Longitudinal EHR Modeling

Autoregressive foundation models trained on tokenized electronic health records (EHRs) can support zero-shot clinical prediction, yet most operate on structured event codes alone, and do not incorporate multiple modalities in a principled way. We present a framework for conditioning such models on auxiliary clinical modalities, including ECG waveforms, chest X-ray images, and clinical notes, using modality-specific latent compression and gated cross-attention with temporal alignment. We investigate two key design choices: (1) how to compress long per-modality sequences (e.g., ECG time series) before they enter the multi-modal cross-attention. This feature may be essential to reduce compute overheads and may be beneficial for generalization; (2) how the choice of pretrained encoder for each modality impacts downstream performance. Through controlled ablations on MIMIC-IV, we show that the best latent-compression configurations outperforms both uncompressed cross-attention and mean pooling. Encoder choice has a clear within-modality effect, with stronger pretrained encoders consistently outperforming weaker alternatives. We further show that merely adding auxiliary modalities does not guarantee improvement on ICU mortality prediction over an EHR-only baseline. This implies that careful design of the fusion architecture and an appropriate evaluation in the clinical context are required.

Autoregressive foundation models for electronic health records (EHRs) typically inherit pretraining methods from language modeling, where patient trajectories are concatenated into a single token stream and windows are sampled from that stream. In EHR data, this choice is consequential: windows may mix multiple patients, and patients with longer records contribute more optimization updates, potentially introducing bias. We propose Patient Sampling, a pretraining sequence-construction method that allows us to control how training signal is distributed across patients. We compare this method to the standard approach, which we refer to as Global Stream. We show that stochastic Patient Sampling with controllable weighting improves performance on real-world EHR data. Across downstream clinical tasks on MIMIC-IV v2.2 and v3.1, Patient Sampling improves Macro AUROC and AUPRC over the Global Stream baseline. These results identify training and validation sequence construction as important and underexplored design choices for autoregressive EHR foundation models.

Clinical irregular multivariate time series are shaped not only by physiological dynamics but also by the measurement process that determines when and what to observe. In event-centric models, however, co-timestamp structure can be flattened too early: measurements acquired at the same timestamp are embedded as isolated nodes, leaving local patient-state context unavailable until later message-passing layers. We study this pre-propagation representation bottleneck and address it by restoring co-timestamp context before message passing begins. We propose MissHyper, a missingness-guided hypergraph forecasting model with pre-propagation synchronicity restoration. MissHyper augments each event with a local support-density cue, aggregates co-timestamp records to recover patient-state context, and uses a missingness-guided gate to adaptively fuse node-specific evidence with the recovered context. Across PhysioNet 2012, MIMIC-III, and MIMIC-IV, MissHyper achieves consistent gains in multi-step forecasting and outperforms a strong hypergraph baseline. These results suggest that improving event initialization can benefit sparse clinical forecasting without requiring a redesigned downstream propagation architecture. Ablations indicate that snapshot restoration, adaptive fusion, and support-density encoding all contribute, pointing to event initialization as a critical design axis for sparse clinical forecasting.

Background: Clinical decision support systems degrade silently as treatment protocols evolve, yet standard adaptation methods treat models as monolithic blocks, unable to distinguish stable patient physiology from shifting institutional practice. Methods: We propose an adaptive clinical intelligence architecture for ICU intervention prediction that structurally decouples physiological from treatment representations, confining parameter updates to the treatment stream upon a dual distributional and accuracy trigger. Automated audit logs record which treatment features drove each adaptation event and how their importance shifted. At inference, an attribution-driven Temporal RAG module grounds each prediction in patient-specific, era-matched PubMed evidence anchored to the patient's dominant physiological features. Experiments used 84,792 MIMIC-IV stays (2008-2022) under strict chronological split. Results: Drift localised entirely to the treatment stream, validating the structural prior. Selective adaptation improved vasopressor and septic shock discrimination and calibration over the static source model. A fully retrained baseline yielded marginally higher aggregate discrimination but missed 26 septic shock cases the framework correctly identified, with none in the reverse direction; retrieval consistency with the pre-adaptation source model was preserved by the framework but degraded substantially in the retrained baseline. Conclusions: Structurally constraining adaptation to drifting components while preserving stable physiological representations enables clinical AI to evolve with practice without distorting learned patient biology. This architecture offers a template for governable, interpretable deployment of adaptive models in high-stakes clinical environments.

