An Interpretable Graph-Regularized Optimal Transport Framework for Diagonal Single-Cell Integrative Analysis

Background Recent advancements in single-cell omics technologies have enabled detailed characterization of cellular processes. However, coassay sequencing technologies remain limited, resulting in un-paired single-cell omics datasets with differing feature dimensions; Finding we present GROTIA (Graph-Regularized Optimal Transport Framework for Diagonal Single-Cell Integrative Analysis), a computational method to align multi-omics datasets without requiring any prior correspondence information. GROTIA achieves global alignment through optimal transport while preserving local relationships via graph regularization. Additionally, our approach provides interpretability by deriving domain-specific feature importance from partial derivatives, highlighting key biological markers. Moreover, the transport plan between modalities can be leveraged for post-integration clustering, enabling a data-driven approach to discover novel cell subpopulations; Conclusions We demonstrate GROTIA’s superior performance on four simulated and four real-world datasets, surpassing state-of-the-art unsupervised alignment methods and confirming the biological significance of the top features identified in each domain. The software is available at https://github.com/PennShenLab/GROTIA .