Cradle-VAE: Enhancing Single-Cell Gene Perturbation Modeling with Counterfactual Reasoning-based Artifact Disentanglement

Abstract Predicting cellular responses to various perturbations is a critical focus in drug discovery and personalized therapeutics, with deep learning models playing a significant role in this endeavor. Single-cell datasets contain technical artifacts that may hinder the predictability of such models, which poses quality control issues highly regarded in this area. To address this, we propose Cradle-VAE, a causal generative framework tailored for single-cell gene perturbation modeling, enhanced with counterfactual reasoning-based artifact disentanglement. Throughout training, Cradle-VAE models the underlying latent distribution of technical artifacts and perturbation effects present in single-cell datasets. It employs counterfactual reasoning to effectively disentangle such artifacts by modulating the latent basal spaces and learns robust features for generating cellular response data with improved quality. Experimental results demonstrate that this approach improves not only treatment effect estimation performance but also generative quality as well.