Chronic diseases often progress differently across patients. Rather than randomly varying, there are typically a small number of subtypes for how a disease progresses across patients. To capture this structured heterogeneity, the Subtype and Stage Inference Event-Based Model (SuStaIn) estimates the number of subtypes, the order of disease progression for each subtype, and assigns each patient to a subtype from primarily cross-sectional data. It has been widely applied to uncover the subtypes of many diseases and inform our understanding of them. But how robust is its performance? In this paper, we develop a principled Bayesian subtype variant of the event-based model (BEBMS) and compare its performance to SuStaIn in a variety of synthetic data experiments with varied levels of model misspecification. BEBMS substantially outperforms SuStaIn across ordering, staging, and subtype assignment tasks. Further, we apply BEBMS and SuStaIn to a real-world Alzheimer's data set. We find BEBMS has results that are more consistent with the scientific consensus of Alzheimer's disease progression than SuStaIn.

Predicting future brain state from a baseline magnetic resonance image (MRI) is a central challenge in neuroimaging and has important implications for studying neurodegenerative diseases such as Alzheimer's disease (AD). Most existing approaches predict future cognitive scores or clinical outcomes, such as conversion from mild cognitive impairment to dementia. Instead, here we investigate longitudinal MRI image-to-image prediction that forecasts a participant's entire brain MRI several years into the future, intrinsically modeling complex, spatially distributed neurodegenerative patterns. We implement and evaluate five deep learning architectures (UNet, U2-Net, UNETR, Time-Embedding UNet, and ODE-UNet) on two longitudinal cohorts (ADNI and AIBL). Predicted follow-up MRIs are directly compared with the actual follow-up scans using metrics that capture global similarity and local differences. The best performing models achieve high-fidelity predictions, and all models generalize well to an independent external dataset, demonstrating robust cross-cohort performance. Our results indicate that deep learning can reliably predict participant-specific brain MRI at the voxel level, offering new opportunities for individualized prognosis.

Alzheimer's disease affects over 55 million people worldwide and is projected to more than double by 2050, necessitating rapid, accurate, and scalable diagnostics. However, existing approaches are limited because they cannot achieve clinically acceptable accuracy, generalization across datasets, robustness to missing modalities, and explainability all at the same time. This inability to satisfy all these requirements simultaneously undermines their reliability in clinical settings. We propose OmniBrain, a multimodal framework that integrates brain MRI, radiomics, gene expression, and clinical data using a unified model with cross-attention and modality dropout. OmniBrain achieves $92.2 \pm 2.4\%$accuracy on the ANMerge dataset and generalizes to the MRI-only ADNI dataset with $70.4 \pm 2.7\%$ accuracy, outperforming unimodal and prior multimodal approaches. Explainability analyses highlight neuropathologically relevant brain regions and genes, enhancing clinical trust. OmniBrain offers a robust, interpretable, and practical solution for real-world Alzheimer's diagnosis.

Recent years have seen a surge in research focused on leveraging graph learning techniques to detect neurodegenerative diseases. However, existing graph-based approaches typically lack the ability to localize and extract the specific brain regions driving neurodegenerative pathology within the full connectome. Additionally, recent works on multimodal brain graph models often suffer from high computational complexity, limiting their practical use in resource-constrained devices. In this study, we present BrainMAP, a novel multimodal graph learning framework designed for precise and computationally efficient identification of brain regions affected by neurodegenerative diseases. First, BrainMAP utilizes an atlas-driven filtering approach guided by the AAL atlas to pinpoint and extract critical brain subgraphs. Unlike recent state-of-the-art methods, which model the entire brain network, BrainMAP achieves more than 50% reduction in computational overhead by concentrating on disease-relevant subgraphs. Second, we employ an advanced multimodal fusion process comprising cross-node attention to align functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data, coupled with an adaptive gating mechanism to blend and integrate these modalities dynamically. Experimental results demonstrate that BrainMAP outperforms state-of-the-art methods in computational efficiency, without compromising predictive accuracy.

Modeling policies for sequential clinical decision-making based on observational data is useful for describing treatment practices, standardizing frequent patterns in treatment, and evaluating alternative policies. For each task, it is essential that the policy model is interpretable. Learning accurate models requires effectively capturing the state of a patient, either through sequence representation learning or carefully crafted summaries of their medical history. While recent work has favored the former, it remains a question as to how histories should best be represented for interpretable policy modeling. Focused on model fit, we systematically compare diverse approaches to summarizing patient history for interpretable modeling of clinical policies across four sequential decision-making tasks. We illustrate differences in the policies learned using various representations by breaking down evaluations by patient subgroups, critical states, and stages of treatment, highlighting challenges specific to common use cases. We find that interpretable sequence models using learned representations perform on par with black-box models across all tasks. Interpretable models using hand-crafted representations perform substantially worse when ignoring history entirely, but are made competitive by incorporating only a few aggregated and recent elements of patient history. The added benefits of using a richer representation are pronounced for subgroups and in specific use cases. This underscores the importance of evaluating policy models in the context of their intended use.

