Robust Multimodal Representation Learning in Healthcare

Medical multimodal representation learning aims to integrate heterogeneous data into unified patient representations to support clinical outcome prediction. However, real-world medical datasets commonly contain systematic biases from multiple sources, which poses significant challenges for medical multimodal representation learning. Existing approaches typically focus on effective multimodal fusion, neglecting inherent biased features that affect the generalization ability. To address these challenges, we propose a Dual-Stream Feature Decorrelation Framework that identifies and handles the biases through structural causal analysis introduced by latent confounders. Our method employs a causal-biased decorrelation framework with dual-stream neural networks to disentangle causal features from spurious correlations, utilizing generalized cross-entropy loss and mutual information minimization for effective decorrelation. The framework is model-agnostic and can be integrated into existing medical multimodal learning methods. Comprehensive experiments on MIMIC-IV, eICU, and ADNI datasets demonstrate consistent performance improvements.

An explainable framework for the relationship between dementia and glucose metabolism patterns

High-dimensional neuroimaging data presents challenges for assessing neurodegenerative diseases due to complex non-linear relationships. Variational Autoencoders (VAEs) can encode scans into lower-dimensional latent spaces capturing disease-relevant features. We propose a semi-supervised VAE framework with a flexible similarity regularization term that aligns selected latent variables with clinical or biomarker measures of dementia progression. This allows adapting the similarity metric and supervised variables to specific goals or available data. We demonstrate the approach using PET scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI), guiding the first latent dimension to align with a cognitive score. Using this supervised latent variable, we generate average reconstructions across levels of cognitive impairment. Voxel-wise GLM analysis reveals reduced metabolism in key regions, mainly the hippocampus, and within major Resting State Networks, particularly the Default Mode and Central Executive Networks. The remaining latent variables encode affine transformations and intensity variations, capturing confounds such as inter-subject variability and site effects. Our framework effectively extracts disease-related patterns aligned with established Alzheimer's biomarkers, offering an interpretable and adaptable tool for studying neurodegenerative progression.

Machine learning-enhanced non-amnestic Alzheimer's disease diagnosis from MRI and clinical features

Alzheimer's disease (AD), defined as an abnormal buildup of amyloid plaques and tau tangles in the brain can be diagnosed with high accuracy based on protein biomarkers via PET or CSF analysis. However, due to the invasive nature of biomarker collection, most AD diagnoses are made in memory clinics using cognitive tests and evaluation of hippocampal atrophy based on MRI. While clinical assessment and hippocampal volume show high diagnostic accuracy for amnestic or typical AD (tAD), a substantial subgroup of AD patients with atypical presentation (atAD) are routinely misdiagnosed. To improve diagnosis of atAD patients, we propose a machine learning approach to distinguish between atAD and non-AD cognitive impairment using clinical testing battery and MRI data collected as standard-of-care. We develop and evaluate our approach using 1410 subjects across four groups (273 tAD, 184 atAD, 235 non-AD, and 685 cognitively normal) collected from one private data set and two public data sets from the National Alzheimer's Coordinating Center (NACC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). We perform multiple atAD vs. non-AD classification experiments using clinical features and hippocampal volume as well as a comprehensive set of MRI features from across the brain. The best performance is achieved by incorporating additional important MRI features, which outperforms using hippocampal volume alone. Furthermore, we use the Boruta statistical approach to identify and visualize significant brain regions distinguishing between diagnostic groups. Our ML approach improves the percentage of correctly diagnosed atAD cases (the recall) from 52% to 69% for NACC and from 34% to 77% for ADNI, while achieving high precision. The proposed approach has important implications for improving diagnostic accuracy for non-amnestic atAD in clinical settings using only clinical testing battery and MRI.

