scPAS: single-cell phenotype-associated subpopulation identifier.

Despite significant advancements in single-cell sequencing analysis for characterizing tissue sample heterogeneity, identifying the associations between cell subpopulations and disease phenotypes remains a challenging task. Here, we introduce scPAS, a new bioinformatics tool designed to integrate bulk data to identify phenotype-associated cell subpopulations within single-cell data. scPAS employs a network-regularized sparse regression model to quantify the association between each cell in single-cell data and a phenotype. Additionally, it estimates the significance of these associations through a permutation test, thereby identifying phenotype-associated cell subpopulations. Utilizing simulated data and various single-cell datasets from breast carcinoma, ovarian cancer, and atherosclerosis, as well as spatial transcriptomics data from multiple cancers, we demonstrated the accuracy, flexibility, and broad applicability of scPAS. Evaluations on large datasets revealed that scPAS exhibits superior operational efficiency compared to other methods. The open-source scPAS R package is available at GitHub website: https://github.com/aiminXie/scPAS.