Early sepsis prediction from electronic health records is challenged by irregular sampling, high missingness, and class imbalance. We systematically compare four modeling paradigms -- self-supervised Joint Embedding Predictive Architecture (JEPA) via masked latent prediction, self-supervised VICReg (variance-invariance-covariance regularization) with two-view augmentation, semi-supervised fine-tuning of a VICReg-pretrained encoder, and supervised Temporal Convolutional Network (TCN) -- alongside raw-feature baselines. All models share a common preprocessing pipeline of hourly binning with forward-fill imputation applied to 7 biomarkers selected via sparsity analysis from the MIMIC-III dataset. Our best model (JEPA + XGBoost + mean pooling) achieves AUPRC 0.636 at the time of onset (H0), approaching the SupMix benchmark (0.667) while using 83% fewer biomarkers. The Tier 1 pipeline -- VICReg pretraining followed by semi-supervised fine-tuning and XGBoost -- achieves AUPRC 0.510 at H0, a 3.1$\times$ improvement over the raw-feature baseline (0.165) and a 7.6% improvement over the end-to-end supervised TCN (0.474). Crucially, the fine-tuned VICReg encoder exhibits the most temporally persistent representations, degrading only 16.8% from H0 to H10 compared to 47.5% for supervised TCN and 65.3% for JEPA, demonstrating that self-supervised pretraining with task-aware fine-tuning yields features that are both sharp near onset and robust across prediction horizons.

Pediatric electronic health records capture developmentally structured clinical trajectories, yet their potential for generative healthcare foundation models remains largely unexplored. Here we present TEDDY (Temporal Event Decoder for Disease in Youth), a 1.84-million-parameter decoder transformer trained on approximately 73 million ICD-10 diagnoses from 1.6 million children at a single pediatric institution. TEDDY models longitudinal diagnosis trajectories and visit timing. Predictions were made before visit codes were revealed, limited to first occurrences, and evaluated against sex- and age-matched controls. Across 797 disease-onset prediction tasks spanning 16 ICD-10 chapters, TEDDY achieved a median AUC of 72.0%, outperforming same-data DenseNet (50.0%), CNN (57.2%), RNN (60.1%), and LSTM (62.7%) baselines on 96-99% of tasks. Performance held across sex and age and was strongest among lower-prevalence diagnoses; 202 of the 225 rarest conditions (90%) had 95% confidence intervals above chance. Predictive signal remained detectable more than two years before first recorded diagnosis, with median AUCs of 59.7% in the unrestricted analysis and 64.4% in a fixed-cohort sensitivity analysis. In asthma and attention-deficit/hyperactivity disorder benchmarks, AUCs were 79.3% and 84.7%, compared with 62.7% and 71.7% for the strongest comparators, including a general-purpose language model three orders of magnitude larger. Visit-timing predictions had a 3.0-day mean absolute restricted mean survival-time error over 365 days, although median and long-tail return intervals remained miscalibrated. Together, these results establish pediatric diagnostic histories as a substrate for compact generative models supporting broad, rare-disease, and long-horizon risk forecasting without population-scale data or billion-parameter models.

Generative modeling of longitudinal Electronic Health Records is increasingly important for privacy-preserving research, yet standard autoregressive models tend to underrepresent the co-occurrence structure of tail events (i.e., diseases, symptoms), reducing the fidelity and faithfulness of generated data for rare subpopulations. To this end, we propose AdaPCLA framework, which enables generative models to adaptively fit and generate EHR data through a data distribution-aware training strategy; this is achieved by internalizing data knowledge parameters by simulated annealing training. It also supports training-free adaptation to a diverse clinical population for generation through zero-shot distribution control. Moreover, our theoretical analysis characterizes rare-code logit updates through the label-wise empirical NTK and derives a prior-internalization bound for how annealing speed and NTK conditioning affect retained prior signals. Experiments on real-world data show that AdaPCLA achieves consistent gains in tail plausibility, downstream utility, and zero-shot control; in particular, it improves TailPairSeen over HALO by 114.2% on MIMIC-III and 65.1% on MIMIC-IV, outperforms GPT-style generation by 3.5% F1 for zero-shot cross-population adaptation.

