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A decision-theoretic approach to the evaluation of machine learning algorithms in computational drug discovery.

ABSTRACT: MOTIVATION:Artificial intelligence, trained via machine learning (e.g. neural nets, random forests) or computational statistical algorithms (e.g. support vector machines, ridge regression), holds much promise for the improvement of small-molecule drug discovery. However, small-molecule structure-activity data are high dimensional with low signal-to-noise ratios and proper validation of predictive methods is difficult. It is poorly understood which, if any, of the currently available machine learning algorithms will best predict new candidate drugs. RESULTS:The quantile-activity bootstrap is proposed as a new model validation framework using quantile splits on the activity distribution function to construct training and testing sets. In addition, we propose two novel rank-based loss functions which penalize only the out-of-sample predicted ranks of high-activity molecules. The combination of these methods was used to assess the performance of neural nets, random forests, support vector machines (regression) and ridge regression applied to 25 diverse high-quality structure-activity datasets publicly available on ChEMBL. Model validation based on random partitioning of available data favours models that overfit and 'memorize' the training set, namely random forests and deep neural nets. Partitioning based on quantiles of the activity distribution correctly penalizes extrapolation of models onto structurally different molecules outside of the training data. Simpler, traditional statistical methods such as ridge regression can outperform state-of-the-art machine learning methods in this setting. In addition, our new rank-based loss functions give considerably different results from mean squared error highlighting the necessity to define model optimality with respect to the decision task at hand. AVAILABILITY AND IMPLEMENTATION:All software and data are available as Jupyter notebooks found at https://github.com/owatson/QuantileBootstrap. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.

SUBMITTER: Watson OP

PROVIDER: S-EPMC6853675 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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A decision-theoretic approach to the evaluation of machine learning algorithms in computational drug discovery.

Watson Oliver P OP Cortes-Ciriano Isidro I Taylor Aimee R AR Watson James A JA

Bioinformatics (Oxford, England) 20191101 22

<h4>Motivation</h4>Artificial intelligence, trained via machine learning (e.g. neural nets, random forests) or computational statistical algorithms (e.g. support vector machines, ridge regression), holds much promise for the improvement of small-molecule drug discovery. However, small-molecule structure-activity data are high dimensional with low signal-to-noise ratios and proper validation of predictive methods is difficult. It is poorly understood which, if any, of the currently available mach ...[more]

PMID: 31070704

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Project description:Machine learning methods are attracting considerable attention from the pharmaceutical industry for use in drug discovery and applications beyond. In recent studies, we and others have applied multiple machine learning algorithms and modeling metrics and, in some cases, compared molecular descriptors to build models for individual targets or properties on a relatively small scale. Several research groups have used large numbers of datasets from public databases such as ChEMBL in order to evaluate machine learning methods of interest to them. The largest of these types of studies used on the order of 1400 datasets. We have now extracted well over 5000 datasets from CHEMBL for use with the ECFP6 fingerprint and in comparison of our proprietary software Assay Central with random forest, k-nearest neighbors, support vector classification, naïve Bayesian, AdaBoosted decision trees, and deep neural networks (three layers). Model performance was assessed using an array of fivefold cross-validation metrics including area-under-the-curve, F1 score, Cohen's kappa, and Matthews correlation coefficient. Based on ranked normalized scores for the metrics or datasets, all methods appeared comparable, while the distance from the top indicated that Assay Central and support vector classification were comparable. Unlike prior studies which have placed considerable emphasis on deep neural networks (deep learning), no advantage was seen in this case. If anything, Assay Central may have been at a slight advantage as the activity cutoff for each of the over 5000 datasets representing over 570,000 unique compounds was based on Assay Central performance, although support vector classification seems to be a strong competitor. We also applied Assay Central to perform prospective predictions for the toxicity targets PXR and hERG to further validate these models. This work appears to be the largest scale comparison of these machine learning algorithms to date. Future studies will likely evaluate additional databases, descriptors, and machine learning algorithms and further refine the methods for evaluating and comparing such models.

Dataset Information

A decision-theoretic approach to the evaluation of machine learning algorithms in computational drug discovery.

Publications

A decision-theoretic approach to the evaluation of machine learning algorithms in computational drug discovery.

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