Longitudinal EHR Modeling

Counterfactual inference enables clinicians to ask "what if" questions about patient outcomes, but standard methods assume feature independence and simultaneous modifiability -- assumptions violated by longitudinal clinical data. We introduce the Sequential Counterfactual Framework, which respects temporal dependencies in electronic health records by distinguishing immutable features (chronic diagnoses) from controllable features (lab values) and modeling how interventions propagate through time. Applied to 2,723 COVID-19 patients (383 Long COVID heart failure cases, 2,340 matched controls), we demonstrate that 38-67% of patients with chronic conditions would require biologically impossible counterfactuals under naive methods. We identify a cardiorenal cascade (CKD -> AKI -> HF) with relative risks of 2.27 and 1.19 at each step, illustrating temporal propagation that sequential -- but not naive -- counterfactuals can capture. Our framework transforms counterfactual explanation from "what if this feature were different?" to "what if we had intervened earlier, and how would that propagate forward?" -- yielding clinically actionable insights grounded in biological plausibility.

Temporal information in structured electronic health records (EHRs) is often lost in sparse one-hot or count-based representations, while sequence models can be costly and data-hungry. We propose PaReGTA, an LLM-based encoding framework that (i) converts longitudinal EHR events into visit-level templated text with explicit temporal cues, (ii) learns domain-adapted visit embeddings via lightweight contrastive fine-tuning of a sentence-embedding model, and (iii) aggregates visit embeddings into a fixed-dimensional patient representation using hybrid temporal pooling that captures both recency and globally informative visits. The resulting fixed-dimensional patient representations can be used with conventional downstream machine-learning models. To examine factor-level sensitivity, we use PaReGTA-RSS (Representation Shift Score), a prespecified factor-removal analysis that recomputes patient representations after removing clinically defined factor groups and quantifies the resulting change in the fitted logit of a fixed logistic-regression model. We evaluated PaReGTA in a cohort of 39,088 patients with migraine from the All of Us Research Program (AoU) on a retrospective patient-level classification task with an EHR-derived target. In an exploratory comparison on the fixed held-out test cohort of 7,818 patients, PaReGTA-Gap + LightGBM, used as a post hoc analytical reference, had the highest reported AUC, accuracy, and F1 values among the evaluated sparse, BERT-based EHR, and recurrent approaches in this cohort.

Electronic health records (EHR) are irregular, asynchronous multivariate time series. As time-series foundation models increasingly tokenize events rather than discretizing time, the input layout becomes a key design choice. Grids expose time$\times$variable structure but require imputation or missingness masks, risking error or sampling-policy shortcuts. Point-set tokenization avoids discretization but loses within-variable trajectories and time-local cross-variable context (Fig.1). We restore these priors in STructure-AwaRe (STAR) Set Transformer by adding parameter-efficient soft attention biases: a temporal locality penalty $-|Δt|/τ$ with learnable timescales and a variable-type affinity $B_{s_i,s_j}$ from a learned feature-compatibility matrix. We benchmark 10 depth-wise fusion schedules (Fig.2). On three ICU prediction tasks, STAR-Set achieves AUC/APR of 0.7158/0.0026 (CPR), 0.9164/0.2033 (mortality), and 0.8373/0.1258 (vasopressor use), outperforming regular-grid, event-time grid, and prior set baselines. Learned $τ$ and $B$ provide interpretable summaries of temporal context and variable interactions, offering a practical plug-in for context-informed time-series models.

The contemporary paradigm of trajectory learning operates fundamentally at the level of group dynamics, systematically reducing individual-level complexity to fit group-level models, thus rendering effective patient subtyping difficult and individual-level modeling largely out of reach. We propose a data-driven paradigm that introduces a dedicated individual-level temporal variable to capture Timing Attention (i.e., the degree of concentration of an event's timing distribution across the patient cohort), thereby rendering timing a computable dimension that enables individualized temporal features in trajectory learning. Instantiated as the Level-of-Individual Time Transformation (LITT) and applied to longitudinal EHR data from 3,276 breast cancer patients, the proposed paradigm demonstrates, for the first time to our knowledge: (1) automatic discovery of clinically significant patient trajectories, and (2) counterfactual timing deduction, that is, a What-If Machine. Both results are purely data-driven, requiring no prior domain knowledge. LITT further achieves strong performance on timing prediction and survival analysis tasks.

