Building and analyzing metacells in single-cell genomics data.

The advent of high-throughput single-cell genomics technologies has fundamentally transformed biological sciences. Currently, millions of cells from complex biological tissues can be phenotypically profiled across multiple modalities. The scaling of computational methods to analyze and visualize such data is a constant challenge, and tools need to be regularly updated, if not redesigned, to cope with ever-growing numbers of cells. Over the last few years, metacells have been introduced to reduce the size and complexity of single-cell genomics data while preserving biologically relevant information and improving interpretability. Here, we review recent studies that capitalize on the concept of metacells-and the many variants in nomenclature that have been used. We further outline how and when metacells should (or should not) be used to analyze single-cell genomics data and what should be considered when analyzing such data at the metacell level. To facilitate the exploration of metacells, we provide a comprehensive tutorial on the construction and analysis of metacells from single-cell RNA-seq data ( https://github.com/GfellerLab/MetacellAnalysisTutorial ) as well as a fully integrated pipeline to rapidly build, visualize and evaluate metacells with different methods ( https://github.com/GfellerLab/MetacellAnalysisToolkit ).

Semi-supervised integration of single-cell transcriptomics data.

Batch effects in single-cell RNA-seq data pose a significant challenge for comparative analyses across samples, individuals, and conditions. Although batch effect correction methods are routinely applied, data integration often leads to overcorrection and can result in the loss of biological variability. In this work we present STACAS, a batch correction method for scRNA-seq that leverages prior knowledge on cell types to preserve biological variability upon integration. Through an open-source benchmark, we show that semi-supervised STACAS outperforms state-of-the-art unsupervised methods, as well as supervised methods such as scANVI and scGen. STACAS scales well to large datasets and is robust to incomplete and imprecise input cell type labels, which are commonly encountered in real-life integration tasks. We argue that the incorporation of prior cell type information should be a common practice in single-cell data integration, and we provide a flexible framework for semi-supervised batch effect correction.