# MoSPR: Histology-to-Gene Expression Prediction with Morpho-Spatial Macrostates and Low-Rank Molecular Programs

arXiv: https://arxiv.org/abs/2609.34280 · HTML: https://mlsanity.com/paper/2609.34280/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 10 of its 26 references that are in the map.
- First posted on arXiv 28 Sep 2026.

## Builds on (most cited first, 10 of 10)

- [Attention-based Deep Multiple Instance Learning](https://mlsanity.com/paper/1802.04712/) (2018)
- [TransMIL: Transformer based Correlated Multiple Instance Learning for Whole Slide Image Classification](https://mlsanity.com/paper/2106.00908/) (2021)
- [Whole Slide Images are 2D Point Clouds: Context-Aware Survival Prediction using Patch-based Graph Convolutional Networks](https://mlsanity.com/paper/2107.13048/) (2021)
- [Revisiting Multiple Instance Neural Networks](https://mlsanity.com/paper/1610.02501/) (2016)
- [MambaMIL: Enhancing Long Sequence Modeling with Sequence Reordering in Computational Pathology](https://mlsanity.com/paper/2403.06800/) (2024)
- [Structured State Space Models for Multiple Instance Learning in Digital Pathology](https://mlsanity.com/paper/2306.15789/) (2023)
- [2DMamba: Efficient State Space Model for Image Representation with Applications on Giga-Pixel Whole Slide Image Classification](https://mlsanity.com/paper/2412.00678/) (2024)
- [Learning to Predict RNA Sequence Expressions from Whole Slide Images with Applications for Search and Classification](https://mlsanity.com/paper/2203.13997/) (2022)
- [Attention-based Interpretable Regression of Gene Expression in Histology](https://mlsanity.com/paper/2208.13776/) (2022)
- [Cell-Type Prototype-Informed Neural Network for Gene Expression Estimation from Pathology Images](https://mlsanity.com/paper/2603.18461/) (2026)

## Abstract (arXiv)

Predicting molecular profiles from histopathology remains challenging because whole-slide images contain spatially organized, heterogeneous tissue patterns, while gene expression comprises thousands of correlated targets. We introduce MoSPR (Morpho-Spatial Program Regression), a linear framework that couples an adjacency-informed histology representation with a low-rank molecular basis. MoSPR clusters frozen patch embeddings into morphology microstates, aggregates their spatial adjacencies across the training cohort, and groups microstates with similar adjacency patterns into shared macrostates. Each slide is then represented by global morphology and macrostate-specific deviations, which are linearly mapped to coefficients of a training-derived low-rank gene-expression basis. Across three cancer cohorts from The Cancer Genome Atlas, MoSPR achieves the highest mean gene-expression prediction scores among all evaluated methods. Without pathway-level supervision, pathway scores derived from its predicted expression profiles rank first in eight of nine comparisons across three pathway collections. Ablation studies on the breast cancer cohort show complementary gains from adjacency-derived macrostate representation and low-rank molecular prediction. Moreover, with half of the training data on this cohort, MoSPR exceeds the full-data gene-prediction score of the strongest competing baseline. Finally, its linear formulation enables exact decomposition of each predicted expression profile into global and macrostate-specific molecular contributions, providing an interpretable link between spatially coherent macrostate regions and their associated molecular programs. Our code is available at https://github.com/Radisen-Panthera/MoSPR.