A deep learning pipeline for PAM50 subtype classification using histopathology images and multi-objective patch selection

Breast cancer is a highly heterogeneous disease with diverse molecular profiles. The PAM50 gene signature is widely recognized as a standard for classifying breast cancer into intrinsic subtypes, enabling more personalized treatment strategies. In this study, we introduce a novel optimization-driven deep learning framework that aims to reduce reliance on costly molecular assays by directly predicting PAM50 subtypes from H&E-stained whole-slide images (WSIs). Our method jointly optimizes patch informativeness, spatial diversity, uncertainty, and patch count by combining the non-dominated sorting genetic algorithm II (NSGA-II) with Monte Carlo dropout-based uncertainty estimation. The proposed method can identify a small but highly informative patch subset for classification. We used a ResNet18 backbone for feature extraction and a custom CNN head for classification. For evaluation, we used the internal TCGA-BRCA dataset as the training cohort and the external CPTAC-BRCA dataset as the test cohort. On the internal dataset, an F1-score of 0.8812 and an AUC of 0.9841 using 627 WSIs from the TCGA-BRCA cohort were achieved. The performance of the proposed approach on the external validation dataset showed an F1-score of 0.7952 and an AUC of 0.9512. These findings indicate that the proposed optimization-guided, uncertainty-aware patch selection can achieve high performance and improve the computational efficiency of histopathology-based PAM50 classification compared to existing methods, suggesting a scalable imaging-based replacement that has the potential to support clinical decision-making.

Beyond Logit Adjustment: A Residual Decomposition Framework for Long-Tailed Reranking

Long-tailed classification, where a small number of frequent classes dominate many rare ones, remains challenging because models systematically favor frequent classes at inference time. Existing post-hoc methods such as logit adjustment address this by adding a fixed classwise offset to the base-model logits. However, the correction required to restore the relative ranking of two classes need not be constant across inputs, and a fixed offset cannot adapt to such variation. We study this problem through Bayes-optimal reranking on a base-model top-k shortlist. The gap between the optimal score and the base score, the residual correction, decomposes into a classwise component that is constant within each class, and a pairwise component that depends on the input and competing labels. When the residual is purely classwise, a fixed offset suffices to recover the Bayes-optimal ordering. We further show that when the same label pair induces incompatible ordering constraints across contexts, no fixed offset can achieve this recovery. This decomposition leads to testable predictions regarding when pairwise correction can improve performance and when cannot. We develop REPAIR (Reranking via Pairwise residual correction), a lightweight post-hoc reranker that combines a shrinkage-stabilized classwise term with a linear pairwise term driven by competition features on the shortlist. Experiments on five benchmarks spanning image classification, species recognition, scene recognition, and rare disease diagnosis confirm that the decomposition explains where pairwise correction helps and where classwise correction alone suffices.

Neuropsychiatric Deviations From Normative Profiles: An MRI-Derived Marker for Early Alzheimer's Disease Detection

Neuropsychiatric symptoms (NPS) such as depression and apathy are common in Alzheimer's disease (AD) and often precede cognitive decline. NPS assessments hold promise as early detection markers due to their correlation with disease progression and their non-invasive nature. Yet current tools cannot distinguish whether NPS are part of aging or early signs of AD, limiting their utility. We present a deep learning-based normative modelling framework to identify atypical NPS burden from structural MRI. A 3D convolutional neural network was trained on cognitively stable participants from the Alzheimer's Disease Neuroimaging Initiative, learning the mapping between brain anatomy and Neuropsychiatric Inventory Questionnaire (NPIQ) scores. Deviations between predicted and observed scores defined the Divergence from NPIQ scores (DNPI). Higher DNPI was associated with future AD conversion (adjusted OR=2.5; p < 0.01) and achieved predictive accuracy comparable to cerebrospinal fluid AB42 (AUC=0.74 vs 0.75). Our approach supports scalable, non-invasive strategies for early AD detection.

