Training Flexible Models of Genetic Variant Effects from Functional Annotations using Accelerated Linear Algebra

To understand how genetic variants in human genomes manifest in phenotypes -- traits like height or diseases like asthma -- geneticists have sequenced and measured hundreds of thousands of individuals. Geneticists use this data to build models that predict how a genetic variant impacts phenotype given genomic features of the variant, like DNA accessibility or the presence of nearby DNA-bound proteins. As more data and features become available, one might expect predictive models to improve. Unfortunately, training these models is bottlenecked by the need to solve expensive linear algebra problems because variants in the genome are correlated with nearby variants, requiring inversion of large matrices. Previous methods have therefore been restricted to fitting small models, and fitting simplified summary statistics, rather than the full likelihood of the statistical model. In this paper, we leverage modern fast linear algebra techniques to develop DeepWAS (Deep genome Wide Association Studies), a method to train large and flexible neural network predictive models to optimize likelihood. Notably, we find that larger models only improve performance when using our full likelihood approach; when trained by fitting traditional summary statistics, larger models perform no better than small ones. We find larger models trained on more features make better predictions, potentially improving disease predictions and therapeutic target identification.

Evaluating Rare Disease Diagnostic Performance in Symptom Checkers: A Synthetic Vignette Simulation Approach

Background: Symptom Checkers (SCs) provide users with personalized medical information. To prevent performance degradation from algorithm updates, SC developers must evaluate diagnostic performance changes for individual diseases before deployment. However, acquiring sufficient evaluation data for rare diseases is difficult, and manually creating numerous clinical vignettes is costly and impractical. Objective: This study proposes and validates a novel Synthetic Vignette Simulation Approach to evaluate diagnostic performance changes for individual rare diseases following SC algorithm updates. Methods: We used disease-phenotype annotations from the Human Phenotype Ontology (HPO), a knowledge database for rare diseases, to generate synthetic vignettes. With these, we simulated SC interviews to estimate the impact of algorithm updates on real-world diagnostic performance. The method's effectiveness was evaluated retrospectively by comparing estimated values with actual metric changes using the R 2(R-squared) coefficient. Results: The experiment included eight past SC algorithm updates. For updates on diseases with frequency information in HPO (n=5), the R^2 for recall@8 change was 0.831 (p=0.031), and for precision@8 change, it was 0.78 (p=0.047), indicating the method can predict post-deployment performance. In contrast, large prediction errors occurred for diseases without frequency information (n=3), highlighting its importance. The manual effort to map HPO phenotypes to SC symptoms was approximately 2 hours per disease. Conclusions: Our method enables pre-deployment evaluation of SC algorithm changes for individual rare diseases using a publicly available, expert-created knowledge base. This transparent and low-cost approach allows developers to efficiently improve diagnostic performance for rare diseases, potentially enhancing support for early diagnosis.

MOSCARD -- Causal Reasoning and De-confounding for Multimodal Opportunistic Screening of Cardiovascular Adverse Events

Major Adverse Cardiovascular Events (MACE) remain the leading cause of mortality globally, as reported in the Global Disease Burden Study 2021. Opportunistic screening leverages data collected from routine health check-ups and multimodal data can play a key role to identify at-risk individuals. Chest X-rays (CXR) provide insights into chronic conditions contributing to major adverse cardiovascular events (MACE), while 12-lead electrocardiogram (ECG) directly assesses cardiac electrical activity and structural abnormalities. Integrating CXR and ECG could offer a more comprehensive risk assessment than conventional models, which rely on clinical scores, computed tomography (CT) measurements, or biomarkers, which may be limited by sampling bias and single modality constraints. We propose a novel predictive modeling framework - MOSCARD, multimodal causal reasoning with co-attention to align two distinct modalities and simultaneously mitigate bias and confounders in opportunistic risk estimation. Primary technical contributions are - (i) multimodal alignment of CXR with ECG guidance; (ii) integration of causal reasoning; (iii) dual back-propagation graph for de-confounding. Evaluated on internal, shift data from emergency department (ED) and external MIMIC datasets, our model outperformed single modality and state-of-the-art foundational models - AUC: 0.75, 0.83, 0.71 respectively. Proposed cost-effective opportunistic screening enables early intervention, improving patient outcomes and reducing disparities.

