Learning interpretable cellular and gene signature embeddings from single-cell transcriptomic data

Yifan Zhao, Huiyu Cai, Zuobai Zhang, Jian Tang () and Yue Li ()
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Yifan Zhao: School of Computer Science, McGill University
Huiyu Cai: Peking University
Zuobai Zhang: School of Computer Science, Fudan University
Jian Tang: HEC Montreal
Yue Li: School of Computer Science, McGill University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract The advent of single-cell RNA sequencing (scRNA-seq) technologies has revolutionized transcriptomic studies. However, large-scale integrative analysis of scRNA-seq data remains a challenge largely due to unwanted batch effects and the limited transferabilty, interpretability, and scalability of the existing computational methods. We present single-cell Embedded Topic Model (scETM). Our key contribution is the utilization of a transferable neural-network-based encoder while having an interpretable linear decoder via a matrix tri-factorization. In particular, scETM simultaneously learns an encoder network to infer cell type mixture and a set of highly interpretable gene embeddings, topic embeddings, and batch-effect linear intercepts from multiple scRNA-seq datasets. scETM is scalable to over 106 cells and confers remarkable cross-tissue and cross-species zero-shot transfer-learning performance. Using gene set enrichment analysis, we find that scETM-learned topics are enriched in biologically meaningful and disease-related pathways. Lastly, scETM enables the incorporation of known gene sets into the gene embeddings, thereby directly learning the associations between pathways and topics via the topic embeddings.

Date: 2021
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DOI: 10.1038/s41467-021-25534-2

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