Bridging the Modality Bottleneck in Pathology MIL through Virtual Molecular Staining
For computational pathology, MIST addresses the modality bottleneck in MIL by incorporating molecular information without requiring transcriptomics at inference, yielding consistent improvements across diverse endpoints.
MIST replaces the projection layer in pathology MIL with a module that uses paired spatial transcriptomics during training to create virtual molecular stains, improving performance across 23 tasks and 8 aggregators with an average gain of +3.5% (up to +5.2% on survival prediction).
Multiple instance learning (MIL) is the dominant framework for whole-slide image analysis in computational pathology, typically combining a frozen patch encoder, a projection layer, and a slide-level aggregator. While encoders and aggregators have been extensively studied, the projection layer remains a largely morphology-only bottleneck. This limits endpoints such as biomarker status and survival, which are governed by a molecular state that is not fully captured by H&E morphology. We introduce Molecularly Informed Staining Transform (MIST), a plug-in replacement for the MIL projection layer that uses paired spatial transcriptomics only during training to construct virtual molecular stains. MIST clusters gene expression profiles into cross-modal prototypes, anchors them in the frozen foundation model feature space, and uses them to reorganize H&E patch features along molecularly guided axes. It requires no transcriptomics at inference and can be inserted before standard MIL aggregators. We evaluate MIST across 23 downstream tasks and 8 MIL aggregators. MIST improves 240 of 256 configurations over the standard projection layer, with an average gain of +3.5%, observed consistently across endpoint types: +5.2% on survival prediction, +3.3% on tissue subtyping, and +2.6% on biomarker prediction. Ablations confirm that gene-derived prototypes are the primary source of the gains, while spatial, biological, and pathological analyses show that cross-modal prototype affinities capture spatially coherent molecular programs from H&E alone.