Transparency in Modeling through Careful Application of OECD's QSAR/QSPR Principles via a Curated Water Solubility...

The need for careful assembly, training, and validation of quantitative structure-activity/property models (QSAR/QSPR) is more significant than ever as data sets become larger and sophisticated machine learning tools become increasingly ubiquitous and accessible to the scientific community. Regulatory agencies such as the United States Environmental Protection Agency must carefully scrutinize each aspect of a resulting QSAR/QSPR model to determine its potential use in environmental exposure and hazard assessment. Herein, we revisit the goals of the Organisation for Economic Cooperation and Development (OECD) in our application and discuss the validation principles for structure-activity models. We apply these principles to a model for predicting water solubility of organic compounds derived using random forest regression, a common machine learning approach in the QSA/PR literature. Using public sources, we carefully assembled and curated a data set consisting of 10,200 unique chemical structures with associated water solubility measurements. This data set was then used as a focal narrative to methodically consider the OECD's QSA/PR principles and how they can be applied to random forests. Despite some expert, mechanistically informed supervision of descriptor selection to enhance model interpretability, we achieved a model of water solubility with comparable performance to previously published models (5-fold cross validated performance 0.81 R² and 0.98 RMSE). We hope this work will catalyze a necessary conversation around the importance of cautiously modernizing and explicitly leveraging OECD principles while pursuing state-of-the-art machine learning approaches to derive QSA/PR models suitable for regulatory consideration.