Musculoskeletal diseases are among the leading causes of disability worldwide and create the greatest global need for rehabilitation. Because recovery, remodelling and degeneration often unfold over months to years, musculoskeletal care requires longitudinal management that repeatedly integrates evolving patient evidence, external medical knowledge and stage-specific functional goals. In routine practice, this evidence is fragmented across visits, departments and hospital systems, limiting individualized, evidence-based care. Here we report OrthoPilot, a clinical artificial intelligence system powered by a large language model that integrates hospital data streams with authoritative external knowledge for continuous musculoskeletal management. OrthoPilot autonomously retrieves real-time imaging, laboratory, pathology and order data and converts evolving patient states into evidence-based decisions from admission diagnosis to rehabilitation planning. We established a specialist-validated benchmark from real-world electronic health records spanning 1,000 disease codes. In a reader study across the complete care pathway, OrthoPilot was compared with 81 orthopaedic physicians and surpassed experts with 25 years of experience in diagnostic reasoning, clinical decision-making and management planning. It also outperformed all evaluated intelligent systems across 60 external clinical centres. In a prospective study of 1,870 complex cases, OrthoPilot increased full-chain management success by 10.6%. During an 8-month randomised deployment involving 8,240 inpatients, it increased cumulative cases per bed by 9.7% and improved patient-reported access to health information. These results move clinical AI from predicting isolated events toward executing longitudinal management across complete musculoskeletal care pathways.

Electronic health record (EHR) data are inherently multimodal, and leveraging multiple modalities can improve predictive performance. However, most existing approaches rely on deep fusion, which obscures how individual modalities contribute to predictions and limits the interpretability of multimodal reasoning. We propose an explicit multimodal routing framework for clinical prediction that enables interpretable, robust, and auditable reasoning across three EHR modalities: structured longitudinal variables (L), clinical notes (N), and chest X-rays (I). Our model constructs discrete unimodal, directional bimodal, and trimodal routes to capture both individual modality signals and asymmetric cross-modal interactions. To audit multimodal reasoning and assess robustness, we introduce inference-time route masking, which simulates missing modalities and reweights the remaining routes without retraining. We analyze changes in performance and routing weights under these scenarios to understand model decision-making. We evaluate our framework on multi-label phenotype prediction (K = 25) and binary ICU mortality prediction using trimodal patient stays from MIMIC-IV, revealing systematic differences in modality reliance across clinical condition groups. Overall, our framework offers a transparent, auditable, and practical approach to multimodal clinical prediction, providing interpretability, robustness, and insights into how different data sources drive model decisions.

In this work, we introduce LongMedBench, a real-world EHR-based benchmark for long-horizon clinical decision-making. Prior evaluations of LLM-based medical agents have largely emphasized short-context knowledge QA and tool use. However, real-world medical care is inherently longitudinal, and clinicians must aggregate evidence across repeated visits, tests, and evolving treatments. Therefore, long-horizon interaction is essential for realistic assessment. LongMedBench is constructed via a reproducible pipeline that integrates MIMIC-IV admission records and clinical notes into time-series event streams and long-context memory datasets, enabling long-horizon, multi-session interactions between agents and a clinical environment. It comprises 335 patients, with 19.72 inpatient visits per patient on average and 44.91 medical events per visit. Guided by the long-horizon decision process, we propose an evaluation taxonomy with three suites: fact-based QA, temporal reasoning, and long-horizon decision-making. This taxonomy measures how agents understand and leverage historical patient information over extended horizons. Our experiments show that while recent LLMs can make good use of explicit timestamps, they have challenges in implicit time inference; The RAG and agent memory system can improve the performance of information retrieval tasks, but the performance of decision-making tasks is highly dependent on the model's immediate context.

Foundation Models for Electronic Health Records (FEMRs) are pretrained on large-scale structured patient data, enabling them to convert longitudinal patient trajectories into generalizable representations for diverse clinical prediction tasks. Despite their effectiveness, FEMRs remain black-box models, raising concerns about bias, interpretability, and clinical trust. To address this, we propose the first token-level explainability approach for FEMRs. We train a Transformer-based surrogate model on input-output pairs from the FEMR across two prediction tasks, approximating its behavior while preserving temporal dynamics. We identify the most influential tokens, providing insights into how FEMRs leverage different aspects of patient history for predictions. To evaluate clinical relevance, we introduce a novel clinical alignment metric that quantifies the correspondence between the surrogate model's key tokens and clinically validated features. Our results demonstrate that the surrogate closely approximates FEMR predictions and that token-level explanations align well with clinical knowledge, offering a practical framework for interpretable and trustworthy clinical AI.

