Probabilistic Random Forest improves bioactivity predictions close to the classification threshold by taking into account experimental uncertainty

Journal of Cheminformatics

Avid M. Afzal¹  Ian P. Barrett¹  Andreas Bender²  Maria-Anna Trapotsi²  Lewis H. Mervin³  Ola Engkvist⁴ 

[1] Data Sciences & Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK;Department of Chemistry, Centre for Molecular Informatics, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK;Molecular AI, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK;Molecular AI, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden;Department of Computer Science and Engineering, Chalmers University of Technology, Gothenburg, Sweden;

关键词: Probabilistic random forest;    Target prediction;    Uncertainty estimation;    Experimental error;    Applicability Domain;   

DOI  :  10.1186/s13321-021-00539-7

来源: Springer

【 摘 要 】

Measurements of protein–ligand interactions have reproducibility limits due to experimental errors. Any model based on such assays will consequentially have such unavoidable errors influencing their performance which should ideally be factored into modelling and output predictions, such as the actual standard deviation of experimental measurements (σ) or the associated comparability of activity values between the aggregated heterogenous activity units (i.e., Ki versus IC50 values) during dataset assimilation. However, experimental errors are usually a neglected aspect of model generation. In order to improve upon the current state-of-the-art, we herein present a novel approach toward predicting protein–ligand interactions using a Probabilistic Random Forest (PRF) classifier. The PRF algorithm was applied toward in silico protein target prediction across ~ 550 tasks from ChEMBL and PubChem. Predictions were evaluated by taking into account various scenarios of experimental standard deviations in both training and test sets and performance was assessed using fivefold stratified shuffled splits for validation. The largest benefit in incorporating the experimental deviation in PRF was observed for data points close to the binary threshold boundary, when such information was not considered in any way in the original RF algorithm. For example, in cases when σ ranged between 0.4–0.6 log units and when ideal probability estimates between 0.4–0.6, the PRF outperformed RF with a median absolute error margin of ~ 17%. In comparison, the baseline RF outperformed PRF for cases with high confidence to belong to the active class (far from the binary decision threshold), although the RF models gave errors smaller than the experimental uncertainty, which could indicate that they were overtrained and/or over-confident. Finally, the PRF models trained with putative inactives decreased the performance compared to PRF models without putative inactives and this could be because putative inactives were not assigned an experimental pXC50 value, and therefore they were considered inactives with a low uncertainty (which in practice might not be true). In conclusion, PRF can be useful for target prediction models in particular for data where class boundaries overlap with the measurement uncertainty, and where a substantial part of the training data is located close to the classification threshold.

【 授权许可】

CC BY