The performance of predictive models in clinical settings often degrades when deployed in new hospitals due to distribution shifts. This paper presents a large-scale study of causality-inspired domain generalization on heterogeneous multi-center intensive care unit (ICU) data. We apply anchor regression and introduce anchor boosting, a novel, tree-based nonlinear extension, to a large dataset comprising 400,000 patients from nine distinct ICU databases. The anchor regularization consistently improves out-of-distribution performance, particularly for the most dissimilar target domains. The methods appear robust to violations of theoretical assumptions, such as anchor exogeneity. Furthermore, we propose a novel conceptual framework to quantify the utility of large external data datasets. By evaluating performance as a function of available target-domain data, we identify three regimes: (i) a domain generalization regime, where only the external model should be used, (ii) a domain adaptation regime, where refitting the external model is optimal, and (iii) a data-rich regime, where external data provides no additional value.

Interpretability plays a vital role in aligning and deploying deep learning models in critical care, especially in constantly evolving conditions that influence patient survival. However, common interpretability algorithms face unique challenges when applied to dynamic prediction tasks, where patient trajectories evolve over time. Gradient, Occlusion, and Permutation-based methods often struggle with time-varying target dependency and temporal smoothness. This work systematically analyzes these failure modes and supports learnable mask-based interpretability frameworks as alternatives, which can incorporate temporal continuity and label consistency constraints to learn feature importance over time. Here, we propose that learnable mask-based approaches for dynamic timeseries prediction problems provide more reliable and consistent interpretations for applications in critical care and similar domains.

Recent advances in deep learning (DL) have prompted the development of high-performing early warning score (EWS) systems, predicting clinical deteriorations such as acute kidney injury, acute myocardial infarction, or circulatory failure. DL models have proven to be powerful tools for various tasks but come with the cost of lacking interpretability and limited generalizability, hindering their clinical applications. To develop a practical EWS system applicable to various outcomes, we propose causally-informed explainable early prediction model, which leverages causal discovery to identify the underlying causal relationships of prediction and thus owns two unique advantages: demonstrating the explicit interpretation of the prediction while exhibiting decent performance when applied to unfamiliar environments. Benefiting from these features, our approach achieves superior accuracy for 6 different critical deteriorations and achieves better generalizability across different patient groups, compared to various baseline algorithms. Besides, we provide explicit causal pathways to serve as references for assistant clinical diagnosis and potential interventions. The proposed approach enhances the practical application of deep learning in various medical scenarios.

Models that can predict the occurrence of events ahead of time with low false-alarm rates are critical to the acceptance of decision support systems in the medical community. This challenging task is typically treated as a simple binary classification, ignoring temporal dependencies between samples, whereas we propose to exploit this structure. We first introduce a common theoretical framework unifying dynamic survival analysis and early event prediction. Following an analysis of objectives from both fields, we propose Temporal Label Smoothing (TLS), a simpler, yet best-performing method that preserves prediction monotonicity over time. By focusing the objective on areas with a stronger predictive signal, TLS improves performance over all baselines on two large-scale benchmark tasks. Gains are particularly notable along clinically relevant measures, such as event recall at low false-alarm rates. TLS reduces the number of missed events by up to a factor of two over previously used approaches in early event prediction.

Analysis of the effect of training set size on model performance by artificially subsampling patients at random and retraining the model. This analysis was performed using the circEWS alarm system evaluation policy. We observed that model performance decreases drastically when subsampling to less than 5% of the original training set size, and that the model did not show obvious saturation effects as we move to the full size of the data. A linear model baseline (logistic regression; "LogReg"), a tree-ensemble based method (based on lightGBM, "GBM"; used to construct circEWS), an individual decision tree (based on lightGBM, "DecTree"), and a recurrent neural network ("LSTM") were compared. The Tree models received identical input as given to GBM.

Intensive care clinicians are presented with large quantities of patient information and measurements from a multitude of monitoring systems. The limited ability of humans to process such complex information hinders physicians to readily recognize and act on early signs of patient deterioration. We used machine learning to develop an early warning system for circulatory failure based on a high-resolution ICU database with 240 patient years of data. This automatic system predicts 90.0% of circulatory failure events (prevalence 3.1%), with 81.8% identified more than two hours in advance, resulting in an area under the receiver operating characteristic curve of 94.0% and area under the precision-recall curve of 63.0%. The model was externally validated in a large independent patient cohort.