Specialist epilepsy expertise is scarce in resource-constrained settings, making LLM-based decision support attractive for frontline clinicians managing longitudinal treatment. Such systems must adapt to local prescribing practice and know when to defer. We study this problem in Ugandan pediatric epilepsy care, predicting anti-seizure medication regimens from longitudinal unstructured clinic notes. Standard prompting achieves non-trivial agreement with physician prescriptions, but neurologist review shows that many errors reflect distribution-miscalibrated prescribing defaults rather than failures to parse the local record. We introduce MANANA, a non-parametric prompt-learning framework that learns local prescribing guidance from a small patient-level training set. MANANA converts observed prescription errors into auditable prompt memories, instantiated in single-agent and multi-agent variants, and improves over classical ML models, direct LLM prompting, and prompt-optimization baselines across two independently collected Ugandan cohorts. We further propose Bayesian prompt averaging, which converts the learned prompt trajectory into prescription likelihoods and an uncertainty-based deferral signal. On the independently collected held-out cohort, this improves visit-level top-3 prescription accuracy by 4-8 percentage points over prompt-optimization baselines and enables selective prediction: the system can auto-handle the most confident half of cases at 95% precision, or the most confident quarter at 99% precision, while deferring lower-confidence cases for specialist review.

Accurately predicting the temporal evolution of clinical biomarkers is crucial for the early diagnosis and management of neurodegenerative diseases such as Alzheimer's disease. However, this relies on longitudinal data to capture biomarker changes over time, which is often sparse and irregular due to the high cost, labor-intensive nature, and patient burden. To address these challenges, we propose ENC-ODE, an Event-level Neurodegenerative modeling in Continuous time with neural Ordinary Differential Equations. ENC-ODE predicts future biomarker evolution by modeling clinical events through diagnosis-conditioned continuous dynamics. A target-conditioned attention mechanism weights and aggregates event-level predictions for the target time and modality without history compression. Extensive experiments on Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrate that ENC-ODE outperforms representative sequence models while offering a scalable and neuroscientifically grounded solution for clinical support. The code is available at https://github.com/JardinDelSol/enc-ode.

The verbose context problem occurs when structured concepts have token-inefficient textual representations. This bottleneck is acute in population health: cohort-level analysis of longitudinal patient records requires reasoning over thousands of medically-coded events, often exceeding 400K tokens in total. We present PopMedQA, a benchmark isolating this problem through computational tasks on groups of longitudinal patient records. We construct the benchmark using neopatient, a new library for language-controlled generation of artificial patient records. Through extensive ablations -- including prompting strategies, prompt compression, and agentic decomposition -- we find that domain-independent methods fail to alleviate the verbose context problem. There remains significant opportunity to exploit domain-specific structure in language model inputs for population-scale reasoning.

Effective sub-typing (also known as grouping or clustering) of patients using their electronic health record (EHR) data can greatly inform precision medicine efforts. However, subtyping temporal EHR datasets is known to be challenging due to inherent EHR issues, including complexity and irregularity. In this study, we propose a self-supervised Mamba-based model that learns effective EHR representations and enables enhanced patient subtyping. We evaluate the proposed model on public and private real-world EHR datasets to classify the data based on the available labels and subtype patients based on the representations learned from the model. Through an extensive set of experiments, we demonstrate that our model's design choices lead to better performance compared to competitive baseline models for prediction. Moreover, we evaluate several clustering techniques to demonstrate that our findings offer valuable insights into subtyping patients based on temporal records from EHR models\footnote{Our implementations are available at https://github.com/healthylaife/triplet_mamba.

Most electronic health record (EHR) foundation models encode clinical events as discrete event tokens from a fixed vocabulary and therefore cannot directly represent events containing unseen concepts or new combinations of concepts and attributes such as numeric values. This limits transfer across institutions and even across deployment pipelines within the same institution. We introduce PORTER, a language-grounded structured EHR foundation model that decouples event representation from this fixed vocabulary. PORTER represents events through their descriptions using a frozen text encoder, integrates numeric values through a dedicated pathway, and learns clinical dynamics over patient timelines with an autoregressively pretrained temporal backbone. Across 74 clinical prediction tasks at a pediatric hospital, PORTER matched the mean AUROC of a fixed-vocabulary model with the same temporal backbone and pretraining objective. When the same patient timelines were rendered using event descriptions not seen during pretraining, PORTER transferred without retraining or vocabulary mapping, recovering 97.1% of the mean AUROC of a model trained directly on the target vocabulary. When transferred to MIMIC, PORTER outperformed the fixed-vocabulary model, which dropped 69% of events because their tokens were unseen. Mechanistic analyses showed cross-vocabulary transfer tracked preservation of patient-level representation geometry rather than the scale of the text encoder, and the numeric pathway improved sensitivity to magnitude without disrupting clinical concept identity. PORTER also achieved higher AUROC than a task-specific text serialization comparator, at 329-fold lower amortized compute. PORTER is a step toward vocabulary-independent EHR foundation models that reduce the need for vocabulary harmonization while preserving in-domain performance and enabling efficient cross-task reuse.

