An integrative machine learning approach for prediction of toxicity-related drug safety.
Ontology highlight
ABSTRACT:
SUBMITTER: Lysenko A
PROVIDER: S-EPMC6262234 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
Publications
An integrative machine learning approach for prediction of toxicity-related drug safety.
Lysenko Artem A Sharma Alok A Boroevich Keith A KA Tsunoda Tatsuhiko T
Life science alliance 20181128 6
Recent trends in drug development have been marked by diminishing returns caused by the escalating costs and falling rates of new drug approval. Unacceptable drug toxicity is a substantial cause of drug failure during clinical trials and the leading cause of drug withdraws after release to the market. Computational methods capable of predicting these failures can reduce the waste of resources and time devoted to the investigation of compounds that ultimately fail. We propose an original machine ...[more]
Similar Datasets
Project description:Different types of chemicals and products may exhibit various health risks when administered into the human body. For toxicity reasons, the number of new drugs entering the market through the conventional drug development process has been reduced over the years. However, with the advent of big data and artificial intelligence, machine learning techniques have emerged as a potential solution for predicting toxicity and ensuring efficient drug development and chemical safety. An ML model for toxicity prediction can reduce experimental costs and time while addressing ethical concerns by drastically reducing the need for animals and clinical trials. Herein, MolToxPred, an ML-based tool, has been developed using a stacked model approach to predict the potential toxicity of small molecules and metabolites. The stacked model consists of random forest, multi-layer perceptron, and LightGBM as base classifiers and Logistic Regression as the meta classifier. For training and validation purposes, a comprehensive set of toxic and non-toxic molecules is curated. Different structural and physicochemical-based features in the form of molecular descriptors and fingerprints were employed. MolToxPred utilizes a comprehensive feature selection process and optimizes its hyperparameters through Bayesian optimization with stratified 5-fold cross-validation. In the evaluation phase, MolToxPred achieved an AUROC of 87.76% on the test set and 88.84% on an external validation set. The McNemar test was used as the post-hoc test to determine if the stacked models' performance was significantly different compared to the base learners. The developed stacked model outperformed its base classifiers and an existing tool in the literature, reaffirming its better performance. The hypothesis is that the incorporation of a diverse set of data, the subsequent feature selection, and a stacked ensemble approach give MolToxPred the edge over other methods. In addition to this, an attempt has been made to identify structural alerts responsible for endpoints of the Tox21 data to determine the association of a molecule with a plausible downstream pathway of action. MolToxPred may be helpful for drug discovery and regulatory pipelines in pharmaceutical and other industries for in silico toxicity prediction of small molecule candidates.
| S-EPMC10826801 | biostudies-literature
Project description:Drug-induced immune thrombocytopenia (DITP) often occurs in patients receiving many drug treatments simultaneously. However, clinicians usually fail to accurately distinguish which drugs can be plausible culprits. Despite significant advances in laboratory-based DITP testing, in vitro experimental assays have been expensive and, in certain cases, cannot provide a timely diagnosis to patients. To address these shortcomings, this paper proposes an efficient machine learning-based method for DITP toxicity prediction. A small dataset consisting of 225 molecules was constructed. The molecules were represented by six fingerprints, three descriptors, and their combinations. Seven classical machine learning-based models were examined to determine an optimal model. The results show that the RDMD + PubChem-k-NN model provides the best prediction performance among all the models, achieving an area under the curve of 76.9% and overall accuracy of 75.6% on the external validation set. The application domain (AD) analysis demonstrates the prediction reliability of the RDMD + PubChem-k-NN model. Five structural fragments related to the DITP toxicity are identified through information gain (IG) method along with fragment frequency analysis. Overall, as far as known, it is the first machine learning-based classification model for recognizing chemicals with DITP toxicity and can be used as an efficient tool in drug design and clinical therapy.
| S-EPMC9143325 | biostudies-literature
Project description:In this review, we outline the current trends in the field of machine learning-driven classification studies related to ADME (absorption, distribution, metabolism and excretion) and toxicity endpoints from the past six years (2015-2021). The study focuses only on classification models with large datasets (i.e. more than a thousand compounds). A comprehensive literature search and meta-analysis was carried out for nine different targets: hERG-mediated cardiotoxicity, blood-brain barrier penetration, permeability glycoprotein (P-gp) substrate/inhibitor, cytochrome P450 enzyme family, acute oral toxicity, mutagenicity, carcinogenicity, respiratory toxicity and irritation/corrosion. The comparison of the best classification models was targeted to reveal the differences between machine learning algorithms and modeling types, endpoint-specific performances, dataset sizes and the different validation protocols. Based on the evaluation of the data, we can say that tree-based algorithms are (still) dominating the field, with consensus modeling being an increasing trend in drug safety predictions. Although one can already find classification models with great performances to hERG-mediated cardiotoxicity and the isoenzymes of the cytochrome P450 enzyme family, these targets are still central to ADMET-related research efforts.
