Generalized Cell Type Annotation and Discovery for Single-Cell RNA-Seq Data.

The rapid development of single-cell RNA sequencing (scRNA-seq) technology allows us to study gene expression heterogeneity at the cellular level. Cell annotation is the basis for subsequent downstream analysis in single-cell data mining. Existing methods rarely explore the fine-grained semantic knowledge of novel cell types absent from the reference data and usually susceptible to batch effects on the classification of seen cell types. Taking into consideration these limitations, this paper proposes a new and practical task called generalized cell type annotation and discovery for scRNA-seq data. In this task, cells of seen cell types are given class labels, while cells of novel cell types are given cluster labels instead of a unified "unassigned" label. To address this problem, we carefully design a comprehensive evaluation benchmark and propose a novel end-to-end algorithm framework called scGAD. Specifically, scGAD first builds the intrinsic correspondence across the reference and target data by retrieving the geometrically and semantically mutual nearest neighbors as anchor pairs. Then we introduce an anchor-based self-supervised learning module with a connectivity-aware attention mechanism to facilitate model prediction capability on unlabeled target data. To enhance the inter-type separation and intra-type compactness, we further propose a confidential prototypical self-supervised learning module to uncover the consensus category structure of the reference and target data. Extensive results on massive real datasets demonstrate the superiority of scGAD over various state-of-the-art clustering and annotation methods.