scRepresenter: a workflow for computing, integrating and benchmarking cellular representations in single-cell transcriptomics

Motivation: Single-cell RNA sequencing (scRNA-seq) has become an attractive tool for studying complex diseases, in which transient cell states affecting diverse cell populations characterise disease development and progression. However, due to data sparsity and disease heterogeneity analysis is often challenging. With recent advances in machine learning, two widely used approaches have emerged for learning cellular representations: large-scale foundation models and biological knowledge-guided methods. Despite their complementary strengths, there is currently no unified workflow for systematically comparing and integrating these approaches. Results: Here, we present scRepresenter, an open-source workflow for computing, integrating, and validating cellular embeddings derived from foundation models and biological knowledge-guided methods in the context of complex diseases. It consists of two components: a command-line workflow that computes cellular embeddings and performs downstream analyses, and an interactive Shiny application for visualizing and comparing the computed embeddings. scRepresenter supports four categories of cellular representations: (1) expression-based, (2) knowledge-guided, (3) foundation model-derived, and (4) hybrid embeddings that combine foundation model-derived representations with knowledge-guided representations. This approach takes a cell-by-gene count matrix as input and outputs an integrated object containing the computed embeddings. Then, this object can be uploaded into our interactive Shiny application to compare different embeddings. Availability: The workflow is available at https://github.com/GuilhermePocas/scRepresenter Contact: AL291@cam.ac.uk; MA2129@cam.ac.uk Keywords: single-cell RNA-sequencing, machine learning, representation learning, foundation models, cellular embeddings, complex diseases, amyotrophic lateral sclerosis, human organoid