CKD-EHR:Clinical Knowledge Distillation for Electronic Health Records

Electronic Health Records (EHR)-based disease prediction models have demonstrated significant clinical value in promoting precision medicine and enabling early intervention. However, existing large language models face two major challenges: insufficient representation of medical knowledge and low efficiency in clinical deployment. To address these challenges, this study proposes the CKD-EHR (Clinical Knowledge Distillation for EHR) framework, which achieves efficient and accurate disease risk prediction through knowledge distillation techniques. Specifically, the large language model Qwen2.5-7B is first fine-tuned on medical knowledge-enhanced data to serve as the teacher model.It then generates interpretable soft labels through a multi-granularity attention distillation mechanism. Finally, the distilled knowledge is transferred to a lightweight BERT student model. Experimental results show that on the MIMIC-III dataset, CKD-EHR significantly outperforms the baseline model:diagnostic accuracy is increased by 9%, F1-score is improved by 27%, and a 22.2 times inference speedup is achieved. This innovative solution not only greatly improves resource utilization efficiency but also significantly enhances the accuracy and timeliness of diagnosis, providing a practical technical approach for resource optimization in clinical settings. The code and data for this research are available athttps://github.com/209506702/CKD_EHR.

Risk Estimation of Knee Osteoarthritis Progression via Predictive Multi-task Modelling from Efficient Diffusion Model using X-ray Images

Medical imaging plays a crucial role in assessing knee osteoarthritis (OA) risk by enabling early detection and disease monitoring. Recent machine learning methods have improved risk estimation (i.e., predicting the likelihood of disease progression) and predictive modelling (i.e., the forecasting of future outcomes based on current data) using medical images, but clinical adoption remains limited due to their lack of interpretability. Existing approaches that generate future images for risk estimation are complex and impractical. Additionally, previous methods fail to localize anatomical knee landmarks, limiting interpretability. We address these gaps with a new interpretable machine learning method to estimate the risk of knee OA progression via multi-task predictive modelling that classifies future knee OA severity and predicts anatomical knee landmarks from efficiently generated high-quality future images. Such image generation is achieved by leveraging a diffusion model in a class-conditioned latent space to forecast disease progression, offering a visual representation of how particular health conditions may evolve. Applied to the Osteoarthritis Initiative dataset, our approach improves the state-of-the-art (SOTA) by 2\%, achieving an AUC of 0.71 in predicting knee OA progression while offering ~9% faster inference time.

Early Prediction of Multiple Sclerosis Disability Progression via Multimodal Foundation Model Benchmarks

Early multiple sclerosis (MS) disability progression prediction is challenging due to disease heterogeneity. This work predicts 48- and 72-week disability using sparse baseline clinical data and 12 weeks of daily digital Floodlight data from the CONSONANCE clinical trial. We employed state-of-the-art tabular and time-series foundation models (FMs), a custom multimodal attention-based transformer, and machine learning methods. Despite the difficulty of early prediction (AUROC 0.63), integrating digital data via advanced models improved performance over clinical data alone. A transformer model using unimodal embeddings from the Moment FM yielded the best result, but our multimodal transformer consistently outperformed its unimodal counterpart, confirming the advantages of combining clinical with digital data. Our findings demonstrate the promise of FMs and multimodal approaches to extract predictive signals from complex and diverse clinical and digital life sciences data (e.g., imaging, omics), enabling more accurate prognostics for MS and potentially other complex diseases.

A Structured Bangla Dataset of Disease-Symptom Associations to Improve Diagnostic Accuracy

