Sepsis

Offline reinforcement learning (RL) offers considerable promise for optimizing ICU treatment decisions, yet standard evaluation metrics Mean Squared Error (MSE) and Fitted Q-Evaluation (FQE) assess only behavioral imitation and cannot detect Toxic Mimicry, a failure mode in which agents replicate harmful patterns such as treatment withdrawal during comfort-care transitions. Using the MIMIC-III database, we propose the Counterfactual Clinical Audit (CCA) framework, which stress-tests RL agents through physiological perturbations anchored in Surviving Sepsis Campaign (SSC) guidelines. We audit a Medical Decision Transformer (MedDT) and a Historical Causal Transformer (HCT-RL), the latter employing Causal Action Shielding, propensity-based importance weighting, and Conservative Q-Learning. CCA reveals that MedDT paradoxically reduces vasopressor dosage as lactate escalates, contradicting resuscitation guidelines, while HCT-RL maintains physiologically consistent responses. These findings expose a systemic misalignment between statistical fit and clinical safety, supporting counterfactual audits as a necessary evaluation standard for medical RL.

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.

Sepsis is a leading cause of mortality, yet optimal treatment policies remain contested. Existing reinforcement learning (RL) approaches learn fixed strategies for sepsis treatment, limiting adaptability to changing clinical objectives during inference. We propose EHRMPC, a framework that decouples learning patient dynamics from optimizing treatment by training a patient digital twin in the form of a generative electronic health record (EHR) model. The digital twin predicts clinical trajectories under interventions and enables model predictive control (MPC) to optimize treatments via inference-time planning over simulations. We evaluate EHR-MPC on a multicenter ICU sepsis cohort spanning 8 hospitals in the Mass General Brigham health system using both off-policy importance sampling and on-policy simulation-based evaluation. Relative to RL baselines, EHR-MPC achieves comparable off-policy performance and improved simulation performance. Unlike RL, this work frames sepsis treatment optimization as inference-time control over learned patient dynamics, establishing a general framework for decision making with generative clinical models.

We consider multi-environment prediction problems. We assume the environments change the distribution of a latent variable, while the mechanisms generating observed covariates and targets remain stable conditional on that variable. For example, hospitals or clinical cohorts may differ in the prevalence of latent patient states, even though the relationships between those states, physiological measurements, and outcomes remain unchanged. Given a dataset from multiple environments, we formulate a Bayesian model for such problems and derive the corresponding variational objective. We show that this objective decomposes into per-environment terms and an additional cross-environment balancing term induced by the model's structure. We use an empirical Bayes method to set the prior and incorporate it into the objective. Based on this objective, we develop an amortized variational algorithm for posterior approximation, and use the resulting learned latent variables to form predictions in new environments.We study our approach through simulations and real-world studies of astronomical source identification, microbiome-based disease detection, and ICU sepsis prediction. Across these settings, our method outperforms previous approaches for prediction in new environments.

Privacy-sensitive and distributed characteristics of multi-center medical data bring severe obstacles to centralized modeling for accurate early prediction of sepsis. Federated learning (FL) has attracted growing attention as a promising framework for collaborative model development, as it allows multiple institutions to jointly train predictive models without directly sharing or centralizing raw data. Nevertheless, its practical performance, robustness, and privacy-preserving benefits remain insufficiently evaluated using real-world clinical datasets. To bridge this gap, this study systematically examines the application of federated learning to multi-center sepsis prediction. The experimental dataset consists of 648 clinically screened samples collected from three tertiary hospitals in China, with rigorous inclusion and exclusion criteria. We establish a centralized training paradigm as the performance baseline, and then implement a horizontal federated learning framework for distributed collaborative modeling. Extensive experimental results demonstrate that the federated learning-based model achieves highly comparable prediction accuracy to the centralized counterpart, while fundamentally avoiding privacy leakage. Further privacy security analysis verifies that malicious attackers cannot reconstruct the original patient data from the transmitted model parameters, indicating strong resistance against data reconstruction attacks. This work not only validates the practicality and security of federated learning in clinical sepsis prediction, but also provides a reliable and feasible solution for privacy-preserving multi-center medical collaboration.

