scDEBART: Predicting in silico Single-Cell Perturbation Responses via Large-Scale Differential Expression Learning

Single-cell foundation models trained on millions of cells can learn gene expression patterns across diverse contexts. However, for predicting genetic perturbation effects they often underperform simple regression models. We hypothesize two potential limitations: targets defined on dropout-prone absolute expression, and pretraining objectives that reconstruct static co-expression rather than encoding how genes co-regulate under expression changes. We introduce $\textbf{scDEBART}$, a perturbation-specific pretraining framework that predicts log fold-changes (logFC) conditioned on basal expression, thereby learning how gene sets co-vary across expression-change contexts at scale. To obtain reliable estimates of expression change under technical sparsity, we compute logFC from scVI-denoised expression and restrict pretraining to genes with robust detection. Pretrained on 6.28 million expression-change profiles from 66.6 million human cells and fine-tuned on five Perturb-seq datasets, scDEBART achieves mean enrichment factor (EF) of 11.96, 4-7$\times$ higher than scGPT and GEARS (mean EF 1.74-2.99), and 71.4% top-1 accuracy for reverse perturbation identification compared to near-zero accuracy for prior models. In cross-modal transfer to drug perturbations (SCIPLEX), the model shows dose-dependent improvement in directional alignment (cosine similarity 0.04→0.30) with above-random DEG enrichment (EF 2.91-4.32), suggesting partial transfer of learned regulatory patterns across modalities. Overall, these results indicate that large-scale pretraining on scVI-denoised expression-change profiles provides a useful inductive bias for perturbation prediction.