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

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 gained enormous popularity, novel methods for analyzing this type of single cell multi-omics data are 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 is 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 label identified from surface protein data as guidance for cell clustering, 2) providing general annotation of confident cell types for each cell cluster, 3) utilizing cells with uncertain or missing cell type label to increase performance, and 4) accurate prediction of confident cell types for scRNA-seq data. Besides, as a model-based approach, SECANT can quantify the uncertainty of the results through easily interpretable posterior probability, and our framework can be potentially 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 datasets from multiple tissues. We believe this new method will be complementary to existing tools for characterizing novel cell types and make new biological discoveries using single cell multi-omics data.

Protein-based cell population discovery and annotation for CITE-seq data identifies cellular phenotypes associated with critical COVID-19 severity

“…However, this method requires manual tuning per-marker to establish positive and negative thresholds, and is limited to closed-reference classification of predefined cell types. SECANT 11 emphasizes supervised classification using previously-generated reference sets defined from ADT data, and similarly to scGate, requires heuristics to identify de novo cell types not present in the reference. CITE-sort 12 is an unsupervised method that clusters cells by fitting parametric statistical models to a sequence of lower-dimensional projections of the ADT data.…”