Predicting the reproductive toxicity of chemicals using ensemble learning methods and molecular fingerprints.

Reproductive toxicity endpoints are a significant safety concern in the assessment of the adverse effects of chemicals in drug discovery. Computational models that can accurately predict a chemical's toxic potential are increasingly pursued to replace traditional animal experiments. Thus, ensemble learning models were built to predict the reproductive toxicity of compounds. Our ensemble models were developed using support vector machine, random forest, and extreme gradient boosting methods and 9 molecular fingerprints calculated for a dataset containing 1823 chemicals. The best prediction performance was achieved by the Ensemble-Top12 model, with an accuracy (ACC) of 86.33 %, a sensitivity (SEN) of 82.02 %, a specificity (SPE) of 90.19 %, and an area under the receiver operating characteristic curve (AUC) of 0.937 in 5-fold cross-validation and ACC, SEN, SPE, and AUC values of 84.38 %, 86.90 %, 90.67 %, and 0.920, respectively, in external validation. We also defined the applicability domain (AD) of the ensemble model by calculating the Tanimoto distance of the training set. Compared with models in existing literature, our ensemble model achieves relatively high ACC, SPE and AUC values. We also identified several fingerprint features related to chemical reproductive toxicity. Considering the performance of model, we recommend using the Ensemble-Top12 model to predict reproductive toxicity in early drug development.

Prediction of hERG potassium channel blockage using ensemble learning methods and molecular fingerprints.

The human ether-a-go-go-related gene (hERG) encodes a tetrameric potassium channel called Kv11.1. This channel can be blocked by certain drugs, which leads to long QT syndrome, causing cardiotoxicity. This is a significant problem during drug development. Using computer models to predict compound cardiotoxicity during the early stages of drug design will help to solve this problem. In this study, we used a dataset of 1865 compounds exhibiting known hERG inhibitory activities as a training set. Thirty cardiotoxicity classification models were established using three machine learning algorithms based on molecular fingerprints and molecular descriptors. Through using these models as the base classifier, a new cardiotoxicity classification model with better predictive performance was developed using ensemble learning method. The accuracy of the best base classifier, which was generated using the XGBoost method with molecular descriptors, was 84.8 %, and the area under the receiver-operating characteristic curve (AUC) was 0.876 in the five fold cross-validation. However, all of the ensemble models that we developed had higher predictive performance than the base classifiers in the five fold cross-validation. The best predictive performance was achieved by the Ensemble-Top7 model, with accuracy of 84.9 % and AUC of 0.887. We also tested the ensemble model using external validation data and achieved accuracy of 85.0 % and AUC of 0.786. Furthermore, we identified several hERG-related substructures, which provide valuable information for designing drug candidates.

Ensemble Learning Models Based on Noninvasive Features for Type 2 Diabetes Screening: Model Development and Validation.

BACKGROUND: Early diabetes screening can effectively reduce the burden of disease. However, natural population-based screening projects require a large number of resources. With the emergence and development of machine learning, researchers have started to pursue more flexible and efficient methods to screen or predict type 2 diabetes. OBJECTIVE: The aim of this study was to build prediction models based on the ensemble learning method for diabetes screening to further improve the health status of the population in a noninvasive and inexpensive manner. METHODS: The dataset for building and evaluating the diabetes prediction model was extracted from the National Health and Nutrition Examination Survey from 2011-2016. After data cleaning and feature selection, the dataset was split into a training set (80%, 2011-2014), test set (20%, 2011-2014) and validation set (2015-2016). Three simple machine learning methods (linear discriminant analysis, support vector machine, and random forest) and easy ensemble methods were used to build diabetes prediction models. The performance of the models was evaluated through 5-fold cross-validation and external validation. The Delong test (2-sided) was used to test the performance differences between the models. RESULTS: We selected 8057 observations and 12 attributes from the database. In the 5-fold cross-validation, the three simple methods yielded highly predictive performance models with areas under the curve (AUCs) over 0.800, wherein the ensemble methods significantly outperformed the simple methods. When we evaluated the models in the test set and validation set, the same trends were observed. The ensemble model of linear discriminant analysis yielded the best performance, with an AUC of 0.849, an accuracy of 0.730, a sensitivity of 0.819, and a specificity of 0.709 in the validation set. CONCLUSIONS: This study indicates that efficient screening using machine learning methods with noninvasive tests can be applied to a large population and achieve the objective of secondary prevention.