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Recent advancements in both single-cell RNA-sequencing technology and computational resources facilitate the study of cell types on global populations. Up to millions of cells can now be sequenced in one experiment; thus, accurate and efficient computational methods are needed to provide clustering and post-analysis of assigning putative and rare cell types. Here, we present a novel unsupervised deep learning clustering framework that is robust and highly scalable. To overcome the high level of noise, scAIDE first incorporates an autoencoder-imputation network with a distance-preserved embedding network (AIDE) to learn a good representation of data, and then applies a random projection hashing based  k -means algorithm to accommodate the detection of rare cell types. We analyzed a 1.3 million neural cell dataset within 30 min, obtaining 64 clusters which were mapped to 19 putative cell types. In particular, we further identified three different neural stem cell developmental trajectories in these clusters. We also classified two subpopulations of malignant cells in a small glioblastoma dataset using scAIDE. We anticipate that scAIDE would provide a more in-depth understanding of cell development and diseases.

scAIDE: clustering of large-scale single-cell RNA-seq data reveals putative and rare cell types