Anatomically Guided Latent Diffusion for Brain MRI Progression Modeling

Accurately modeling longitudinal brain MRI progression is crucial for understanding neurodegenerative diseases and predicting individualized structural changes. Existing state-of-the-art approaches, such as Brain Latent Progression (BrLP), often use multi-stage training pipelines with auxiliary conditioning modules but suffer from architectural complexity, suboptimal use of conditional clinical covariates, and limited guarantees of anatomical consistency. We propose Anatomically Guided Latent Diffusion Model (AG-LDM), a segmentation-guided framework that enforces anatomically consistent progression while substantially simplifying the training pipeline. AG-LDM conditions latent diffusion by directly fusing baseline anatomy, noisy follow-up states, and clinical covariates at the input level, a strategy that avoids auxiliary control networks by learning a unified, end-to-end model that represents both anatomy and progression. A lightweight 3D tissue segmentation model (WarpSeg) provides explicit anatomical supervision during both autoencoder fine-tuning and diffusion model training, ensuring consistent brain tissue boundaries and morphometric fidelity. Experiments on 31,713 ADNI longitudinal pairs and zero-shot evaluation on OASIS-3 demonstrate that AG-LDM matches or surpasses more complex diffusion models, achieving state-of-the-art image quality and 15-20\% reduction in volumetric errors in generated images. AG-LDM also exhibits markedly stronger utilization of temporal and clinical covariates (up to 31.5x higher sensitivity than BrLP) and generates biologically plausible counterfactual trajectories, accurately capturing hallmarks of Alzheimer's progression such as limbic atrophy and ventricular expansion. These results highlight AG-LDM as an efficient, anatomically grounded framework for reliable brain MRI progression modeling.

ARMARecon: An ARMA Convolutional Filter based Graph Neural Network for Neurodegenerative Dementias Classification

Early detection of neurodegenerative diseases such as Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) is essential for reducing the risk of progression to severe disease stages. As AD and FTD propagate along white-matter regions in a global, graph-dependent manner, graph-based neural networks are well suited to capture these patterns. Hence, we introduce ARMARecon, a unified graph learning framework that integrates Autoregressive Moving Average (ARMA) graph filtering with a reconstruction-driven objective to enhance feature representation and improve classification accuracy. ARMARecon effectively models both local and global connectivity by leveraging 20-bin Fractional Anisotropy (FA) histogram features extracted from white-matter regions, while mitigating over-smoothing. Overall, ARMARecon achieves superior performance compared to state-of-the-art methods on the multi-site dMRI datasets ADNI and NIFD.

DW-DGAT: Dynamically Weighted Dual Graph Attention Network for Neurodegenerative Disease Diagnosis

Parkinson's disease (PD) and Alzheimer's disease (AD) are the two most prevalent and incurable neurodegenerative diseases (NDs) worldwide, for which early diagnosis is critical to delay their progression. However, the high dimensionality of multi-metric data with diverse structural forms, the heterogeneity of neuroimaging and phenotypic data, and class imbalance collectively pose significant challenges to early ND diagnosis. To address these challenges, we propose a dynamically weighted dual graph attention network (DW-DGAT) that integrates: (1) a general-purpose data fusion strategy to merge three structural forms of multi-metric data; (2) a dual graph attention architecture based on brain regions and inter-sample relationships to extract both micro- and macro-level features; and (3) a class weight generation mechanism combined with two stable and effective loss functions to mitigate class imbalance. Rigorous experiments, based on the Parkinson Progression Marker Initiative (PPMI) and Alzhermer's Disease Neuroimaging Initiative (ADNI) studies, demonstrate the state-of-the-art performance of our approach.

Dementia-R1: Reinforced Pretraining and Reasoning from Unstructured Clinical Notes for Real-World Dementia Prognosis

While Large Language Models (LLMs) have shown strong performance on clinical text understanding, they struggle with longitudinal prediction tasks such as dementia prognosis, which require reasoning over complex, non-monotonic symptom trajectories across multiple visits. Standard supervised training lacks explicit annotations for symptom evolution, while direct Reinforcement Learning (RL) is hindered by sparse binary rewards. To address this challenge, we introduce Dementia-R1, an RL-based framework for longitudinal dementia prognosis from unstructured clinical notes. Our approach adopts a Cold-Start RL strategy that pre-trains the model to predict verifiable clinical indices extracted from patient histories, enhancing the capability to reason about disease progression before determining the final clinical status. Extensive experiments demonstrate that Dementia-R1 achieves an F1 score of 77.03% on real-world unstructured clinical datasets. Notably, on the ADNI benchmark, our 7B model rivals GPT-4o, effectively capturing fluctuating cognitive trajectories. Code is available at https://anonymous.4open.science/r/dementiar1-CDB5

