Abstract The recent advance of single cell sequencing (scRNA-seq) technology such as Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) allows researchers to quantify cell surface protein abundance and RNA expression simultaneously at single cell resolution. Although CITE-seq and other similar technologies have quickly gained enormous popularity, novel methods for analyzing this new type of single cell multi-omics data are still in urgent need. A limited number of available tools utilize data-driven approach, which may undermine the biological importance of surface protein data. In this study, we developed SECANT, a biology-guided SEmi-supervised method for Clustering, classification, and ANnoTation of single-cell multi-omics. SECANT can be used to analyze CITE-seq data, or jointly analyze CITE-seq and scRNA-seq data. The novelties of SECANT include 1) using confident cell type labels identified from surface protein data as guidance for cell clustering, 2) providing general annotation of confident cell types for each cell cluster, 3) fully utilizing cells with uncertain or missing cell type labels to increase performance, and 4) accurate prediction of confident cell types identified from surface protein data for scRNA-seq data. Besides, as a model-based approach, SECANT can quantify the uncertainty of the results, and our framework can be easily extended to handle other types of multi-omics data. We successfully demonstrated the validity and advantages of SECANT via simulation studies and analysis of public and in-house real datasets. We believe this new method will greatly help researchers characterize novel cell types and make new biological discoveries using single cell multi-omics data.

SECANT: a biology-guided semi-supervised method for clustering, classification, and annotation of single-cell multi-omics