We introduce VISTA Architect, a database-oriented AI architecture for integrating large language models (LLMs) with longitudinal electronic health records (EHRs). At ingestion, it transforms complex clinical documentation into a persistent, provenance-linked knowledge graph, eliminating repeated reprocessing of raw records at query time. The architecture has two layers: a source-faithful MEDS Graph preserving granular EHR structure with full provenance, and a clinically abstracted Timeline Object Architecture (TOA) that uses graph-guided LLM extraction to synthesize a concise timeline of deduplicated, temporally coherent clinical events. This addresses key limitations of direct long-context prompting and retrieval-augmented generation (RAG), which often miss temporal relationships and incur high cost and latency from repeated raw-text processing. By precomputing clinical synthesis once, downstream queries access an organized patient state and traverse to source documentation only when detailed verification is needed. We demonstrate the system in multidisciplinary thoracic oncology tumor boards at Stanford Medicine, where precise reconstruction of patient histories is critical. Across 1,180 patients, VISTA Architect achieved 96.4% accuracy (mean 9.75/10) on 15 tumor board-salient variables (17,700 evaluations; 95% CI 96.1-96.7%), surpassing a matched BM25 RAG baseline and recent benchmarks for LLM-based clinical extraction. An agentic interface reduced preparation for a 30-patient held-out cohort to about 2.2 minutes without sacrificing accuracy. While configured here for thoracic oncology, the modular design adapts to other specialties through customizable event definitions, episode structures, and agentic tools; validation beyond thoracic oncology remains future work.

Foundation models have achieved remarkable performance across medical question answering, imaging, and electronic health record (EHR) tasks, yet reliable clinical deployment remains challenging due to limited interpretability, vulnerability to distribution shift, and weak alignment with clinician reasoning. We argue that these limitations arise because existing approaches prioritize representation learning while treating patient comparison as an emergent property rather than a primary source of clinical evidence. To address this gap, we propose CAFM, a Cohort-Anchored Foundation Model framework that elevates patient cohorts to a first-class object throughout the learning pipeline. The framework consists of four stages: deviation-aware data curation, cohort-conditioned pretraining, multimodal cohort alignment, and clinician-in-the-loop refinement. Together, these stages improve data quality, organize representations around clinically meaningful cohort structure, preserve modality-specific relationships, and support auditable clinical decision-making. The framework is compositional and can augment existing EHR foundation models without modifying their underlying encoders. We illustrate CAFM through four clinical case studies spanning acute kidney injury prediction, cardiovascular risk stratification from electrocardiograms, optic neuropathy triage from orbital imaging, and electroretinogram-grounded report generation. We further present five empirically testable hypotheses and identify open challenges in data quality, irregular temporality, multimodal learning, distribution shift, and evaluation beyond predictive accuracy. We argue that explicitly anchoring foundation models to patient cohorts provides a principled path toward trustworthy clinical AI.

Real-world clinical decision support requires reasoning over heterogeneous and longitudinal patient information rather than answering isolated medical questions. However, current medical large language models and retrieval-augmented generation systems often rely on single-step prompting or retrieval, which can be fragile when clinical evidence is distributed across long electronic health records, medical images, sensor streams, guidelines, and referral constraints. This paper proposes MedRLM, a Recursive Multimodal Health Intelligence framework for long-context clinical reasoning, sensor-guided screening, and community-to-tertiary referral support. Instead of compressing all patient information into one prompt, MedRLM treats the patient case as an external clinical environment that can be recursively inspected, decomposed, retrieved, verified, and synthesized. The framework coordinates specialized agents for clinical text, longitudinal EHR, medical imaging, physiological sensor signals, guideline retrieval, uncertainty auditing, and referral planning. It further introduces a Clinical Evidence Graph Memory to connect patient-specific observations with retrieved evidence, standardized definitions, sensor-derived biomarkers, and referral criteria. A sensor-guided recursive triggering mechanism activates deeper reasoning when abnormal physiological or behavioral patterns are detected, while uncertainty-gated refinement supports clinician review for high-risk or low-confidence cases. We also outline a real-data evaluation design using public and credentialed clinical datasets spanning EHR, radiology, ECG, ICU time series, and referral-proxy outcomes. MedRLM aims to move medical AI from static question answering toward auditable, multimodal, and workflow-aware clinical decision support.

