SAFAARI: Contrastive Adversarial Open-set Domain Adaptation for Single-cell Integration & Annotation

Abstract Single-cell sequencing technologies have enabled in-depth analysis of cellular heterogeneity across tissues and disease contexts. However, as datasets increase in size and complexity, characterizing diverse cellular populations, integrating data across multiple modalities, and correcting batch effects remain challenges. We present SAFAARI (Single-cell Annotation and Fusion with Adversarial Open-set Domain Adaptation Reliable for Data Integration), a unified deep learning framework designed for cell annotation, batch correction, and multi-omics integration. SAFAARI leverages supervised contrastive learning and adversarial domain adaptation to achieve domain-invariant embeddings and enables label transfer across datasets, addressing challenges posed by batch effects, biological domain shifts, and multi-omics modalities. SAFAARI identifies novel cell types and mitigates class imbalance to enhance the detection of rare cell types. Through comprehensive benchmarking, we evaluated SAFAARI against existing annotation and integration methods across real-world datasets exhibiting batch effects and domain shifts, as well as simulated and multi-omics data. SAFAARI demonstrated scalability and robust performance in cell annotation via label transfer across heterogeneous datasets, detection of unknown cell types, correction of batch effects, and cross-omics data integration while leveraging available annotations for improved integration. SAFAARI’s innovative approach outperformed competing methods in both qualitative and quantitative metrics, offering a flexible, accurate, and scalable solution for single-cell analysis with broad applicability to diverse biological and clinical research questions. An open-source implementation of the SAFAARI algorithm is available at https://github.com/VafaeeLab/SAFAARI.