Tissueformer: extending single-cell foundation models to predict population-level phenotypes

BACKGROUND: Single-cell RNA sequencing technologies have enabled unprecedented insights into gene expression and opened new pathways for diagnostics and tissue annotation. At present, most computational approaches for interpreting single-cell data predict labels or properties based on isolated single-cell transcriptomic profiles. This approach overlooks the cellular composition within a sample, which is often critical for inferring tissue identity or other sample-level phenotypes. RESULTS: To address this limitation, we introduce TissueFormer, a Transformer-based neural network that infers population-level labels from groups of single-cell RNA profiles while retaining single-cell resolution. We applied TissueFormer to two tasks: predicting COVID-19 severity from single-cell RNA sequencing of blood samples, and predicting cortical area identity from spatial transcriptomic data in mouse brains. TissueFormer outperformed single-cell foundation models and machine learning methods applied to pseudobulk and cell type composition. CONCLUSIONS: TissueFormer's higher performance promises more accurate diagnostics and enables the automated construction of high-resolution brain region maps in individual mice directly from spatial transcriptomic data. Applied to mice with developmental perturbations to visual input, these maps revealed a significant reduction in predicted visual cortex area, illustrating how individual differences in neuroanatomy can be quantified. More broadly, TissueFormer provides a framework for predicting any population-level phenotypes which are influenced by cellular diversity and tissue-level organization.