Deep identifiable modeling of single-cell atlases enables zero-shot query of cellular states

How to identify true biological differences across samples while overcoming batch effects has been a persistent challenge in single-cell RNA-seq data analysis, hindering analyses across datasets for transferable biological findings. In this work, we show that scaling up deep identifiable models leads to a surprisingly effective solution for this challenging task. We developed scShift, a deep variational inference framework with theoretical support in disentangling batch-dependent and independent variations. By training the model with compendiums of scRNA-seq atlases, scShift shows remarkable zero-shot capabilities in revealing representations of cell types and biological states in single-cell data while overcoming batch effects. We employed scShift to systematically compare lung fibrosis states across different datasets, tissues and experimental systems. scShift uniquely extrapolates lung fibrosis states to previously unseen post-COVID-19 fibrosis, characterizing universal myeloid-fibrosis signatures, potential repurposing drug targets and fibrosis-associated cell interactions. Evaluations of over 200 trained scShift models demonstrate emergent zero-shot capabilities and a scaling law beyond a transition threshold, with respect to dataset diversity. With its scaling performance on massive single-cell compendiums and exceptional zero-shot capabilities, scShift represents an important advance toward next-generation computational models for single-cell analysis.