Causal Invariant Hierarchical Molecular Representation for Out-of-distribution Molecular Property Prediction

Molecular representation learning is widely used in the field of drug discovery, due to its ability to accurately capture the complex features of compounds in high-dimensional space. However, existing molecular representation learning models are prone to be influenced by spurious parts during distribution shifts (also known as out-of-distribution, or OOD), which results in models mistakenly treating these spurious parts as crucial features of molecules, thereby limiting the generalization capability of the models. To tackle this issue, a novel invariant molecular representation learning model, called Causal Invariant Hierarchical Molecular Representation Graph Neural Networks (CHiMoGNN), is proposed for OOD molecular property prediction. In CHiMoGNN, a Feature Enhancement (FE) module is designed to leverage the multi-level molecular parts to enhance the expression of invariant features, thereby enhancing the model’s capability to capture key molecular information. In addition, a Cartesian Product based Environmental Impact (EI) module is adopted to generate counterfactual samples with environmental diversity. Consequently, these samples are utilized to train a classifier that maintains consistent performance across various environments. Extensive experiments on seven real-world datasets demonstrate that CHiMoGNN outperforms 9 state-of-the-art models, achieving a 5.73% increase in average ROC-AUC, and the results also show that CHiMoGNN can effectively maintain generalization in various distribution shifts. Code and datasets are available at https://github.com/Chertuion/CHiMoGNN.