Feature Space Selection and Heterogeneous Effect Estimation for Blood-Brain Barrier Permeability: A Random Forest to the Generalized Random Forest Pipeline

Tshemollo Rapolai, Seite Makgai, Mohammad Arashi

Predicting blood-brain barrier (BBB) permeability is critical for central nervous system drug discovery. Using the MoleculeNet BBBP dataset (n = 2039), this study systematically ablates molecular feature spaces to isolate featurisation from model architecture. We evaluate three feature families (Morgan fingerprints, RDKit physicochemical descriptors, SMILES bigrams) across four learning algorithms. Results demonstrate that predictive performance depends jointly on feature representation and algorithm. Dynamic Random Forest using combined features achieved the highest mean AUC (0.970, 95% CI: 0.963-0.977). Second, this optimal representation enables exploratory estimation of heterogeneous associations between molecular structure and BBB permeability using Generalized Random Forests. Constructing a pseudo-treatment from a LogP median split, we applied double/debiased machine learning to account for confounding. Orthogonalization substantially attenuates the heterogeneity detected by naive causal forests; no conditional effects remained significant after false discovery rate correction (smallest adjusted p = 0.082). Furthermore, orthogonalized feature importance shifted toward…