Abstract
BACKGROUND: Single-cell RNA sequencing (scRNA-seq) provides a powerful tool to capture transcriptomes at single-cell resolution. However, dropout events distort the gene expression levels and underlying biological signals, misleading the downstream analysis of scRNA-seq data. RESULTS: We develop a statistical model-based multidimensional imputation algorithm, scMTD, that identifies local cell neighbors and specific gene co-expression networks based on the pseudo-time of cells, leveraging information on cell-level, gene-level, and transcriptome dynamic to recover scRNA-seq data. Compared with the state-of-the-art imputation methods through several real-data-based analytical experiments, scMTD effectively recovers biological signals of transcriptomes and consistently outperforms the other algorithms in improving FISH validation, trajectory inference, differential expression analysis, clustering analysis, and identification of cell types. CONCLUSIONS: scMTD maintains the gene expression characteristics, enhances the clustering of cell subpopulations, assists the study of gene expression dynamics, contributes to the discovery of rare cell types, and applies to both UMI-based and non-UMI-based data. Overall, scMTD's reliability, applicability, and scalability make it a promising imputation approach for scRNA-seq data.