Generative AI can encode substantial medical knowledge, but patient-specific answers remain constrained by the context supplied at inference time. Electronic health records and FHIR support documentation and interoperability, but they do not by themselves define the complete, current, and auditable context a model should receive. Similarity-based retrieval can find related text, but it neither guarantees collection of clinically connected records nor makes omissions explicit. We introduce MedBeads, an AI-facing clinical record substrate that assembles a declared closure of longitudinal patient information before generation. A Bead is an immutable clinical or knowledge object identified by SHA-256 over canonical content and stored as an append-only frame in a patient-scoped Pod. Structural parent edges form a patient-rooted Merkle DAG. Typed clinical links occupy a separate, reconstructable interpretation layer derived from signed, versioned knowledge rules; they can be recomputed when knowledge changes without rewriting clinical facts. Retrieval follows authorized structural and clinical edges, resolves amendments and retractions, and reports policy or token truncation. An open-source Go implementation uses append-only Pods and reconstructable SQLite projections. File-based conversion of 1,135 synthetic Synthea FHIR bundles produced approximately one million Beads and demonstrated deterministic clinical-link derivation and interpretation-layer reconstruction. These engineering results establish feasibility and reproducibility, not reduced hallucination or improved clinical outcomes. MedBeads reframes grounding as a data-structure problem by delivering a policy-bounded, provenance-bearing clinical subgraph rather than an opaque list of similar fragments.

Chronic Kidney Disease (CKD) affects nearly 10% of the global population and often progresses to end-stage renal failure. Accurate prognosis prediction is vital for timely interventions and resource optimization. We present a transformer-based framework for predicting CKD progression using multi-modal electronic health records (EHR) from the Seoul National University Hospital OMOP Common Data Model. Our approach (ProQ-BERT) integrates demographic, clinical, and laboratory data, employing quantization-based tokenization for continuous lab values and attention mechanisms for interpretability. The model was pretrained with masked language modeling and fine-tuned for binary classification tasks predicting progression from stage 3a to stage 5 across varying follow-up and assessment periods. Evaluated on a cohort of 91,816 patients, our model consistently outperformed CEHR-BERT, achieving ROC-AUC up to 0.995 and PR-AUC up to 0.989 for short-term prediction. These results highlight the effectiveness of transformer architectures and temporal design choices in clinical prognosis modeling, offering a promising direction for personalized CKD care.

Electronic health Records (EHRs) have become a cornerstone in modern-day healthcare. They are a crucial part for analyzing the progression of patient health; however, their complexity, characterized by long, multivariate sequences, sparsity, and missing values poses significant challenges in traditional deep learning modeling. While Transformer-based models have demonstrated success in modeling EHR data and predicting clinical outcomes, their quadratic computational complexity and limited context length hinder their efficiency and practical applications. On the other hand, State Space Models (SSMs) like Mamba present a promising alternative offering linear-time sequence modeling and improved efficiency for handling long sequences, but focus mostly on mixing sequence-level information rather than channel-level data. To overcome these challenges, we propose HyMaTE (A Hybrid Mamba and Transformer Model for EHR Representation Learning), a novel hybrid model tailored for representing longitudinal data, combining the strengths of SSMs with advanced attention mechanisms. By testing the model on predictive tasks on multiple clinical datasets, we demonstrate HyMaTE's ability to capture an effective, richer, and more nuanced unified representation of EHR data. Additionally, the interpretability of the outcomes achieved by self-attention illustrates the effectiveness of our model as a scalable and generalizable solution for real-world healthcare applications. Codes are available at: https://github.com/healthylaife/HyMaTE.

Cancer treatments are known to introduce cardiotoxicity, negatively impacting outcomes and survivorship. Identifying cancer patients at risk of heart failure (HF) is critical to improving cancer treatment outcomes and safety. This study examined machine learning (ML) models to identify cancer patients at risk of HF using electronic health records (EHRs), including traditional ML, Time-Aware long short-term memory (T-LSTM), and large language models (LLMs) using novel narrative features derived from the structured medical codes. We identified a cancer cohort of 12,806 patients from the University of Florida Health, diagnosed with lung, breast, and colorectal cancers, among which 1,602 individuals developed HF after cancer. The LLM, GatorTron-3.9B, achieved the best F1 scores, outperforming the traditional support vector machines by 39%, the T-LSTM deep learning model by 7%, and a widely used transformer model, BERT, by 5.6%. The analysis shows that the proposed narrative features remarkably increased feature density and improved performance.