| S-EPMC8342376 | biostudies-literature
Project description:Since the last published update in 2014, the SuperPred webserver has been continuously developed to offer state-of-the-art models for drug classification according to ATC classes and target prediction. For the first time, a thoroughly filtered ATC dataset, that is suitable for accurate predictions, is provided along with detailed information on the achieved predictions. This aims to overcome the challenges in comparing different published prediction methods, since performance can vary greatly depending on the training dataset used. Additionally, both ATC and target prediction have been reworked and are now based on machine learning models instead of overall structural similarity, stressing the importance of functional groups for the mechanism of action of small molecule substances. Additionally, the dataset for the target prediction has been extensively filtered and is no longer only based on confirmed binders but also includes non-binding substances to reduce false positives. Using these methods, accuracy for the ATC prediction could be increased by almost 5% to 80.5% compared to the previous version, and additionally the scoring function now offers values which are easily assessable at first glance. SuperPred 3.0 is publicly available without the need for registration at: https://prediction.charite.de/index.php.
| S-EPMC9252837 | biostudies-literature
Project description:The identification of drug/compound-target interactions (DTIs) constitutes the basis of drug discovery, for which computational predictive approaches have been developed. As a relatively new data-driven paradigm, proteochemometric (PCM) modeling utilizes both protein and compound properties as a pair at the input level and processes them via statistical/machine learning. The representation of input samples (i.e., proteins and their ligands) in the form of quantitative feature vectors is crucial for the extraction of interaction-related properties during the artificial learning and subsequent prediction of DTIs. Lately, the representation learning approach, in which input samples are automatically featurized via training and applying a machine/deep learning model, has been utilized in biomedical sciences. In this study, we performed a comprehensive investigation of different computational approaches/techniques for protein featurization (including both conventional approaches and the novel learned embeddings), data preparation and exploration, machine learning-based modeling, and performance evaluation with the aim of achieving better data representations and more successful learning in DTI prediction. For this, we first constructed realistic and challenging benchmark datasets on small, medium, and large scales to be used as reliable gold standards for specific DTI modeling tasks. We developed and applied a network analysis-based splitting strategy to divide datasets into structurally different training and test folds. Using these datasets together with various featurization methods, we trained and tested DTI prediction models and evaluated their performance from different angles. Our main findings can be summarized under 3 items: (i) random splitting of datasets into train and test folds leads to near-complete data memorization and produce highly over-optimistic results, as a result, should be avoided, (ii) learned protein sequence embeddings work well in DTI prediction and offer high potential, despite interaction-related properties (e.g., structures) of proteins are unused during their self-supervised model training, and (iii) during the learning process, PCM models tend to rely heavily on compound features while partially ignoring protein features, primarily due to the inherent bias in DTI data, indicating the requirement for new and unbiased datasets. We hope this study will aid researchers in designing robust and high-performing data-driven DTI prediction systems that have real-world translational value in drug discovery.
| S-EPMC9901167 | biostudies-literature
Project description:By predicting ERα bioactivity and mining the potential relationship between Absorption, Distribution, Metabolism, Excretion, Toxicity (ADMET) attributes in drug research and development, the development efficiency of specific drugs for breast cancer will be effectively improved and the misjudgment rate of R&D personnel will be reduced. The quantitative prediction model of ERα bioactivity and classification prediction model of Absorption, Distribution, Metabolism, Excretion, Toxicity properties were constructed. The prediction results of ERα bioactivity were compared by XGBoot, Light GBM, Random Forest and MLP neural network. Two models with high prediction accuracy were selected and fused to obtain ERα bioactivity prediction model from Mean absolute error (MAE), mean squared error (MSE) and R2. The data were further subjected to model-based feature selection and FDR/FPR-based feature selection, respectively, and the results were placed in a voting machine to obtain Absorption, Distribution, Metabolism, Excretion, Toxicity classification prediction model. In this study, 430 molecular descriptors were removed, and finally 20 molecular descriptors with the most significant effect on biological activity obtained by the dual feature screening combined optimization method were used to establish a compound molecular descriptor prediction model for ERα biological activity, and further classification and prediction of the Absorption, Distribution, Metabolism, Excretion, Toxicity properties of the drugs were made. Eighty variables were selected by the model ExtraTreesClassifier Classifie, and 40 variables were selected by the model GradientBoostingClassifier to complete the model-based feature selection. At the same time, the feature selection method based on FDR/FPR is also selected, and the three classification models obtained by the two methods are placed into the voting machine to obtain the final model. The experimental results showed that the model's evaluation indexes and roc diagram were excellent and could accurately predict ERα bioactivity and Absorption, Distribution, Metabolism, Excretion, Toxicity properties. The model constructed in this study has high accuracy, fast convergence and robustness, has a very high accuracy for Absorption, Distribution, Metabolism, Excretion, Toxicity and ERα classification prediction, has bright prospects in the biopharmaceutical field, and is an important method for energy conservation and yield increase in the future.
| S-EPMC9845410 | biostudies-literature
Project description:Gene expression profiles were generated from 199 primary breast cancer patients. Samples 1-176 were used in another study, GEO Series GSE22820, and form the training data set in this study. Sample numbers 200-222 form a validation set. This data is used to model a machine learning classifier for Estrogen Receptor Status. RNA was isolated from 199 primary breast cancer patients. A machine learning classifier was built to predict ER status using only three gene features.