Routine laboratory panels drawn during cancer treatment constitute longitudinal physiological recordings of organ function, yet their temporal structure is discarded by single-timepoint prognostic tools. A transformer trained on 2,777,595 laboratory measurements from 3,905 patients with multiple myeloma or ovarian cancer predicted the two-year onset of 162 treatment-associated complications, including therapy-related myelodysplastic syndromes, spanning eight clinical categories, achieving 1.5- to 6.1-fold enrichment above prevalence at the group level. It matched or outperformed non-sequential baselines across grouped endpoints (AUROC gains up to +0.11), demonstrating that longitudinal laboratory trajectories capture evolving complication-specific physiology inaccessible from isolated measurements. Predictions generalised across both cancers, divergence concentrating in disease-specific complications, and biomarker masking recovered signatures consistent with established pathophysiology. External validation on MIMIC-IV and MMRF CoMMpass confirmed transferability across independent healthcare systems (AUROC up to 0.85). Routine oncological laboratory data encode organ deterioration weeks to months before clinical onset, enabling complication-specific surveillance without additional testing infrastructure.

Multimodal clinical learning is increasingly important for integrating diverse patient data, including imaging, text, and personalised health records. However, it faces two fundamental challenges: i) modality missingness, where arbitrary subsets of modalities are unavailable at a given patient visit, ii) longitudinal dynamics, where the diagnostic significance of an observation depends on the patient's evolving disease trajectory over time. Existing methods address these challenges in isolation: missing-modality frameworks treat each visit as an independent static snapshot and discard temporal context, while longitudinal models often assume complete modality availability and degrade under systematic modality incompleteness. We propose LongMoE (Longitudinal Mixture-of-Experts), the unified framework to jointly address both challenges. LongMoE combines a context-aware imputation module with an attentional tokenization module that captures frequency-domain temporal patterns across irregular visit sequences, a trajectory-aware encoder for modeling disease progression, and context-conditioned Sparse MoE routing for patient-specific expert selection. Experiments on ADNI, OASIS-3, and MIMIC-IV show that LongMoE improves robustness under missing or weak contemporaneous modalities and remains competitive in full-modality settings, establishing a strong foundation for longitudinally-aware multimodal clinical learning.

The generation of high-fidelity synthetic Electronic Health Records (EHR) is crucial for advancing medical research while preserving patient privacy. However, head-to-head comparison of existing generative models is hindered by disjointed codebases, incompatible data loaders, conflicting library dependencies, and inconsistent evaluation protocols. To address these gaps, we introduce a lightweight, end-to-end benchmarking framework for reproducible synthetic EHR evaluation, organized as a unified pipeline spanning data ingestion, standardized model training, and architecture-agnostic evaluation. Our current implementation targets the generation of longitudinal ICD diagnosis codes -- the most commonly studied modality in this literature -- and is built on the community-maintained PyHealth library. We reimplement and unify strong baselines (MedGAN, CorGAN, PromptEHR, HALO) under full ICD-9 vocabulary granularity, and add a lightweight GPT-2 baseline from the general-purpose sequence-modeling literature. We contribute a rigorous, architecture-agnostic privacy-utility evaluation suite that applies identically to GAN- and transformer-based generators, and report bootstrapped confidence intervals across all metrics. We further analyze the poor long-tailed performance of existing models and discuss the extensibility of our framework beyond diagnosis codes. By lowering the engineering barrier to running, extending, and evaluating under a single pipeline, we introduce a starting point for community-driven reproducibility and benchmarking synthetic EHR models.

Huntington's disease (HD) is a progressive brain disorder that gradually affects movement, cognitive function, and behavior. Identifying the stage of the disease accurately and consistently is important for understanding its course, grouping patients, personalized care, and discovering treatment. Existing clinical staging frameworks rely primarily on predefined clinical measurement thresholds and clinical expert decisions, yet these discrete cut-offs may obscure meaningful intra-stage variability and remain vulnerable to inter-rater differences, especially in motor and functional assessments. To address these limitations, we developed an unsupervised machine learning framework based on dynamic graph representation learning to capture temporal relationships within and across patients from longitudinal clinical measurements. Using the learned representations, we applied K-means++ clustering to identify well-separated groups. We then iteratively increased the number of clusters (k), using stability analysis to assess robustness and reveal additional meaningful clusters beyond the initial optimal solution. We applied the framework to 302 individuals from the Enroll-HD cohort (1,477 visits, 44 clinical variables per visit; 80% manifest participants), enabling data-driven discovery of HD stages reflecting natural clinical progression. Despite the limited cohort size, the proposed framework achieved robust clustering performance using a four-dimensional latent space, identifying four meaningful and statistically distinct disease stages through clustering stability analysis. Each stage corresponded to well-defined clinical measurement boundaries, with minimal overlap compared to previously established clinical staging methods.

