# Concept-based explanation of gene expression prediction from H&E images

arXiv: https://arxiv.org/abs/2608.16669 · HTML: https://mlsanity.com/paper/2608.16669/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 15 of its 47 references that are in the map.
- First posted on arXiv 17 Aug 2026.

## Builds on (most cited first, 15 of 15)

- [An Image is Worth 16x16 Words: Transformers for Image Recognition at Scale](https://mlsanity.com/paper/2010.11929/) (2020)
- [Attention-based Deep Multiple Instance Learning](https://mlsanity.com/paper/1802.04712/) (2018)
- [Toy Models of Superposition](https://mlsanity.com/paper/2209.10652/) (2022)
- [The Geometry of Categorical and Hierarchical Concepts in Large Language Models](https://mlsanity.com/paper/2406.01506/) (2024)
- [HEST-1k: A Dataset for Spatial Transcriptomics and Histology Image Analysis](https://mlsanity.com/paper/2406.16192/) (2024)
- [Spatially Resolved Gene Expression Prediction from H&E Histology Images via Bi-modal Contrastive Learning](https://mlsanity.com/paper/2306.01859/) (2023)
- [Archetypal SAE: Adaptive and Stable Dictionary Learning for Concept Extraction in Large Vision Models](https://mlsanity.com/paper/2502.12892/) (2025)
- [Software for Dataset-wide XAI: From Local Explanations to Global Insights with Zennit, CoRelAy, and ViRelAy](https://mlsanity.com/paper/2106.13200/) (2021)
- [Selective Inference for Hierarchical Clustering](https://mlsanity.com/paper/2012.02936/) (2020)
- [Into the Rabbit Hull: From Task-Relevant Concepts in DINO to Minkowski Geometry](https://mlsanity.com/paper/2510.08638/) (2025)
- [Toward Explainable AI for Regression Models](https://mlsanity.com/paper/2112.11407/) (2021)
- [Understanding the (Extra-)Ordinary: Validating Deep Model Decisions with Prototypical Concept-based Explanations](https://mlsanity.com/paper/2311.16681/) (2023)
- [The Manifold Hypothesis for Gradient-Based Explanations](https://mlsanity.com/paper/2206.07387/) (2022)
- [xMIL: Insightful Explanations for Multiple Instance Learning in Histopathology](https://mlsanity.com/paper/2406.04280/) (2024)
- [Measuring the (Un)Faithfulness of Concept-Based Explanations](https://mlsanity.com/paper/2504.10833/) (2025)

## Abstract (arXiv)

Recent advances in pathology foundation models have enabled accurate prediction of spatial transcriptomics (ST) from routine H&E images. However, existing explainability methods for vision transformer (ViT)-based models are largely limited to local heatmaps and do not reveal how morphological concepts contribute to ST predictions. Here, we introduce an explainable framework that combines relevance propagation and concept discovery to link transcriptional programs to tissue morphology. We developed a ViT-based framework for virtual ST from H&E images that combines ViT-aware layer-wise relevance propagation with relaxed archetypal TopK sparse autoencoder-based concept discovery. This approach provides both local explanations and global insights into the morphological patterns associated with transcriptional programs. We applied the framework to colorectal cancer ST data from the HEST-1k cohort and evaluated its generalizability in TCGA COAD. Our architecture accurately predicts clinically relevant ST signatures and accompanying molecular phenotypes. Measured and predicted gene expression profiles reveal substantial spatial heterogeneity of the colorectal cancer subtypes iCMS2 and iCMS3 across a large number of samples. Spatially resolved and aggregated iCMS classification achieve weighted F1 scores of 0.872 and 0.819 (0.770 in TCGA COAD), respectively, and both stratify patient outcome. Beyond prediction, our framework establishes a relevance-based concept atlas linking molecular phenotypes to histopathological representations. Comparison of activation- with relevance-derived concepts demonstrates that relevances provide a more direct link between tissue morphology and downstream predictions. We establish a general strategy for concept-based explanation of spatial prediction, and our framework is readily applicable to a broad range of ViT-based pathology models.