Predicting Neuromodulation Outcome for Parkinson's Disease with Generative Virtual Brain Model

Parkinson's disease (PD) affects over ten million people worldwide. Although temporal interference (TI) and deep brain stimulation (DBS) are promising therapies, inter-individual variability limits empirical treatment selection, increasing non-negligible surgical risk and cost. Previous explorations either resort to limited statistical biomarkers that are insufficient to characterize variability, or employ AI-driven methods which is prone to overfitting and opacity. We bridge this gap with a pretraining-finetuning framework to predict outcomes directly from resting-state fMRI. Critically, a generative virtual brain foundation model, pretrained on a collective dataset (2707 subjects, 5621 sessions) to capture universal disorder patterns, was finetuned on PD cohorts receiving TI (n=51) or DBS (n=55) to yield individualized virtual brains with high fidelity to empirical functional connectivity (r=0.935). By constructing counterfactual estimations between pathological and healthy neural states within these personalized models, we predicted clinical responses (TI: AUPR=0.853; DBS: AUPR=0.915), substantially outperforming baselines. External and prospective validations (n=14, n=11) highlight the feasibility of clinical translation. Moreover, our framework provides state-dependent regional patterns linked to response, offering hypothesis-generating mechanistic insights.

Automating Early Disease Prediction Via Structured and Unstructured Clinical Data

This study presents a fully automated methodology for early prediction studies in clinical settings, leveraging information extracted from unstructured discharge reports. The proposed pipeline uses discharge reports to support the three main steps of early prediction: cohort selection, dataset generation, and outcome labeling. By processing discharge reports with natural language processing techniques, we can efficiently identify relevant patient cohorts, enrich structured datasets with additional clinical variables, and generate high-quality labels without manual intervention. This approach addresses the frequent issue of missing or incomplete data in codified electronic health records (EHR), capturing clinically relevant information that is often underrepresented. We evaluate the methodology in the context of predicting atrial fibrillation (AF) progression, showing that predictive models trained on datasets enriched with discharge report information achieve higher accuracy and correlation with true outcomes compared to models trained solely on structured EHR data, while also surpassing traditional clinical scores. These results demonstrate that automating the integration of unstructured clinical text can streamline early prediction studies, improve data quality, and enhance the reliability of predictive models for clinical decision-making.

Building evidence-based knowledge graphs from full-text literature for disease-specific biomedical reasoning

Biomedical knowledge resources often either preserve evidence as unstructured text or compress it into flat triples that omit study design, provenance, and quantitative support. Here we present EvidenceNet, a framework and dataset for building disease-specific knowledge graphs from full-text biomedical literature. EvidenceNet uses a large language model (LLM)-assisted pipeline to extract experimentally grounded findings as structured evidence nodes, normalize biomedical entities, score evidence quality, and connect evidence records through typed semantic relations. We release two resources: EvidenceNet-HCC with 7,872 evidence records, 10,328 graph nodes, and 49,756 edges, and EvidenceNet-CRC with 6,622 records, 8,795 nodes, and 39,361 edges. Technical validation shows high component fidelity, including 98.3% field-level extraction accuracy, 100.0% high-confidence entity-link accuracy, 87.5% fusion integrity, and 90.0% semantic relation-type accuracy. In downstream evaluation, EvidenceNet improves internal and external retrieval-augmented question answering and retains structural signal for future link prediction and target prioritization. These results establish EvidenceNet as a disease-specific resource for evidence-aware biomedical reasoning and hypothesis generation.

Learning a dynamic four-chamber shape model of the human heart for 95,695 UK Biobank participants

The human heart is a sophisticated system composed of four cardiac chambers with distinct shapes, which function in a coordinated manner. Existing shape models of the heart mainly focus on the ventricular chambers and they are derived from relatively small datasets. Here, we present a spatio-temporal (3D+t) statistical shape model of all four cardiac chambers, learnt from a large population of nearly 100,000 participants from the UK Biobank. A deep learning-based pipeline is developed to reconstruct 3D+t four-chamber meshes from the cardiac magnetic resonance images of the UK Biobank imaging population. Based on the reconstructed meshes, a 3D+t statistical shape model is learnt to characterise the shape variations and motion patterns of the four cardiac chambers. We reveal the associations of the four-chamber shape model with demographics, anthropometrics, cardiovascular risk factors, and cardiac diseases. Compared to conventional image-derived phenotypes, we validate that the four-chamber shape-derived phenotypes significantly enhance the performance in downstream tasks, including cardiovascular disease classification and heart age prediction. Furthermore, we demonstrate the effectiveness of shape-derived phenotypes in novel applications such as heart shape retrieval and heart re-identification from longitudinal data. To facilitate future research, we will release the learning-based mesh reconstruction pipeline, the four-chamber cardiac shape model, and return all derived four-chamber meshes to the UK Biobank.