Medical knowledge graphs (MKGs) infused with clinical knowledge have been increasingly used to model electronic health records (EHRs) to support interpretable predictions in healthcare domain. However, existing MKG-based approaches are limited in capturing pairwise relations between clinical concepts (e.g., conditions, procedures, and medications), and restricts their ability to model higher-order interactions among co-occurring or semantically related concepts. In addition, most representation learning methods that leverage MKGs either collapse temporal information across visits or lack an explicit mechanism for modeling long-range temporal dependencies, which is critical for clinical tasks such as mortality prediction. To mitigate these limitations, we propose HoT-SSM, a parameter efficient and higher-order temporal graph reasoning with state space models. For each visit, HoT-SSM constructs hypergraphs by grouping semantically related clinical concepts into hyperedges using domain knowledge, thereby preserving visit-level clinical context. Further, to model the temporal dynamics while learning the representations, we introduce a novel dynamic hypergraph-based state space model that explicitly captures patients latent state evolution over time while preserving long-range information. The learned representations are used for downstream clinical prediction and reasoning. Experiments on MIMIC-III and MIMIC-IV datasets shows significant performance improvement over the current state-of-the-art models, demonstrating the effectiveness of jointly modeling higher-order clinical interactions and long-range temporal dependencies.

Longitudinal treatment decisions from multivariate time-series data require predicting potential outcomes under future treatment sequences in the presence of time-varying confounding, heterogeneous patient dynamics, and limited domain-specific data. Existing longitudinal causal estimators typically address this problem by training a new model for each cohort or simulator. We introduce Causal Longitudinal Prior-Fitted Networks (CausalLongPFN), a prior-fitted network for time-series causal inference in longitudinal treatment-response data and zero-shot in-context counterfactual outcome prediction. The model is pretrained entirely on synthetic episodes sampled from a broad prior over temporal structural causal models, exposing it to treatment-confounder feedback, latent heterogeneity, nonlinear state evolution, delayed effects, and cumulative treatment responses. At test time, CausalLongPFN remains frozen and is used zero-shot: it conditions on support trajectories, a query history, and a planned future treatment sequence, and returns a predictive distribution over future outcomes without gradient updates or propensity-model fitting. Multi-step predictions are obtained by recursively applying the one-step predictor under the specified treatment sequence. We evaluate the model on branchable cancer, HIV, and warfarin benchmarks with ground-truth counterfactual labels, and on factual-only rolling-origin prediction in MIMIC-III ICU trajectories. CausalLongPFN is competitive with domain-trained longitudinal baselines on counterfactual benchmarks and performs strongly on factual MIMIC-III prediction, suggesting that broad synthetic causal pretraining can provide a frozen, amortized alternative for zero-shot longitudinal treatment-response prediction when repeated domain-specific training is costly or impractical.

Cancer care requires a longitudinal approach in which treatments are planned and delivered over time according to the needs of each individual patient. While prior research has thoroughly explored how clinical and demographic factors, such as comorbidities and age, inform treatment planning, far less attention has been devoted to the delivery phase of care. Yet planning and delivery are both team-based processes that depend on coordinated efforts among multiple healthcare professionals (HCPs). As such, the human factors embedded in these collaborative practices are crucial to optimizing patient outcomes. Despite this importance, the existing literature on human factors in cancer care is limited, and very few studies have investigated how collaboration within care teams evolves over the course of treatment. To fill this gap, this work examine how HCPs' collaboration, captured through electronic health record (EHR) systems, affects cancer patient outcomes, with particular emphasis on teamwork dynamics. We represent EHR-mediated HCP interactions as networks and apply machine learning methods to identify predictive signals of patient survival embedded in these collaborative structures. We further interpret model predictions by pinpointing network characteristics and dynamic patterns associated with particular outcomes. We evaluate our model through robustness analyses to ensure that the findings are stable and not driven by stochastic variation in training. Additionally, our insights align with hypotheses proposed in the medical literature, and our results provide the empirical, data-driven evidence supporting these claims. Overall, our work contributes a practical workflow for leveraging digital traces of collaboration to evaluate and strengthen longitudinal team-based healthcare, offering actionable insights to guide data-informed interventions in healthcare delivery.

