IDclust: Iterative clustering for unsupervised identification of cell types with single cell transcriptomics and epigenomics.

The increasing diversity of single-cell datasets require systematic cell type characterization. Clustering is a critical step in single-cell analysis, heavily influencing downstream analyses. However, current unsupervised clustering algorithms rely on biologically irrelevant parameters that require manual optimization and fail to capture hierarchical relationships between clusters. We developed IDclust, a framework that identifies clusters with significant biological features at multiple resolutions using biologically meaningful thresholds like fold change, adjusted P-value and fraction of expressing cells. By iteratively processing and clustering subsets of the dataset, IDclust guarantees that all clusters found have significantly different features and stops only when no more interpretable cluster is found. It also creates a hierarchy of clusters, enabling visualization of the hierarchical relationships between different clusters. Analyzing multiple single-cell transcriptomic reference datasets, IDclust achieves superior clustering accuracy compared to state of the art algorithms. We showcase its utility by identifying previously unannotated clusters and identifying branching patterns in scATAC datasets. Using it's unsupervised nature and ability to analyze different -omics, we compare the resolution of different histone marks in multi-omic paired-tag dataset. Overall, IDclust automates single-cell exploration, facilitates cell type annotation and provides a biologically interpretable basis for clustering.