scMoE: single-cell mixture of experts for learning hierarchical, cell-type-specific, and interpretable representations from heterogeneous scRNA-seq data

Advancements in single-cell transcriptomics methods have resulted in a wealth of single-cell RNA sequencing (scRNA-seq) data. Methods to learn cell representation from atlas-level scRNA-seq data across diverse tissues can shed light into cell functions implicated in diseases such as cancer. However, integrating large-scale and heterogeneous scRNA-seq data is challenging due to the disparity of cell-types and batch effects. We present single-cell Mixture of Expert (scMoE), a hierarchical mixture of experts single-cell topic model. Our key contributions are the cell-type specific experts, which explicitly aligns topics with cell-types, and the integration of hierarchical cell-type lineages and domain knowledge. scMoE is both transferable and highly interpretable. We benchmarked our scMoE’s performance on 9 single-cell RNA-seq datasets for clustering and 3 simulated spatial datasets for spatial deconvolution. We additionally show that our model, using single-cell references, yields meaningful biological results by deconvolving 3 cancer bulk RNA-seq datasets and 2 spatial transcriptomics datasets. scMoE is able to identify cell-types of survival importance, find cancer subtype specific deconvolutional patterns, and capture meaningful spatially distinct cell-type distributions.