Learning multi-cellular representations of single-cell transcriptomics data enables characterization of patient-level disease states

Single-cell RNA sequencing (scRNA-seq) is a prominent tool for studying human disease biology. The availability of massive scRNA-seq datasets and advanced machine learning has driven the development of single-cell foundation models that provide versatile cell representations based on expression. To understand disease states, we need to account for entire tissue ecosystems, simultaneously considering many different interacting cells. Here, we tackle this challenge by generating patient-level representations derived from multi-cellular expression contexts measured with scRNA-seq of tissues. We develop PaSCient, a machine learning model that employs a multi-level representation learning paradigm and provides importance scores at the cell and gene levels for fine-grained analysis of disease characteristics. We apply PaSCient to a large-scale scRNA-seq atlas of 12.5 million cells from over 2,700 patients. Comprehensive benchmarking demonstrates the superiority of PaSCient in disease classification and multiple downstream applications, including dimensionality reduction, feature prioritization, and patient subgroup discovery.