HyGAnno: Hybrid graph neural network-based cell type annotation for single-cell ATAC sequencing data

Reliable cell type annotations are crucial for investigating cellular heterogeneity in single-cell omics data. Although various computational approaches have been proposed for single-cell RNA sequencing (scRNA-seq) annotation, high-quality cell labels are still lacking in single-cell ATAC sequencing (scATAC-seq) data, because of extreme sparsity and inconsistent chromatin accessibility between datasets. This calls for novel cell type annotation methods in scATAC-seq, to better explore cell type-specific gene regulatory mechanisms and provide a complementary epigenomic layer to scRNA-seq data. Here, we present a novel automated cell annotation method that transfers cell type information from a well-labeled scRNA-seq reference to an unlabeled scATAC-seq target, via a parallel graph neural network, in a semi-supervised manner. Unlike existing methods that utilize only gene expression or gene activity features, HyGAnno integrates genomewide accessibility peak features to facilitate the training process. In addition, HyGAnno reconstructs a reference-target cell graph that can be used to detect cells with low prediction reliability, according to their specific graph connectivity patterns. HyGAnno was tested using large datasets and demonstrated the advantages of accurate cell annotation, interpretable cell embedding, robustness to noisy reference data, and adaptability to tumor tissues.