2013-01-01 | E-GEOD-29210 | biostudies-arrayexpress
Project description:The rise of artificial intelligence (AI) based algorithms has gained a lot of interest in the pharmaceutical development field. Our study demonstrates utilization of traditional machine learning techniques such as random forest (RF), support-vector machine (SVM), extreme gradient boosting (XGBoost), deep neural network (DNN) as well as advanced deep learning techniques like gated recurrent unit-based DNN (GRU-DNN) and graph neural network (GNN), towards predicting human ether-á-go-go related gene (hERG) derived toxicity. Using the largest hERG dataset derived to date, we have utilized 203,853 and 87,366 compounds for training and testing the models, respectively. The results show that GNN, SVM, XGBoost, DNN, RF, and GRU-DNN all performed well, with validation set AUC ROC scores equals 0.96, 0.95, 0.95, 0.94, 0.94 and 0.94, respectively. The GNN was found to be the top performing model based on predictive power and generalizability. The GNN technique is free of any feature engineering steps while having a minimal human intervention. The GNN approach may serve as a basis for comprehensive automation in predictive toxicology. We believe that the models presented here may serve as a promising tool, both for academic institutes as well as pharmaceutical industries, in predicting hERG-liability in new molecular structures.
| S-EPMC10493507 | biostudies-literature
Project description:BackgroundVaccine safety surveillance is important because it is related to vaccine hesitancy, which affects vaccination rate. To increase confidence in vaccination, the active monitoring of vaccine adverse events is important. For effective active surveillance, we developed and verified a machine learning-based active surveillance system using national claim data.MethodsWe used two databases, one from the Korea Disease Control and Prevention Agency, which contains flu vaccination records for the elderly, and another from the National Health Insurance Service, which contains the claim data of vaccinated people. We developed a case-crossover design based machine learning model to predict the health outcome of interest events (anaphylaxis and agranulocytosis) using a random forest. Feature importance values were evaluated to determine candidate associations with each outcome. We investigated the relationship of the features to each event via a literature review, comparison with the Side Effect Resource, and using the Local Interpretable Model-agnostic Explanation method.ResultsThe trained model predicted each health outcome of interest with a high accuracy (approximately 70%). We found literature supporting our results, and most of the important drug-related features were listed in the Side Effect Resource database as inducing the health outcome of interest. For anaphylaxis, flu vaccination ranked high in our feature importance analysis and had a positive association in Local Interpretable Model-Agnostic Explanation analysis. Although the feature importance of vaccination was lower for agranulocytosis, it also had a positive relationship in the Local Interpretable Model-Agnostic Explanation analysis.ConclusionWe developed a machine learning-based active surveillance system for detecting possible factors that can induce adverse events using health claim and vaccination databases. The results of the study demonstrated a potentially useful application of two linked national health record databases. Our model can contribute to the establishment of a system for conducting active surveillance on vaccination.
| S-EPMC8352788 | biostudies-literature
Project description:Identification of the correct targets is a key element for successful drug development. However, there are limited approaches for predicting drug targets for specific diseases using omics data, and few have leveraged expression profiles from gene perturbations. We present a novel computational approach for drug target discovery based on machine learning (ML) models. ML models are first trained on drug-induced expression profiles with outcomes defined as whether the drug treats the studied disease. The goal is to "learn" the expression patterns associated with treatment. Then, the fitted ML models were applied to expression profiles from gene perturbations (overexpression (OE)/knockdown (KD)). We prioritized targets based on predicted probabilities from the ML model, which reflects treatment potential. The methodology was applied to predict targets for hypertension, diabetes mellitus (DM), rheumatoid arthritis (RA), and schizophrenia (SCZ). We validated our approach by evaluating whether the identified targets may 're-discover' known drug targets from an external database (OpenTargets). Indeed, we found evidence of significant enrichment across all diseases under study. A further literature search revealed that many candidates were supported by previous studies. For example, we predicted PSMB8 inhibition to be associated with the treatment of RA, which was supported by a study showing that PSMB8 inhibitors (PR-957) ameliorated experimental RA in mice. In conclusion, we propose a new ML approach to integrate the expression profiles from drugs and gene perturbations and validated the framework. Our approach is flexible and may provide an independent source of information when prioritizing drug targets.
| S-EPMC8878225 | biostudies-literature