Concept-based explanation of gene expression prediction from H&E images

Recent advances in pathology foundation models have enabled accurate prediction of spatial transcriptomics (ST) from routine H&E images. However, existing explainability methods for vision transformer (ViT)-based models are largely limited to local heatmaps and do not reveal how morphological concepts contribute to ST predictions. Here, we introduce an explainable framework that combines relevance propagation and concept discovery to link transcriptional programs to tissue morphology. We developed a ViT-based framework for virtual ST from H&E images that combines ViT-aware layer-wise relevance propagation with relaxed archetypal TopK sparse autoencoder-based concept discovery. This approach provides both local explanations and global insights into the morphological patterns associated with transcriptional programs. We applied the framework to colorectal cancer ST data from the HEST-1k cohort and evaluated its generalizability in TCGA COAD. Our architecture accurately predicts clinically relevant ST signatures and accompanying molecular phenotypes. Measured and predicted gene expression profiles reveal substantial spatial heterogeneity of the colorectal cancer subtypes iCMS2 and iCMS3 across a large number of samples. Spatially resolved and aggregated iCMS classification achieve weighted F1 scores of 0.872 and 0.819 (0.770 in TCGA COAD), respectively, and both stratify patient outcome. Beyond prediction, our framework establishes a relevance-based concept atlas linking molecular phenotypes to histopathological representations. Comparison of activation- with relevance-derived concepts demonstrates that relevances provide a more direct link between tissue morphology and downstream predictions. We establish a general strategy for concept-based explanation of spatial prediction, and our framework is readily applicable to a broad range of ViT-based pathology models.

Deep learning-based computed tomography (CT) derived body composition classifier for colorectal cancer patients

Background: Accurate body composition analysis using Computed Tomography (CT) scans is essential for assessing skeletal muscle area (SMA) and skeletal muscle density (SMD), key markers of nutritional status in cancer patients. Conventional manual methods are labour-intensive and require specialist expertise, limiting their routine clinical use. Therefore, this study serves as a feasibility and pilot investigation to explore the potential of deep learning-based automated regression for body composition analysis within a clinical workflow. Methods: Four deep learning architectures (AlexNet, UNet, GoogLeNet, and ResNet34) were trained to predict SMA, SMD, subcutaneous fat area (SFA), and visceral fat area (VFA) from CT scans of colorectal cancer patients. Systematic hyperparameter optimization identified the most accurate models, which were subsequently implemented in a web application for clinical use. Results: GoogLeNet achieved the best performance, with a mean percentage error (PE) of 4.96% for SMA prediction, while AlexNet reached 8.12% for SMD. Independent testing demonstrated robust accuracy, correctly classifying body composition metrics in 80% of cases. The web application delivered rapid and consistent outputs, supporting integration into clinical workflows. Conclusion: Optimized deep learning models, particularly GoogLeNet and AlexNet, can automate CT-derived body composition analysis with a Mean Percentage Error (PE) of 4.96% for SMA and 8.12% for SMD. These tools have the potential to streamline clinical practice by reducing the time and expertise required for manual segmentation. Further validation in larger, more diverse datasets is warranted.

PolypVision: A Three-Stage Hierarchical Deep Learning Framework for Classification and Segmentation of Colorectal Polyps

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, predominantly arising from precancerous polyps. Accurate detection, segmentation, and endoscopic and histological classification of colorectal polyps are crucial for timely clinical intervention. In this study, we present PolypVision, a three-stage hierarchical deep learning framework that sequentially performs: (Stage 1) binary classification of polyps as adenomatous or hyperplastic, with simultaneous Paris and JNet classification, using EfficientNetV2-M with Focal Loss; (Stage 2) polyp segmentation with recommended resection method using a UNet++ decoder with the Stage 1 backbone as encoder, optimized with Dice and BCE losses; and (Stage 3) adenoma subtype classification (tubular, tubulovillous, villous) using EfficientNetV2-M with transfer learning from Stage 2. Evaluated on three public datasets -- PolypGen, Kvasir-SEG, and CVC-ClinicDB -- PolypVision achieves an AUC of approximately 0.99 for frame classification and a detection mAP@50 of 94.4% on Kvasir-SEG, outperforming or matching state-of-the-art methods. Gradient-weighted Class Activation Maps (Grad-CAM) confirm that the model attends to clinically relevant lesion features. The framework is device-independent, operating across diverse endoscopic imaging systems without hardware-specific adaptation. These results demonstrate that a hierarchical, transfer-learning-driven pipeline with task-specific loss functions offers a robust, device-independent, and clinically meaningful approach to automated colorectal polyp analysis. PolypVision is freely available as a web application at https://polypvision.com, a DataBioX initiative, with a free usage tier open to all users.

