Bashar Ramadan

Inhyeok Lee, Luke Solo, Michael C. Burkhart et al.

Every prediction from a generative medical event model is bounded by how clinical events are tokenized, yet input representation is rarely isolated from other system and architectural choices. We evaluate how representation decisions affect downstream prediction after a shared one-epoch pretraining budget. We train 28 matched transformers on MIMIC-IV and evaluate them on 30 clinical outcomes in three experiments: (1) quantization granularity, reference-range anchoring, and code-value fusion; (2) value encoding (hard bins, soft discretization, code-normalized xVal) crossed with temporal encoding (event order, time tokens, admission-relative RoPE); and (3) native MIMIC laboratory/vital codes versus the Common Longitudinal ICU Format (CLIF)-remapped laboratory/vital codes with compression-preserving perturbation arms. In Experiment 1, fused code-value tokenization improves mortality AUROC from 0.891 to 0.915 (BH-adjusted p < 0.001), hospital length-of-stay AUROC from 0.763 to 0.788 (BH-adjusted p < 0.001), and, for the decile fused-vs-unfused comparison, mean regression Spearman rho across the 13 regression outcomes from 0.414 to 0.494. Across the three temporal encodings, event order only and admission-relative RoPE match or exceed inserting time tokens on average while shortening sequences by 11%. CLIF remapping preserves downstream performance in our single-site setting while yielding a smaller, clinically interpretable token set compatible with multi-site use. Finer-than-decile quantization, reference-range anchoring, and soft discretization help in selective outcomes, while code-normalized xVal remains well below the discrete and soft families, consistent with near-median suppression that persists after the affine variant.

Luke Solo, Matthew B. A. McDermott, William F. Parker et al.

Generative models trained using self-supervision of tokenized electronic health record (EHR) timelines show promise for clinical outcome prediction. This is typically done using Monte Carlo simulation for future patient trajectories. However, existing approaches suffer from three key limitations: sparse estimate distributions that poorly differentiate patient risk levels, extreme computational costs, and high sampling variance. We propose two new estimators: the Sum of Conditional Outcome Probability Estimator (SCOPE) and Risk Estimation from Anticipated Conditional Hazards (REACH), that leverage next-token probability distributions discarded by standard Monte Carlo. We prove both estimators are unbiased and that REACH guarantees variance reduction over Monte Carlo sampling for any model and outcome. Empirically, on hospital mortality prediction in MIMIC-IV using the ETHOS-ARES framework, SCOPE and REACH match 100-sample Monte Carlo performance using only 10-11 samples (95% CI: [9,11]), representing a ~10x reduction in inference cost without degrading calibration. For ICU admission prediction, efficiency gains are more modest (~1.2x), which we attribute to the outcome's lower "spontaneity," a property we characterize theoretically and empirically. These methods substantially improve the feasibility of deploying generative EHR models in resource-constrained clinical settings.

Sahil Sethi, David Chen, Thomas Statchen et al.

Deep learning-based electrocardiogram (ECG) classification has shown impressive performance but clinical adoption has been slowed by the lack of transparent and faithful explanations. Post hoc methods such as saliency maps may fail to reflect a model's true decision process. Prototype-based reasoning offers a more transparent alternative by grounding decisions in similarity to learned representations of real ECG segments, enabling faithful, case-based explanations. We introduce ProtoECGNet, a prototype-based deep learning model for interpretable, multi-label ECG classification. ProtoECGNet employs a structured, multi-branch architecture that reflects clinical interpretation workflows: it integrates a 1D CNN with global prototypes for rhythm classification, a 2D CNN with time-localized prototypes for morphology-based reasoning, and a 2D CNN with global prototypes for diffuse abnormalities. Each branch is trained with a prototype loss designed for multi-label learning, combining clustering, separation, diversity, and a novel contrastive loss that encourages appropriate separation between prototypes of unrelated classes while allowing clustering for frequently co-occurring diagnoses. We evaluate ProtoECGNet on all 71 diagnostic labels from the PTB-XL dataset, demonstrating competitive performance relative to state-of-the-art black-box models while providing structured, case-based explanations. To assess prototype quality, we conduct a structured clinician review of the final model's projected prototypes, finding that they are rated as representative and clear. ProtoECGNet shows that prototype learning can be effectively scaled to complex, multi-label time-series classification, offering a practical path toward transparent and trustworthy deep learning models for clinical decision support.

Michael C. Burkhart, Bashar Ramadan, Zewei Liao et al.

Foundation models (FMs) trained on electronic health records (EHRs) have shown strong performance on a range of clinical prediction tasks. However, adapting these models to local health systems remains challenging due to limited data availability and resource constraints. In this study, we investigated what these models learn and evaluated the transferability of an FM trained on MIMIC-IV to an institutional EHR dataset at the University of Chicago Medical Center. We assessed their ability to identify outlier patients and examined representation-space patient trajectories in relation to future clinical outcomes. We also evaluated the performance of supervised fine-tuned classifiers on both source and target datasets. Our findings offer insights into the adaptability of FMs across different healthcare systems, highlight considerations for their effective implementation, and provide an empirical analysis of the underlying factors that contribute to their predictive performance.

Sahil Sethi, David Chen, Michael C. Burkhart et al.

Prototype-based neural networks offer interpretable predictions by comparing inputs to learned, representative signal patterns anchored in training data. While such models have shown promise in the classification of physiological data, it remains unclear whether their prototypes capture an underlying structure that aligns with broader clinical phenotypes. We use a prototype-based deep learning model trained for multi-label ECG classification using the PTB-XL dataset. Then without modification we performed inference on the MIMIC-IV clinical database. We assess whether individual prototypes, trained solely for classification, are associated with hospital discharge diagnoses in the form of phecodes in this external population. Individual prototypes demonstrate significantly stronger and more specific associations with clinical outcomes compared to the classifier's class predictions, NLP-extracted concepts, or broader prototype classes across all phecode categories. Prototype classes with mixed significance patterns exhibit significantly greater intra-class distances (p $<$ 0.0001), indicating the model learned to differentiate clinically meaningful variations within diagnostic categories. The prototypes achieve strong predictive performance across diverse conditions, with AUCs ranging from 0.89 for atrial fibrillation to 0.91 for heart failure, while also showing substantial signal for non-cardiac conditions such as sepsis and renal disease. These findings suggest that prototype-based models can support interpretable digital phenotyping from physiologic time-series data, providing transferable intermediate phenotypes that capture clinically meaningful physiologic signatures beyond their original training objectives.

Michael C. Burkhart, Bashar Ramadan, Luke Solo et al.

We present a foundation model-derived method to identify highly informative tokens and events in electronic health records. Our approach considers incoming data in the entire context of a patient's hospitalization and so can flag anomalous events that rule-based approaches would consider within a normal range. We demonstrate that the events our model flags are significant for predicting downstream patient outcomes and that a fraction of events identified as carrying little information can safely be dropped. Additionally, we show how informativeness can help interpret the predictions of prognostic models trained on foundation model-derived representations.