Disease-symptom datasets are significant and in demand for medical research, disease diagnosis, clinical decision-making, and AI-driven health management applications. These datasets help identify symptom patterns associated with specific diseases, thus improving diagnostic accuracy and enabling early detection. The dataset presented in this study systematically compiles disease-symptom relationships from various online sources, medical literature, and publicly available health databases. The data was gathered through analyzing peer-reviewed medical articles, clinical case studies, and disease-symptom association reports. Only the verified medical sources were included in the dataset, while those from non-peer-reviewed and anecdotal sources were excluded. The dataset is structured in a tabular format, where the first column represents diseases, and the remaining columns represent symptoms. Each symptom cell contains a binary value (1 or 0), indicating whether a symptom is associated with a disease (1 for presence, 0 for absence). Thereby, this structured representation makes the dataset very useful for a wide range of applications, including machine learning-based disease prediction, clinical decision support systems, and epidemiological studies. Although there are some advancements in the field of disease-symptom datasets, there is a significant gap in structured datasets for the Bangla language. This dataset aims to bridge that gap by facilitating the development of multilingual medical informatics tools and improving disease prediction models for underrepresented linguistic communities. Further developments should include region-specific diseases and further fine-tuning of symptom associations for better diagnostic performance

Interpreting Biomedical VLMs on High-Imbalance Out-of-Distributions: An Insight into BiomedCLIP on Radiology

In this paper, we construct two research objectives: i) explore the learned embedding space of BiomedCLIP, an open-source large vision language model, to analyse meaningful class separations, and ii) quantify the limitations of BiomedCLIP when applied to a highly imbalanced, out-of-distribution multi-label medical dataset. We experiment on IU-xray dataset, which exhibits the aforementioned criteria, and evaluate BiomedCLIP in classifying images (radiographs) in three contexts: zero-shot inference, full finetuning, and linear probing. The results show that the model under zero-shot settings over-predicts all labels, leading to poor precision and inter-class separability. Full fine-tuning improves classification of distinct diseases, while linear probing detects overlapping features. We demonstrate visual understanding of the model using Grad-CAM heatmaps and compare with 15 annotations by a radiologist. We highlight the need for careful adaptations of the models to foster reliability and applicability in a real-world setting. The code for the experiments in this work is available and maintained on GitHub.

NeuroMoE: A Transformer-Based Mixture-of-Experts Framework for Multi-Modal Neurological Disorder Classification

The integration of multi-modal Magnetic Resonance Imaging (MRI) and clinical data holds great promise for enhancing the diagnosis of neurological disorders (NDs) in real-world clinical settings. Deep Learning (DL) has recently emerged as a powerful tool for extracting meaningful patterns from medical data to aid in diagnosis. However, existing DL approaches struggle to effectively leverage multi-modal MRI and clinical data, leading to suboptimal performance. To address this challenge, we utilize a unique, proprietary multi-modal clinical dataset curated for ND research. Based on this dataset, we propose a novel transformer-based Mixture-of-Experts (MoE) framework for ND classification, leveraging multiple MRI modalities-anatomical (aMRI), Diffusion Tensor Imaging (DTI), and functional (fMRI)-alongside clinical assessments. Our framework employs transformer encoders to capture spatial relationships within volumetric MRI data while utilizing modality-specific experts for targeted feature extraction. A gating mechanism with adaptive fusion dynamically integrates expert outputs, ensuring optimal predictive performance. Comprehensive experiments and comparisons with multiple baselines demonstrate that our multi-modal approach significantly enhances diagnostic accuracy, particularly in distinguishing overlapping disease states. Our framework achieves a validation accuracy of 82.47\%, outperforming baseline methods by over 10\%, highlighting its potential to improve ND diagnosis by applying multi-modal learning to real-world clinical data.

PhenoKG: Knowledge Graph-Driven Gene Discovery and Patient Insights from Phenotypes Alone

Identifying causative genes from patient phenotypes remains a significant challenge in precision medicine, with important implications for the diagnosis and treatment of genetic disorders. We propose a novel graph-based approach for predicting causative genes from patient phenotypes, with or without an available list of candidate genes, by integrating a rare disease knowledge graph (KG). Our model, combining graph neural networks and transformers, achieves substantial improvements over the current state-of-the-art. On the real-world MyGene2 dataset, it attains a mean reciprocal rank (MRR) of 24.64\% and nDCG@100 of 33.64\%, surpassing the best baseline (SHEPHERD) at 19.02\% MRR and 30.54\% nDCG@100. We perform extensive ablation studies to validate the contribution of each model component. Notably, the approach generalizes to cases where only phenotypic data are available, addressing key challenges in clinical decision support when genomic information is incomplete.