scBalFlow: A Staged Flow Matching Framework for Imbalanced Single-Cell Drug Perturbation Prediction.

MOTIVATION: Conventional drug perturbation prediction models typically employ end-to-end encoder-decoder architectures, directly mapping control samples and perturbation conditions to post-perturbation gene expression profiles. However, these approaches widely overlook the severe class imbalance inherent in perturbation datasets, leading to a predictive bias toward weakly responsive samples. RESULTS: To address this bottleneck, we propose scBalFlow, a decoupled two-stage training framework. The first stage predicts the perturbation response intensity under given conditions, employing a Gaussian-Augmented Inference (GAI) strategy to counteract data imbalance. Crucially, the second stage bypasses weakly responsive conditions, while utilizing a Flow Matching model to synthesize highly responsive samples. Comprehensive evaluations on large-scale benchmarks, including SciPlex3 and McFarland, demonstrate that scBalFlow effectively overcomes the imbalance issue and significantly outperforms existing state-of-the-art methods on imbalanced datasets, particularly in capturing complex distribution shifts and maintaining single-cell distributional consistency. AVAILABILITY: The source code and datasets are available at GitHub https://github.com/hanwenlv-cmd/scBalFlow and Figshare with DOI: 10.6084/m9.figshare.33137447. The datasets of SciPlex3, ComboSciPlex, and McFarland underlying this study are available via the pertpy package. Alternatively, they can be downloaded manually from https://exampledata.scverse.org/pertpy/srivatsan_2020_sciplex3.h5ad for SciPlex3, https://exampledata.scverse.org/pertpy/combosciplex.h5ad for combosciplex, and https://exampledata.scverse.org/pertpy/mcfarland_2020.h5ad for McFarland. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.