Spatial transcriptomics (ST) enables spatially resolved gene profiling but remains expensive and low-throughput, limiting large-cohort studies and routine clinical use. Predicting spatial gene expression from routine hematoxylin and eosin (H&E) slides is a promising alternative, yet under realistic leave-one-slide-out evaluation, existing models often suffer from slide-level appearance shifts and regression-driven over-smoothing that suppress biologically meaningful variation. CHRep is a two-phase framework for robust histology-to-expression prediction. In the training phase, CHRep learns a structure-aware representation by jointly optimizing correlation-aware regression, symmetric image-expression alignment, and coordinate-induced spatial topology regularization. In the inference phase, cross-slide robustness is improved without backbone fine-tuning through a lightweight calibration module trained on the training slides, which combines a non-parametric estimate from a training gallery with a magnitude-regularized correction module. Unlike prior embedding-alignment or retrieval-based transfer methods that rely on a single prediction route, CHRep couples topology-preserving representation learning with post-hoc calibration, enabling stable neighborhood retrieval and controlled bias correction under slide-level shifts. Across the three cohorts, CHRep consistently improves gene-wise correlation under leave-one-slide-out evaluation, with the largest gains observed on Alex+10x. Relative to HAGE, the Pearson correlation coefficient on all considered genes [PCC(ACG)] increases by 4.0% on cSCC and 9.8% on HER2+. Relative to mclSTExp, PCC(ACG) further improves by 39.5% on Alex+10x, together with 9.7% and 9.0% reductions in mean squared error (MSE) and mean absolute error (MAE), respectively.
Spatial transcriptomics (ST) links gene expression with tissue morphology but remains expensive and low-throughput, motivating surrogates that infer expression from routine histology. Whole-slide H&E-to-ST inference pairs a gigapixel image with gene measurements at a sparse, irregular set of locations, making multiscale modeling challenging without incurring dense-grid overhead or quadratic token mixing. We propose HiST, a hierarchical sparse transformer that treats measured locations as a lattice-indexed sparse field and builds a dyadic encoder--decoder directly on the active tissue footprint. HiST combines sparse window attention for local geometric correspondence with resolution-changing operators for rapid multiscale context integration. For a fixed window size, the dominant runtime and memory scale with the number of observed locations rather than the dense slide area. To mitigate slide-specific acquisition variation, HiST adds a bottlenecked global conditioning pathway via a \emph{slide calibration token} that summarizes slide-level context and conditions local representations. On a multi-organ benchmark spanning diverse tissues and acquisition sources, HiST improves predictive performance over recent baselines while reducing runtime and peak memory.
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
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.