.25%, and the accuracy of the test set was 81.67%. This model could be used for drug-induced liver injury prediction.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6747689 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

In Silico Prediction of Drug-Induced Liver Injury Based on Ensemble Classifier Method.

Wang Yangyang Y Xiao Qingxin Q Chen Peng P Wang Bing B

International journal of molecular sciences 20190822 17

Drug-induced liver injury (DILI) is a major factor in the development of drugs and the safety of drugs. If the DILI cannot be effectively predicted during the development of the drug, it will cause the drug to be withdrawn from markets. Therefore, DILI is crucial at the early stages of drug research. This work presents a 2-class ensemble classifier model for predicting DILI, with 2D molecular descriptors and fingerprints on a dataset of 450 compounds. The purpose of our study is to investigate w ...[more]

PMID: 31443562

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Project description:BackgroundMany classifiers which are constructed with chosen gene markers have been proposed to forecast the prognosis of patients who suffer from breast cancer. However, few of them has been applied in clinical practice because of the bad generalization, which results from the situation that markers selected by one method are very different from those obtained by another method, and thus such markers always lack discriminative capability in the other data sets.MethodsIn this work, a new ensemble classifier, on the basis of context specific miRNA regulation modules, has been proposed to forecast the metastasis risk of cancer sufferers. First, we defined all of the miRNAs which regulate the same context as a module that contains miRNAs and their regulating context, and applied the CoMi (Context-specific miRNA activity) score in order to illustrate a miRNA's effect which happened in a particular background; then the miRNA regulation modules with distinguishing abilities were detected and each of them was responsible for building a weak classifier separately; at last, by using majority voting strategy, we integrated all weak classifiers to establish an ensembled one that was applied to forecast the prognosis of patients who suffer from cancer.ResultsAfter comparing, the results on the cohorts containing over 1,000 samples showed that the proposed ensemble classifier is superior to other three classifiers based on miRNA expression profiles, mRNA expression profiles and CoMi activity patterns respectively. Significantly, our method outperforms the representative works. Moreover, the detected modules from different data sets show great stability (with p-value of 6.40e-08). For investigating the biological significance of those selected modules, case studies have been done by us and the results suggested that our method do help to reveal latent mechanism in metastasis of breast cancer.ConclusionsOne context specific miRNA regulation module can uncover one critical biological process and its involved miRNAs that are related to the cancer outcome, and several modules together can help to study the biological mechanism in cancer metastasis, thus the classifer based on ensembling multiple classifers which were built with different context specific miRNA regulation modules has showed promising performances in terms with both prediction accuracy and generalization.

Project description:BackgroundDrug-induced liver injury (DILI) is a major safety concern characterized by a complex and diverse pathogenesis. In order to identify DILI early in drug development, a better understanding of the injury and models with better predictivity are urgently needed. One approach in this regard are in silico models which aim at predicting the risk of DILI based on the compound structure. However, these models do not yet show sufficient predictive performance or interpretability to be useful for decision making by themselves, the former partially stemming from the underlying problem of labeling the in vivo DILI risk of compounds in a meaningful way for generating machine learning models.ResultsAs part of the Critical Assessment of Massive Data Analysis (CAMDA) "CMap Drug Safety Challenge" 2019 ( http://camda2019.bioinf.jku.at ), chemical structure-based models were generated using the binarized DILIrank annotations. Support Vector Machine (SVM) and Random Forest (RF) classifiers showed comparable performance to previously published models with a mean balanced accuracy over models generated using 5-fold LOCO-CV inside a 10-fold training scheme of 0.759?±?0.027 when predicting an external test set. In the models which used predicted protein targets as compound descriptors, we identified the most information-rich proteins which agreed with the mechanisms of action and toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs), one of the most important drug classes causing DILI, stress response via TP53 and biotransformation. In addition, we identified multiple proteins involved in xenobiotic metabolism which could be novel DILI-related off-targets, such as CLK1 and DYRK2. Moreover, we derived potential structural alerts for DILI with high precision, including furan and hydrazine derivatives; however, all derived alerts were present in approved drugs and were over specific indicating the need to consider quantitative variables such as dose.ConclusionUsing chemical structure-based descriptors such as structural fingerprints and predicted protein targets, DILI prediction models were built with a predictive performance comparable to previous literature. In addition, we derived insights on proteins and pathways statistically (and potentially causally) linked to DILI from these models and inferred new structural alerts related to this adverse endpoint.

Dataset Information

In Silico Prediction of Drug-Induced Liver Injury Based on Ensemble Classifier Method.

Publications

In Silico Prediction of Drug-Induced Liver Injury Based on Ensemble Classifier Method.

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