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.
Predicting spatial gene expression from routine hematoxylin and eosin (H&E) images provides a practical complement to experimental spatial transcriptomics. Existing approaches focus on local or multi-scale visual features and often treat pretrained gene representations as fixed priors, although the interpretation of local morphology and the relevance of gene priors depend on tissue context. We propose HistoGPA, a context-conditioned gene-prior attention framework that uses a shared slide-level representation in two parallel pathways: one modulates local morphological features, whereas the other conditions pretrained gene embeddings and retrieves gene-prior information through cross-attention. This design enables each spatial location to retrieve context-adapted gene-prior information using its local morphology, position, and slide context. Across ten cancer types in HEST-1k, HistoGPA achieves the highest macro-averaged gene-wise Pearson correlation coefficient among the compared methods under the same evaluation protocol for both the top-50 and top-1,500 highly variable gene sets. Additional analyses show that HistoGPA better recovers the spatial expression patterns of cancer-associated genes and yields greater agreement between clusters derived independently from predicted and ground-truth expression profiles. Together, these findings motivate a context-dependent view of histology-to-expression prediction, in which local morphological representations and gene priors are jointly adapted to the broader tissue context.
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
Spatial transcriptomics assays remain costly and technically demanding, restricting transcriptome-wide profiling to specialist settings and preventing routine clinical deployment. Predicting spatially resolved gene expression from H&E histology could close this gap, yet current methods largely ignore the underlying tissue architecture and rarely quantify how their predictions can be trusted. We introduce HierarchicalDAEW, a dual-graph architecture that addresses both gaps. On the spot graph, a Domain-Aware Edge-Weighted convolutional operator learns separate projections for inter-domain, intra-domain, and boundary edges derived from Leiden clustering, allowing the model to treat tissue heterogeneity as an explicit structural signal rather than an implicit one. A second gene-level graph then fuses protein-protein interaction priors from STRING-DB with tissue-specific co-expression through learned attention gating, propagating predictions from a landmark gene set to a broader gene panel. Reliability is handled through evidential uncertainty estimation, which produces far better calibrated confidence intervals than Monte Carlo dropout under identical conditions. Across six human Visium sections spanning breast, colorectal, prostate, and cerebellar tissue, and against thirteen published baselines, HierarchicalDAEW achieves the strongest correlation with ground-truth expression, with gains that hold up under multi-seed reproducibility checks and negative controls that rule out positional shortcuts. Ablations further confirm that both the domain-aware edge typing and the hierarchical depth are necessary to this improvement, and calibrated uncertainty estimates identify low-confidence predictions for pathologist review before clinical action.
Kritanu Chattopadhyay, Soumya Chatterjee, Ondrej Krejcar +1