An Agentic Generative Large Language Model for Treatment Planning of Colorectal Cancer

Treatment planning in precision oncology requires synthesizing heterogeneous patient information with rapidly evolving clinical guidelines to ensure guideline-concordant care. While large language models (LLMs) show promise in many diagnostic tasks, their adoption for high-stakes treatment planning is hindered by complex reasoning, adherence to timely clinical guidelines, and safety concerns. In this study, we present GatorOnco, an agentic LLM for colorectal cancer (CRC) treatment planning. GatorOnco is developed using a total of 282 billion tokens of biomedical text, including healthcare system-scale clinical text comprising 166 billion tokens from UF Health. We implemented a domain-adaptation method that integrates pre-training, model merging, a two-stage post-training approach, and agent-based reinforcement learning. An agentic retrieval-augmented generation (RAG) approach dynamically integrates time-sensitive clinical guidelines into the reasoning process. In a blind, randomized clinical evaluation conducted by five UF Health oncologists, GatorOnco significantly outperformed open-source LLMs (P < 0.01) and achieved expert-level performance comparable to UF Health oncologists. Compared with expert oncologists, GatorOnco received significantly higher ratings for readability (4.46 vs. 4.19, P < 0.01) and completeness (3.91 vs. 3.52, P < 0.01), while showing statistically comparable performance in correctness (4.09 vs. 4.11, P = 0.921), currency (4.04 vs. 3.98, P = 0.478), and safety (4.22 vs. 4.22, P = 0.999). These findings demonstrate that integrating agentic reasoning with large-scale domain adaptation can help bridge the gap for generative AI in high-stakes cancer treatment planning.

CRC-HGD: A Histopathological Image Dataset for Grading Colorectal Cancer

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related deaths globally, with approximately 1,926,425 new cases and 904,019 deaths reported in 2022. Accurate histologic grading plays a critical role in prognosis and treatment planning for colorectal adenocarcinoma. In recent years, artificial intelligence and its subcategories, including machine learning and deep learning, have been increasingly employed for automated cancer detection and classification. An appropriate and well-organized dataset is the essential first step to achieve this goal. This paper introduces CRC-HGD, a histopathological microscopy image dataset of 1,914 images obtained from 214 colorectal adenocarcinoma patients (Grade I: 106, Grade II: 75, Grade III: 33). The specimens are H&E-stained colorectal tissue sections acquired at the Poursina Hakim Research Center of Isfahan University of Medical Sciences, Iran, diagnosed between 2014 and 2019, and graded according to the World Health Organization (WHO) criteria into three grades: well-differentiated (Grade I), moderately differentiated (Grade II), and poorly differentiated (Grade III). For each specimen, four magnification levels are provided: 4x, 10x, 20x, and 40x. The dataset is accessible via Mendeley Data (https://doi.org/10.17632/yfp5sfj47m.4) and at http://databiox.com, where the latest version is also available. The distinctive feature of this dataset is the provision of labeled specimens across all three differentiation grades at multiple magnification levels, enabling comprehensive computational analysis of colorectal cancer grading.

Autonomous mechanistic discovery of colorectal cancer vulnerabilities via multi-scale AI swarms

The acceleration of automated scientific discovery has been fundamentally bottlenecked by the epistemic gap between the semantic reasoning of large language models (LLMs) and the deterministic physics of mammalian biology. While recent multi-agent frameworks have achieved autonomous hypothesis generation and in vitro experimental analysis, they lack the mathematically grounded, causal constraints required for multi-scale clinical translation. Furthermore, while algorithmic clinical digital twins successfully forecast biological states, they rely on black-box latent spaces, sacrificing mechanistic interpretability for predictive accuracy. Here, we introduce the Multi-Scale Autonomous Discovery Engine (Octopus), a neuro-symbolic architecture that unites zero-leakage, local LLM swarms with strict algorithmic physics engines. Rather than stopping at isolated cellular assays, the system autonomously generated therapeutic hypotheses against in vitro CRISPR dependency data (CCLE), traced dynamic causal cascades using mechanistic interpretability (XGBoost SHAP vectors), and orthogonally translated the emergent vulnerabilities in silico to predict in vivo mammalian tumor trajectory (PDX) and human overall survival (Marisa). In a fully unsupervised sweep of colorectal cancer transcriptomes, the pipeline autonomously identified Insulin-like Growth Factor 2 (IGF2) as a strictly bounded vulnerability to 5-Fluorouracil resistance. The discovery maintained significance after rigorous Benjamini-Hochberg false discovery rate correction (q=0.0292, Log-Rank p=0.0007 ) and successfully predicted significant in vivo tumor volume shrinkage in an independent mouse cohort (Mann-Whitney p=0.0373). By bridging the chasm between multi-agent reasoning and mathematically bounded clinical survival, this framework establishes a verifiable, zero-leakage paradigm for automated, end-to-end biomedical discovery.