Access to large-scale high-quality healthcare databases is key to accelerate medical research and make insightful discoveries about diseases. However, access to such data is often limited by patient privacy concerns, data sharing restrictions and high costs. To overcome these limitations, synthetic patient data has emerged as an alternative. However, synthetic data generation (SDG) methods typically rely on machine learning (ML) models trained on original data, leading back to the data scarcity problem. We propose an approach to generate synthetic tabular patient data that does not require access to the original data, but only a description of the desired database. We leverage prior medical knowledge and in-context learning capabilities of large language models (LLMs) to generate realistic patient data, even in a low-resource setting. We quantitatively evaluate our approach against state-of-the-art SDG models, using fidelity, privacy, and utility metrics. Our results show that while LLMs may not match the performance of state-of-the-art models trained on the original data, they effectively generate realistic patient data with well-preserved clinical correlations. An ablation study highlights key elements of our prompt contributing to high-quality synthetic patient data generation. This approach, which is easy to use and does not require original data or advanced ML skills, is particularly valuable for quickly generating custom-designed patient data, supporting project implementation and providing educational resources.

Recent advancements in medicine have confirmed that brain disorders often comprise multiple subtypes of mechanisms, developmental trajectories, or severity levels. Such heterogeneity is often associated with demographic aspects (e.g., sex) or disease-related contributors (e.g., genetics). Thus, the predictive power of machine learning models used for symptom prediction varies across subjects based on such factors. To model this heterogeneity, one can assign each training sample a factor-dependent weight, which modulates the subject's contribution to the overall objective loss function. To this end, we propose to model the subject weights as a linear combination of the eigenbases of a spectral population graph that captures the similarity of factors across subjects. In doing so, the learned weights smoothly vary across the graph, highlighting sub-cohorts with high and low predictability. Our proposed sample weighting scheme is evaluated on two tasks. First, we predict initiation of heavy alcohol drinking in young adulthood from imaging and neuropsychological measures from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA). Next, we detect Dementia vs. Mild Cognitive Impairment (MCI) using imaging and demographic measurements in subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Compared to existing sample weighting schemes, our sample weights improve interpretability and highlight sub-cohorts with distinct characteristics and varying model accuracy.

Alzheimer's Disease (AD) is a currently incurable neurodegeneartive disease. Accurately detecting AD, especially in the early stage, represents a high research priority. AD is characterized by progressive cognitive impairments that are related to alterations in brain functional connectivity (FC). Based on this association, many studies have been published over the decades using FC and machine learning to differentiate AD from healthy aging. The most recent development in this detection method highlights the use of graph neural network (GNN) as the brain functionality analysis. In this paper, we proposed a stack of spatio-temporal feature extraction and graph generation based AD classification model using resting state fMRI. The proposed multi-level generated connectome (MLC) based graph convolutional network (GCN) (MLC-GCN) contains a multi-graph generation block and a GCN prediction block. The multi-graph generation block consists of a hierarchy of spatio-temporal feature extraction layers for extracting spatio-temporal rsfMRI features at different depths and building the corresponding connectomes. The GCN prediction block takes the learned multi-level connectomes to build and optimize GCNs at each level and concatenates the learned graphical features as the final predicting features for AD classification. Through independent cohort validations, MLC-GCN shows better performance for differentiating MCI, AD, and normal aging than state-of-art GCN and rsfMRI based AD classifiers. The proposed MLC-GCN also showed high explainability in terms of learning clinically reasonable connectome node and connectivity features from two independent datasets. While we only tested MLC-GCN on AD, the basic rsfMRI-based multi-level learned GCN based outcome prediction strategy is valid for other diseases or clinical outcomes.

Motivation: Electronic Health Records (EHR) represent a comprehensive resource of a patient's medical history. EHR are essential for utilizing advanced technologies such as deep learning (DL), enabling healthcare providers to analyze extensive data, extract valuable insights, and make precise and data-driven clinical decisions. DL methods such as Recurrent Neural Networks (RNN) have been utilized to analyze EHR to model disease progression and predict diagnosis. However, these methods do not address some inherent irregularities in EHR data such as irregular time intervals between clinical visits. Furthermore, most DL models are not interpretable. In this study, we propose two interpretable DL architectures based on RNN, namely Time-Aware RNN (TA-RNN) and TA-RNN-Autoencoder (TA-RNN-AE) to predict patient's clinical outcome in EHR at next visit and multiple visits ahead, respectively. To mitigate the impact of irregular time intervals, we propose incorporating time embedding of the elapsed times between visits. For interpretability, we propose employing a dual-level attention mechanism that operates between visits and features within each visit. Results: The results of the experiments conducted on Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Alzheimer's Coordinating Center (NACC) datasets indicated superior performance of proposed models for predicting Alzheimer's Disease (AD) compared to state-of-the-art and baseline approaches based on F2 and sensitivity. Additionally, TA-RNN showed superior performance on Medical Information Mart for Intensive Care (MIMIC-III) dataset for mortality prediction. In our ablation study, we observed enhanced predictive performance by incorporating time embedding and attention mechanisms. Finally, investigating attention weights helped identify influential visits and features in predictions.