Despite strong predictive results in the clinical machine learning literature, the translation of these models into bedside use remains limited by systems-level barriers: heterogeneous data representations, the absence of standardized deployment workflows, and a mismatch between research prototypes and the concurrency and latency requirements of hospital environments. We present the SepsisAI-Orchestrator, an open-source modular platform that addresses this deployment gap for early sepsis detection. The platform integrates HL7 FHIR-inspired Clinical Document Architecture (CDA) preprocessing, NoSQL storage, a containerized LightGBM classifier served via REST APIs, and a Streamlit clinical dashboard, orchestrated with Docker and Kubernetes. A previously validated LightGBM model (F1 0.87-0.94 on PhysioNet 2019) is reused without modification; the contribution lies in the surrounding infrastructure and its empirical characterization under load. Using k6 with 50-1000 concurrent virtual users, we find that replica count must be matched to the physical CPU thread count of the host: scaling from 3 to 12 replicas on a 12-thread CPU reduces p95 latency from 3.3s to 1.41s (57.3% reduction) and eliminates all request failures, while over-provisioning to 24 or 48 replicas degrades performance due to scheduler contention. To our knowledge this U-shaped scaling behavior has not been quantified previously for clinical AI inference workloads. We do not claim prospective clinical validation. Source code and deployment manifests are available at https://github.com/nucleusai/sepsisai-orchestrator.

Numerical time-series models can effectively process irregular electronic health record (EHR) trajectories, but they do not naturally expose the measurements and temporal patterns supporting each risk estimate as readable evidence. Existing text-based interfaces improve readability, but typically rely on either raw serialization, which is lengthy and redundant, or patient-level free-form summaries, which are difficult to trace to source measurements and time windows. To bridge this gap, we introduce TreeText-CTS (Clinical Time-Series), which converts irregular EHR trajectories into human-readable, compact, source-traceable tree-path evidence units without patient-level summarization or inference-time autoregressive decoding. TreeText-CTS routes multi-scale window summaries through frozen XGBoost models and verbalizes activated tree paths as deterministic, source-traceable evidence units composed of threshold conditions. An evidence selector assembles an informative subset of these units, which a language-model encoder then integrates for prediction. Across PhysioNet 2012 mortality, MIMIC-III mortality, and PhysioNet 2019 sepsis-onset forecasting, TreeText-CTS achieves the best AUROC and AUPRC among evaluated text-based EHR time-series interfaces, improving AUPRC by 6.0 to 9.7 absolute percentage points over the strongest prior text-based interface while remaining competitive with numerical time-series models. Ablations show that tree-path evidence construction, evidence selection, and language-model composition each contribute to performance. Because every span passed to the language-model encoder is constructed from activated tree-path threshold conditions, TreeText-CTS makes the evidence supplied to the final predictor inspectable and source-traceable.

Sepsis management in the ICU requires sequential treatment decisions under rapidly evolving patient physiology. Although large language models (LLMs) encode broad clinical knowledge and can reason over guidelines, they are not inherently grounded in action-conditioned patient dynamics. We introduce SepsisAgent, a world model-augmented LLM agent for sepsis treatment recommendation. SepsisAgent uses a learned Clinical World Model to simulate patient responses under candidate fluid--vasopressor interventions, and follows a propose--simulate--refine workflow before committing to a prescription. We first show that world-model access alone yields inconsistent LLM decision performance, motivating agent-specific training. We then train SepsisAgent through a three-stage curriculum: patient-dynamics supervised fine-tuning, propose--simulate--refine behavior cloning, and world-model-based agentic reinforcement learning. On MIMIC-IV sepsis trajectories, SepsisAgent outperforms all traditional RL and LLM-based baselines in off-policy value while achieving the best safety profile under guideline adherence and unsafe-action metrics. Further analysis shows that repeated interaction with the Clinical World Model enables the agent to learn regularities in patient evolution, which remain useful even when simulator access is removed.