Modeling patient trajectories from longitudinal electronic health records (EHRs) requires reasoning over sparse, noisy, and long-context multimodal sequences. Existing LLM-based multi-agent systems address context length but process patients in isolation, failing to mirror how clinicians leverage accumulated experience from similar prior cases. We present Traj-Evolve, a self-evolving multi-agent system with two complementary evolving mechanisms. First, an Experience Pool (ExPool) acts as a non-parametric memory, indexing rejection-sampled reasoning traces to retrieve similar patients as few-shot contexts. Second, multi-agent reinforcement learning (MARL) via reward-ranked fine-tuning parametrically optimizes inter-agent and agent-memory collaboration. A leave-one-out cross-retrieval strategy unifies the two, aligning training- and inference-time behavior under retrieval augmentation. On a lung cancer prediction task utilizing up to five years of multimodal EHRs, Traj-Evolve outperforms 9 strong baselines on the overall population and a challenging never-smoker population. Analysis of the evolving dynamics highlights three key findings: (1) expanding the ExPool shifts optimal retrieval from diverse to specific samples; (2) under MARL, the manager agent's prediction loss converges quickly while the worker agents' temporal reasoning continues to benefit from more verified patients; and (3) the two mechanisms are complementary on the predicted risk, where ExPool improves specificity while MARL improves sensitivity.

Large language models (LLMs) exhibit strong natural-language reasoning abilities for clinical decision support, but struggle to effectively model structured longitudinal electronic health records (EHRs). In contrast, EHR foundation models can learn predictive patient representations, yet lack interpretable language-based reasoning. To bridge this gap, we propose ChatHealthAI, a multimodal reasoning framework that aligns structured EHR representations from a pretrained EHR foundation model with the semantic space of a frozen LLM through a task-aware resampler. By integrating longitudinal patient representations with refined clinical event descriptions, ChatHealthAI enables clinically grounded natural-language reasoning while maintaining accurate patient prediction. We evaluated ChatHealthAI on three clinical predictive tasks from the EHRSHOT benchmark. Results show that ChatHealthAI improves reasoning quality and interpretability while preserving competitive predictive performance. These findings highlight the potential of integrating EHR foundation models with pretrained LLMs for interpretable clinical prediction.

Estimating the causal effect of time-varying treatments on survival outcomes in large observational studies is computationally demanding, particularly when outcomes are rare. While g-formula-based methods such as the iterative conditional expectation (ICE) estimator provide a principled framework for longitudinal causal inference, they become computationally expensive, especially when bootstrap-based variance estimation is required. In addition, outcome rarity at each time point induces severe class imbalance, leading to instability and convergence issues in logistic regression and related models. To address these challenges, we propose a principled subsampling and reweighting strategy for longitudinal survival data that can be applied to a range of existing causal effect estimators in this setting, including the ICE estimator. The proposed method substantially reduces computational burden while preserving consistency and improving estimation stability in rare-outcome settings. We evaluate the method through simulations and validate it using a large-scale EHR cohort study on social and behavioral determinants of health (SBDH) and suicide risk, demonstrating its effectiveness for modeling rare outcomes in longitudinal data.

Earlier detection of pancreatic cancer is key to enabling wider access to curative treatment and reducing cancer deaths; however, screening is presently not viable. Latent digital indicators of pathology are evident in an individual's disease and blood test trajectories and may predict the development of pancreatic cancer. Longitudinal sequences of coded diagnoses and blood test values accrued by patients throughout their clinical interactions were used to train a custom Transformer-based neural network with a multi-head attention mechanism to predict risk of pancreatic cancer with a multi-year lead time and risk-stratify populations for targeted screening. Mayo Clinic Platform with trained model from Mayo Clinic Rochester validated at Mayo Clinic Arizona, Mayo Clinic Florida, and Mayo Clinic Health Systems. The cohort comprised 6,017 adults with pancreatic cancer and 177,081 controls (median age 75, 45% female) with median 12 years (interquartile range 6.9-16.2) of medical history prior to pancreatic cancer diagnosis. External validation via leave-one-site-out, out-of-sample testing predicting pancreatic cancer 1-, 2-, and 3-years prior to diagnosis demonstrated mean area under the receiver operating characteristic of 0.837 (95% confidence interval 0.827-0.848), 0.797 (95% confidence interval 0.782-0.813), and 0.760 (95% confidence interval 0.745-0.776), respectively. Estimated pancreatic cancer risks were well-calibrated (calibration plot slope 1.08, intercept of -0.077; Brier score 0.025), and a Bayesian population pancreatic cancer prevalence update allows estimated cancer risk outputs to be transportable across settings. At testing, a screening threshold of >3.3% risk of pancreatic cancer in 1-year offered a diagnostic odds ratio of 18.2. Our work therefore lays the foundation for a digital population-level risk enrichment tool that could widen access to curative-intent management.