MIST: Multi-Scale Spatial Context for Gene Expression Prediction from Histology

Koushik Howlader, Tirtho Roy, Md Tauhidul Islam, Wei Le

Predicting spatial gene expression from standard H&E images could extend molecular analysis to tissues without spatial transcriptomic measurements. A standard Transformer applies self-attention over spots but ignores where each spot sits in the tissue, whereas a spot's molecular state depends on tissue context at multiple spatial scales. Building on this insight, we introduce MIST, a Multi-context Spatial Transformer that augments the self-attention backbone with two context pathways applied in every layer: a coordinate-invariant local pathway that attends over spatial k-nearest-neighbor spots, and a slide pathway that broadcasts a whole-slide summary to every spot; the model predicts all spots in a single forward pass. Because coordinates enter only through pairwise distances, the local pathway is invariant to translations, rotations, and reflections when image features are fixed. In intra-cohort evaluation across six human organ cohorts from HEST-1k, MIST improves mean Pearson correlation over the strongest evaluated baseline by 9.7%, 11.6%, and 11.4% for 10-, 50-, and 100-gene panels, respectively, with the lowest average MSE and MAE. MIST further improves leave-one-organ-out…