A copula based topology preserving graph convolution network for clustering of single-cell RNA-seq data

Annotation of cells in single-cell clustering requires a homogeneous grouping of cell populations. There are various issues in single cell sequencing that effect homogeneous grouping (clustering) of cells, such as small amount of starting RNA, limited per-cell sequenced reads, cell-to-cell variability due to cell-cycle, cellular morphology, and variable reagent concentrations. Moreover, single cell data is susceptible to technical noise, which affects the quality of genes (or features) selected/extracted prior to clustering.Here we introduce sc-CGconv (copula based graph convolution network for single clustering), a stepwise robust unsupervised feature extraction and clustering approach that formulates and aggregates cell–cell relationships using copula correlation (Ccor), followed by a graph convolution network based clustering approach. sc-CGconv formulates a cell-cell graph using Ccor that is learned by a graph-based artificial intelligence model, graph convolution network. The learned representation (low dimensional embedding) is utilized for cell clustering. sc-CGconv features the following advantages. a. sc-CGconv works with substantially smaller sample sizes to identify homogeneous clusters. b. sc-CGconv can model the expression co-variability of a large number of genes, thereby outperforming state-of-the-art gene selection/extraction methods for clustering. c. sc-CGconv preserves the cell-to-cell variability within the selected gene set by constructing a cell-cell graph through copula correlation measure. d. sc-CGconv provides a topology-preserving embedding of cells in low dimensional space.Author summary: One of the important aspects of single cell downstream analysis is to classify cells into subpopulations. This immediately leads to clustering of cells into homogeneous groups, which faces lots of issues due to (i) small amount of starting RNA, (ii) cell-to-cell variability, (iii) technical noise incorporated within the single cell sequencing technology, and (iv) unavailability of discriminating selected/extracted genes (features) in the preprocessing step of downstream analysis. We proposed sc-CGconv, stepwise feature extraction and clustering framework, which leverage landmark advantage of copula and graph convolution network in single-cell analysis domain. sc-CGconv outperforms the state-of-the-art feature selection/extraction methods in the preprocessing steps, performs well with small sample size data, can preserve the cell-to-cell variability within the extracted features, provides a topology-preserving embedding of cells in low dimensional space. sc-CGconv therefore successfully addresses the above-mentioned key challenges.