Statistical Inference for Fuzzy Clustering

Clustering is a central tool in biomedical research for discovering heterogeneous patient subpopulations, where group boundaries are often diffuse rather than sharply separated. Traditional methods produce hard partitions, whereas soft clustering methods such as fuzzy $c$-means (FCM) allow mixed memberships and better capture uncertainty and gradual transitions. Despite the widespread use of FCM, principled statistical inference for fuzzy clustering remains limited. We develop a new framework for weighted fuzzy $c$-means (WFCM) for settings with potential cluster size imbalance. Cluster-specific weights rebalance the classical FCM criterion so that smaller clusters are not overwhelmed by dominant groups, and the weighted objective induces a normalized density model with scale parameter $σ$ and fuzziness parameter $m$. Estimation is performed via a blockwise majorize--minimize (MM) procedure that alternates closed-form membership and centroid updates with likelihood-based updates of $(σ,\bw)$. The intractable normalizing constant is approximated by importance sampling using a data-adaptive Gaussian mixture proposal. We further provide likelihood ratio tests for comparing cluster centers and bootstrap-based confidence intervals. We establish consistency and asymptotic normality of the maximum likelihood estimator, validate the method through simulations, and illustrate it using single-cell RNA-seq and Alzheimer disease Neuroimaging Initiative (ADNI) data. These applications demonstrate stable uncertainty quantification and biologically meaningful soft memberships, ranging from well-separated cell populations under imbalance to a graded AD versus non-AD continuum consistent with disease progression.

MethConvTransformer: A Deep Learning Framework for Cross-Tissue Alzheimer's Disease Detection

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and widespread epigenetic dysregulation in the brain. DNA methylation, as a stable yet dynamic epigenetic modification, holds promise as a noninvasive biomarker for early AD detection. However, methylation signatures vary substantially across tissues and studies, limiting reproducibility and translational utility. To address these challenges, we develop MethConvTransformer, a transformer-based deep learning framework that integrates DNA methylation profiles from both brain and peripheral tissues to enable biomarker discovery. The model couples a CpG-wise linear projection with convolutional and self-attention layers to capture local and long-range dependencies among CpG sites, while incorporating subject-level covariates and tissue embeddings to disentangle shared and region-specific methylation effects. In experiments across six GEO datasets and an independent ADNI validation cohort, our model consistently outperforms conventional machine-learning baselines, achieving superior discrimination and generalization. Moreover, interpretability analyses using linear projection, SHAP, and Grad-CAM++ reveal biologically meaningful methylation patterns aligned with AD-associated pathways, including immune receptor signaling, glycosylation, lipid metabolism, and endomembrane (ER/Golgi) organization. Together, these results indicate that MethConvTransformer delivers robust, cross-tissue epigenetic biomarkers for AD while providing multi-resolution interpretability, thereby advancing reproducible methylation-based diagnostics and offering testable hypotheses on disease mechanisms.

R-GenIMA: Integrating Neuroimaging and Genetics with Interpretable Multimodal AI for Alzheimer's Disease Progression

Early detection of Alzheimer's disease (AD) requires models capable of integrating macro-scale neuroanatomical alterations with micro-scale genetic susceptibility, yet existing multimodal approaches struggle to align these heterogeneous signals. We introduce R-GenIMA, an interpretable multimodal large language model that couples a novel ROI-wise vision transformer with genetic prompting to jointly model structural MRI and single nucleotide polymorphisms (SNPs) variations. By representing each anatomically parcellated brain region as a visual token and encoding SNP profiles as structured text, the framework enables cross-modal attention that links regional atrophy patterns to underlying genetic factors. Applied to the ADNI cohort, R-GenIMA achieves state-of-the-art performance in four-way classification across normal cognition (NC), subjective memory concerns (SMC), mild cognitive impairment (MCI), and AD. Beyond predictive accuracy, the model yields biologically meaningful explanations by identifying stage-specific brain regions and gene signatures, as well as coherent ROI-Gene association patterns across the disease continuum. Attention-based attribution revealed genes consistently enriched for established GWAS-supported AD risk loci, including APOE, BIN1, CLU, and RBFOX1. Stage-resolved neuroanatomical signatures identified shared vulnerability hubs across disease stages alongside stage-specific patterns: striatal involvement in subjective decline, frontotemporal engagement during prodromal impairment, and consolidated multimodal network disruption in AD. These results demonstrate that interpretable multimodal AI can synthesize imaging and genetics to reveal mechanistic insights, providing a foundation for clinically deployable tools that enable earlier risk stratification and inform precision therapeutic strategies in Alzheimer's disease.