# Gene Ontology-Guided Hierarchical Spatial Gene Expression Prediction from Histopathology Images

arXiv: https://arxiv.org/abs/2608.00405 · HTML: https://mlsanity.com/paper/2608.00405/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 12 of its 44 references that are in the map.
- First posted on arXiv 1 Aug 2026.

## Builds on (most cited first, 12 of 12)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [An Image is Worth 16x16 Words: Transformers for Image Recognition at Scale](https://mlsanity.com/paper/2010.11929/) (2020)
- [Graph Attention Networks](https://mlsanity.com/paper/1710.10903/) (2017)
- [Densely Connected Convolutional Networks](https://mlsanity.com/paper/1608.06993/) (2016)
- [Dynamic Routing Between Capsules](https://mlsanity.com/paper/1710.09829/) (2017)
- [HEST-1k: A Dataset for Spatial Transcriptomics and Histology Image Analysis](https://mlsanity.com/paper/2406.16192/) (2024)
- [Accurate Spatial Gene Expression Prediction by integrating Multi-resolution features](https://mlsanity.com/paper/2403.07592/) (2024)
- [Exemplar Guided Deep Neural Network for Spatial Transcriptomics Analysis of Gene Expression Prediction](https://mlsanity.com/paper/2210.16721/) (2022)
- [Diffusion Generative Modeling for Spatially Resolved Gene Expression Inference from Histology Images](https://mlsanity.com/paper/2501.15598/) (2025)
- [Scalable Generation of Spatial Transcriptomics from Histology Images via Whole-Slide Flow Matching](https://mlsanity.com/paper/2506.05361/) (2025)
- [M2OST: Many-to-one Regression for Predicting Spatial Transcriptomics from Digital Pathology Images](https://mlsanity.com/paper/2409.15092/) (2024)
- [MMAP: A Multi-Magnification and Prototype-Aware Architecture for Predicting Spatial Gene Expression](https://mlsanity.com/paper/2510.11344/) (2025)

## Abstract (arXiv)

Predicting spatial gene expression from histopathology images enables large-scale transcriptomic profiling without the cost of direct measurement. Existing methods decode the target gene set as a flat, unstructured vector, ignoring the inter-gene dependencies arising from shared biological pathways and regulatory programs. Without explicit structural guidance, models must infer these dependencies entirely from limited paired data, constraining prediction quality. We propose MSGR (Multi-Scale Gene Refiner), which bridges this gap by incorporating the Gene Ontology (GO), a curated functional hierarchy of genes, as an explicit structural prior. MSGR organizes target genes into a four-level GO tree. Its GO-guided decoder then progressively refines predictions from coarse functional domains to fine individual genes via residual corrections under scale-weighted supervision. Operating solely on the gene side, the GO-guided decoder serves as a seamless plug-in replacement that consistently improves existing architectures without requiring any image-side modifications. Extensive experiments on nine datasets from the HEST-1k benchmark provide empirical evidence for two central claims: GO-structured decoding consistently outperforms flat decoding, even against a state-of-the-art generative baseline, and the gain is attributable to biological ontology structure rather than hierarchical decomposition per se, as confirmed by a +0.027 margin over a structurally equivalent random hierarchy.