Preserving DEG Rankings for Gene Discovery in Histology-Based Spatial Gene Expression Prediction

Spatial transcriptomics enables profiling of spatial gene expression but is limited by high cost and low throughput, motivating prediction from H&E histopathology images. Existing context-aware methods mainly supervise absolute expression, while relative expression relationships between spots are rarely used explicitly. We propose COAST, a context-aware differential learning framework for spatial gene expression prediction. COAST conditions the local and global context features with type-specific modulation and aggregates the target and context spot tokens using a Transformer encoder to capture both fine-grained local patterns and slide-level structure. It is trained with a joint objective that combines absolute expression regression with signed differential regression between the target and context spots. Experiments on multiple spatial transcriptomics datasets show consistent improvements in correlation- and distribution-based metrics, demonstrating the effectiveness of context-aware differential learning for histology-based spatial gene expression prediction.

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.

Spatial Transcriptomics (ST) has transformed biomedical research by enabling the spatial mapping of gene expression across tissue sections. However, high operational costs, specialized equipment requirements, and sensitivity to experimental noise limit the accessibility and scalability of ST. Recent computer vision approaches aim to overcome these limitations by predicting spatial gene expression directly from histopathology images. While effective, current approaches often suffer from gene expression over-smoothing and overly uniform predictions across tissue regions, suggesting that further progress depends on learning representations that reflect the hierarchical and asymmetric structure of gene regulation and tissue morphology. To address these issues, we propose Hyperbolic Contrastive Learning with Entailment for Spatial Transcriptomics (HyCLoST), a hyperbolic contrastive learning model that captures the intrinsic hierarchical relationships within ST data. By leveraging hyperbolic geometry and a gene-to-image entailment loss, HyCLoST learns structured, biologically grounded representations that improve gene expression prediction accuracy, achieving a 6% reduction in MSE and an 8% increase in PCC across 26 ST datasets, over previous methods. Our source code is publicly available at https://github.com/BCV-Uniandes/HyCLoST