Timely and interpretable early warning of sepsis remains a major clinical challenge due to the complex temporal dynamics of physiological deterioration. Traditional data-driven models often provide accurate yet opaque predictions, limiting physicians' confidence and clinical applicability. To address this limitation, we propose a Large Language Model (LLM)-guided temporal simulation framework that explicitly models physiological trajectories prior to disease onset for clinically interpretable prediction. The framework consists of a spatiotemporal feature extraction module that captures dynamic dependencies among multivariate vital signs, a Medical Prompt-as-Prefix module that embeds clinical reasoning cues into LLMs, and an agent-based post-processing component that constrains predictions within physiologically plausible ranges. By first simulating the evolution of key physiological indicators and then classifying sepsis onset, our model offers transparent prediction mechanisms that align with clinical judgment. Evaluated on the MIMIC-IV and eICU databases, the proposed method achieves superior AUC scores (0.861-0.903) across 24-4-hour pre-onset prediction tasks, outperforming conventional deep learning and rule-based approaches. More importantly, it provides interpretable trajectories and risk trends that can assist clinicians in early intervention and personalized decision-making in intensive care environments.

Causal inference from electronic health records (EHR) is fundamentally limited by unmeasured confounding: critical clinical states such as frailty, goals of care, and mental status are documented in free-text notes but absent from structured data. Large language models can extract these latent confounders as interpretable, structured covariates, yet how to effectively integrate them into causal estimation pipelines has not been systematically studied. Using the MIMIC-IV database with 21,859 sepsis patients, we compare seven covariate-integration strategies for estimating the effect of early vasopressor initiation on 28-day mortality, spanning tabular-only baselines, traditional NLP representations, and three LLM-augmented approaches. A central finding is that not all integration strategies are equally effective: directly augmenting the propensity score model with LLM covariates achieves the best performance, while dual-caliper matching on text-derived categorical distances restricts the donor pool and degrades estimation. In semi-synthetic experiments with known ground-truth effects, LLM-augmented propensity scores reduce estimation bias from 0.0143 to 0.0003 relative to tabular-only methods, and this advantage persists under substantial simulated extraction error. On real data, incorporating LLM-extracted covariates reduces the estimated treatment effect from 0.055 to 0.027, directionally consistent with the CLOVERS randomized trial, and a doubly robust estimator yielding 0.019 confirms the robustness of this finding. Our results offer practical guidance on when and how text-derived covariates improve causal estimation in critical care.

Accurate prediction of future risk and disease progression in sepsis is clinically important for early warning and timely intervention in intensive care. However, short-window sepsis prediction remains challenging, because shorter observation windows provide limited historical evidence, whereas longer prediction horizons reduce the number of patient trajectories with valid future supervision. To address this problem, we propose CSRA, a Controlled Spectral Residual Augmentation framework for short-window multi-system ICU time series. CSRA first groups variables by clinical systems and extracts system-level and global representations. It then performs input-adaptive residual perturbation in the spectral domain to generate structured and clinically plausible trajectory variations. To improve augmentation stability and controllability, CSRA is trained end-to-end with the downstream predictor under a unified objective, together with anchor consistency loss and controller regularization. Experiments on a MIMIC-IV sepsis cohort across multiple downstream models show that CSRA is consistently competitive and often superior, reducing regression error by 10.2% in MSE and 3.7% in MAE over the non-augmentation baseline, while also yielding consistent gains on classification. CSRA further maintains more favorable performance under shorter observation windows, longer prediction horizons, and smaller training data scales, while also remaining effective on an external clinical dataset~(ZiGongICUinfection), indicating stronger robustness and generalizability in clinically constrained settings.