Performance and Interpretability of Convolutional, Transformer, and Hybrid Deep Learning Models in Colorectal Histology Classification

Deep learning has become an important tool in computational pathology, enabling automated analysis of histopathological images. While convolutional neural networks (CNNs) have traditionally dominated this field, transformer-based and hybrid architectures have recently demonstrated promising performance. However, comprehensive comparisons of these approaches for colorectal histopathology remain limited. This study evaluated twelve ImageNet-pretrained CNN, transformer, and hybrid architectures using the Kather colorectal histopathology dataset containing 5,000 image tiles from eight tissue classes. All models were trained using a standardized transfer-learning and fine-tuning protocol and assessed using multiple performance metrics, including accuracy, precision, sensitivity, specificity, F1-score, ROC-AUC, Cohen's kappa, and Matthews correlation coefficient. All evaluated models achieved high classification performance, with accuracies ranging from 93.2% to 97.1%. EVA-02 achieved the highest overall performance (97.1% accuracy, 97.0% F1-score), closely followed by ViT-B/16. Among CNNs, ResNet34 and ConvNeXt-Tiny demonstrated highly competitive performance, achieving accuracies of 96.4% and 96.3%, respectively. Transformer architectures generally produced the strongest results across evaluation metrics, although the performance gap between the best transformer and CNN models was relatively small. Per-class analysis showed consistently strong classification performance across all tissue categories, with Complex Stroma representing the most challenging class. Overall, transformer-based architectures achieved the highest predictive performance, whereas modern CNNs provided a favorable balance between accuracy and model complexity. These findings provide a comprehensive benchmark of major deep learning paradigms for colorectal histopathology classification.

Predicting High-Risk Colorectal Polyps in African Americans Using Pre-Colonoscopy Clinical Features: Machine Learning Model Development and Temporal Validation

Risk stratification for advanced colorectal polyps typically relies on colonoscopy and/or pathology findings. However, there is growing interest in whether non-invasive features available prior to colonoscopy can help identify patients at higher risk. Such approaches may enhance clinical decision-making by prioritizing surveillance for individuals most likely to harbor high-risk polyps, when colonoscopy resources are limited while potentially reducing unnecessary procedures in lower-risk patients. Importantly, the use of non-invasive, pre-procedural information may also help promote more equitable access to risk stratification, particularly in settings where colonoscopy resources are limited or unevenly distributed. We aimed to develop and externally validate machine learning models to predict high-risk colorectal polyps using only non-invasive, pre-colonoscopy demographic, clinical, and behavioral features in a diverse, predominantly African American, urban cohort. We conducted a retrospective cohort study using demographic, lifestyle, and comorbidity data from patients who underwent colonoscopy at Howard University Hospital to develop and validate several machine learning models, including neural networks, random forest, support vector machines (SVM), Naive Bayes, logistic regression, decision trees, k-nearest neighbors (KNN), and XGBoost, for predicting high-risk colorectal polyps. High-risk polyps (HRP) were defined as villous or tubullovillous adenomas, high-grade dysplasia, polyps >= 10 mm in size, and/or the presence of >= 3 polyps per procedure; all other cases were classified as low-risk polyps (LRP). The dataset included 4,681 patients from 2015-2022 used for internal validation and 1,562 patients from 2023-2024 used for external validation.

Magnitude-Based Features for Multispecies Spatial Data

Multispecies spatial data arise in many applications where interactions between different entities are central to system behaviour, including biomedical imaging, geospatial analysis, and species ecology. Despite their importance, relatively few quantitative tools exist to capture such interactions. In this work, we propose magnitude-based features for the analysis of multispecies spatial data. Magnitude is a real-valued invariant of finite metric spaces that can be interpreted as an effective number of points, incorporating both spatial configuration and scale. We develop global and local magnitude feature vectors and demonstrate their utility on synthetic tumour microenvironment data, and in tissue microarray data from human colorectal cancer samples. Locally, the method identifies distinct neighbourhood types and reveals spatial heterogeneity; in the model, this includes radial patterns associated with different qualitative outcomes of the simulations, while in the real-world data it reflects the importance of tertiary lymphoid structure-like interactions between B and T cell populations. Globally, the approach recovers known classifications of long-term simulation outcomes across parameter regimes in synthetic data, and suggests important roles for CD4+ T cells and CD163+ macrophages in distinguishing patients with favourable Crohn's like reactions from unfavourable diffuse immune infiltration. Together, these results suggest that magnitude-based features provide a powerful and flexible tool for the analysis of multispecies spatial data.