Longitudinal Boundary Sharpness Coefficient Slopes Predict Time to Alzheimer's Disease Conversion in Mild Cognitive Impairment: A Survival Analysis Using the ADNI Cohort

Predicting whether someone with mild cognitive impairment (MCI) will progress to Alzheimer's disease (AD) is crucial in the early stages of neurodegeneration. This uncertainty limits enrollment in clinical trials and delays urgent treatment. The Boundary Sharpness Coefficient (BSC) measures how well-defined the gray-white matter boundary looks on structural MRI. This study measures how BSC changes over time, namely, how fast the boundary degrades each year works much better than looking at a single baseline scan for predicting MCI-to-AD conversion. This study analyzed 1,824 T1-weighted MRI scans from 450 ADNI subjects (95 converters, 355 stable; mean follow-up: 4.84 years). BSC voxel-wise maps were computed using tissue segmentation at the gray-white matter cortical ribbon. Previous studies have used CNN and RNN models that reached 96.0% accuracy for AD classification and 84.2% for MCI conversion, but those approaches disregard specific regions within the brain. This study focused specifically on the gray-white matter interface. The approach uses temporal slope features capturing boundary degradation rates, feeding them into Random Survival Forest, a non-parametric ensemble method for right-censored survival data. The Random Survival Forest trained on BSC slopes achieved a test C-index of 0.63, a 163% improvement over baseline parametric models (test C-index: 0.24). Structural MRI costs a fraction of PET imaging ($800--$1,500 vs. $5,000--$7,000) and does not require CSF collection. These temporal biomarkers could help with patient-centered safety screening as well as risk assessment.

MEDIC-AD: Towards Medical Vision-Language Model's Clinical Intelligence

Lesion detection, symptom tracking, and visual explainability are central to real-world medical image analysis, yet current medical Vision-Language Models (VLMs) still lack mechanisms that translate their broad knowledge into clinically actionable outputs. To bridge this gap, we present MEDIC-AD, a clinically oriented VLM that strengthens these three capabilities through a stage-wise framework. First, learnable anomaly-aware tokens (<Ano>) encourage the model to focus on abnormal regions and build more discriminative lesion centered representations. Second, inter image difference tokens (<Diff>) explicitly encode temporal changes between studies, allowing the model to distinguish worsening, improvement, and stability in disease burden. Finally, a dedicated explainability stage trains the model to generate heatmaps that highlight lesion-related regions, offering clear visual evidence that is consistent with the model's reasoning. Through our staged design, MEDIC-AD steadily boosts performance across anomaly detection, symptom tracking, and anomaly segmentation, achieving state-of-the-art results compared with both closed source and medical-specialized baselines. Evaluations on real longitudinal clinical data collected from real hospital workflows further show that MEDIC-AD delivers stable predictions and clinically faithful explanations in practical patient-monitoring and decision-support workflows

Autonomous Agent-Orchestrated Digital Twins (AADT): Leveraging the OpenClaw Framework for State Synchronization in Rare Genetic Disorders

Background: Medical Digital Twins (MDTs) are computational representations of individual patients that integrate clinical, genomic, and physiological data to support diagnosis, treatment planning, and outcome prediction. However, most MDTs remain static or passively updated, creating a critical synchronization gap, especially in rare genetic disorders where phenotypes, genomic interpretations, and care guidelines evolve over time. Methods: We propose an agent-orchestrated digital twin framework using OpenClaw's proactive "heartbeat" mechanism and modular Agent Skills. This Autonomous Agent-orchestrated Digital Twin (AADT) system continuously monitors local and external data streams (e.g., patient-reported phenotypes and updates in variant classification databases) and executes automated workflows for data ingestion, normalization, state updates, and trigger-based analysis. Results: A prototype implementation demonstrates that agent orchestration can continuously synchronize MDT states with both longitudinal phenotype updates and evolving genomic knowledge. In rare disease settings, this enables earlier diagnosis and more accurate modeling of disease progression. We present two case studies, including variant reinterpretation and longitudinal phenotype tracking, highlighting how AADTs support timely, auditable updates for both research and clinical care. Conclusion: The AADT framework addresses the key bottleneck of real-time synchronization in MDTs, enabling scalable and continuously updated patient models. We also discuss data security considerations and mitigation strategies through human-in-the-loop system design.