# FLAG: Foundation model representation with Latent diffusion Alignment via Graph for spatial gene expression prediction

arXiv: https://arxiv.org/abs/2605.18055 · HTML: https://mlsanity.com/paper/2605.18055/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Medical imaging and segmentation, one of 14 directions in Diffusion models.
- Builds on 20 of its 51 references that are in the map.
- First posted on arXiv 18 May 2026.

## Placed in

- Diffusion models / [Medical imaging and segmentation](https://mlsanity.com/diffusion/medical-imaging-and-segmentation/)

## Builds on (most cited first, 20 of 20)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [High-Resolution Image Synthesis with Latent Diffusion Models](https://mlsanity.com/paper/2112.10752/) (2021)
- [Score-Based Generative Modeling through Stochastic Differential Equations](https://mlsanity.com/paper/2011.13456/) (2020)
- [DINOv2: Learning Robust Visual Features without Supervision](https://mlsanity.com/paper/2304.07193/) (2023)
- [Elucidating the Design Space of Diffusion-Based Generative Models](https://mlsanity.com/paper/2206.00364/) (2022)
- [Representation Alignment for Generation: Training Diffusion Transformers Is Easier Than You Think](https://mlsanity.com/paper/2410.06940/) (2024)
- [DiGress: Discrete Denoising diffusion for graph generation](https://mlsanity.com/paper/2209.14734/) (2022)
- [Score-based Generative Modeling of Graphs via the System of Stochastic Differential Equations](https://mlsanity.com/paper/2202.02514/) (2022)
- [Visual Language Pretrained Multiple Instance Zero-Shot Transfer for Histopathology Images](https://mlsanity.com/paper/2306.07831/) (2023)
- [HEST-1k: A Dataset for Spatial Transcriptomics and Histology Image Analysis](https://mlsanity.com/paper/2406.16192/) (2024)
- [Latent Diffusion Model without Variational Autoencoder](https://mlsanity.com/paper/2510.15301/) (2025)
- [Spatially Resolved Gene Expression Prediction from H&E Histology Images via Bi-modal Contrastive Learning](https://mlsanity.com/paper/2306.01859/) (2023)
- [Accurate Spatial Gene Expression Prediction by integrating Multi-resolution features](https://mlsanity.com/paper/2403.07592/) (2024)
- [Graph Diffusion Transformers for Multi-Conditional Molecular Generation](https://mlsanity.com/paper/2401.13858/) (2024)
- [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)
- [MERGE: Multi-faceted Hierarchical Graph-based GNN for Gene Expression Prediction from Whole Slide Histopathology Images](https://mlsanity.com/paper/2412.02601/) (2024)
- [SEPAL: Spatial Gene Expression Prediction from Local Graphs](https://mlsanity.com/paper/2309.01036/) (2023)
- [SpaDiT: Diffusion Transformer for Spatial Gene Expression Prediction using scRNA-seq](https://mlsanity.com/paper/2407.13182/) (2024)
- [Img2ST-Net: Efficient High-Resolution Spatial Omics Prediction from Whole Slide Histology Images via Fully Convolutional Image-to-Image Learning](https://mlsanity.com/paper/2508.14393/) (2025)

## Abstract (arXiv)

Predicting spatial gene expression from routine H&E enables large-scale molecular profiling, yet current models treat this as isolated pointwise tasks, thereby overlooking essential biological structures like gene coordination and spatial distribution. To preserve these relationships, we introduce FLAG, a diffusion-based framework that redefines this task as structured distribution modeling. At the same time, we identify the critical Gene Dimension Curse, where joint modeling gene expression and their spatial interactions fail in high-dimensional spaces, and FLAG solves this challenge by integrating a spatial graph encoder for topological consistency and utilizing Gene Foundation Model (GFM) alignment for gene-gene fidelity in the generation process. To rigorously assess model performance, we propose a set of novel structural evaluation metrics, including Gene Structural Correlation (GSC) and Spatial Structural Correlation (SSC). Our experiments demonstrate that FLAG is highly competitive in traditional accuracy (PCC/MSE) while achieving significantly enhanced structural fidelity in capturing both gene-gene and gene-spatial relationships. The code is available at https://github.com/darkflash03/FLAG.