Estimating Individualized Treatment Effects in Acute Ischemic Stroke with Causal Transformation Models (TRAM-DAG): A Multi-Centre Observational Study with External RCT Validation

Recent offline reinforcement learning (RL) studies report policies that outperform physician decisions on clinical outcomes. We conduct a systematic, partially crossed evaluation of five offline RL algorithm families and 14 reward designs in 44,894 post-2018 acute ischemic stroke patients from a nationwide registry (N = 129,033). Standard Fitted Q-Evaluation (FQE) yields an apparent policy-improvement estimate of +0.0069; adding an Early Neurological Deterioration penalty increases it to +0.0101. We identify reward-embedded confounding, in which a proxy terminal reward encodes baseline severity and prognosis as well as treatment efficacy. A 2 x 2 factorial analysis finds that terminal reward confounding accounts for 218.6% of the observed signal change, so its removal overshoots the null. After DML-inspired GBM reward residualization, the FQE estimate attenuates to +0.0033 (p = 0.132), and full deconfounding yields +0.0025 (p = 0.291). FQE-based diagnostics, T-learner analyses, and direct recurrence analyses converge away from a clinically meaningful aggregate improvement. A 1-year mRS factorial analysis replicates the attenuation. We provide an empirically motivated six-step evaluation checklist. NIHSS-stratified heterogeneity is hypothesis-generating for prospective trial design; hospital-level disagreement does not persist after full reward deconfounding.

Machine learning models achieve strong predictive accuracy for 90-day outcome prediction in acute ischaemic stroke, yet clinical adoption is limited by the misalignment of model explanations with clinicians' reasoning. Motivated by a clinician user study calling for clinical guideline-aligned cut-offs, we ask whether continuous predictors can be replaced by clinically informed categorical encodings without sacrificing performance. On a multi-centre European registry stratified into three treatment cohorts, we compare standard and fully categorised gradient-boosted models, the latter using stroke guideline-aligned, treatment-specific thresholds. The fully categorised models are statistically indistinguishable from their continuous counterparts in two of the treatment cohorts, with a significant drop in predictive accuracy in one cohort. Global feature importance rankings remain consistent, suggesting that discretising continuous predictors into guideline-based categories preserves the core hierarchy of prognostic factors across all treatment groups. Guideline-based categorisation is thus a viable design choice for stroke-outcome models.

$\textbf{Objective:}$ Brain-predicted age difference (BrainAGE) is a neuroimaging biomarker reflecting brain health. However, training robust BrainAGE models requires large datasets, often restricted by privacy concerns. This study evaluates the performance of federated learning (FL) for BrainAGE estimation in ischemic stroke patients treated with mechanical thrombectomy, and investigates its association with clinical phenotypes and functional outcomes. $\textbf{Methods:}$ We used FLAIR brain images from 1674 stroke patients across 16 hospital centers. We implemented standard machine learning and deep learning models for BrainAGE estimates under three data management strategies: centralized learning (pooled data), FL (local training at each site), and single-site learning. We reported prediction errors and examined associations between BrainAGE and vascular risk factors (e.g., diabetes mellitus, hypertension, smoking), as well as functional outcomes at three months post-stroke. Logistic regression evaluated BrainAGE's predictive value for these outcomes, adjusting for age, sex, vascular risk factors, stroke severity, time between MRI and arterial puncture, prior intravenous thrombolysis, and recanalisation outcome. $\textbf{Results:}$ While centralized learning yielded the most accurate predictions, FL consistently outperformed single-site models. BrainAGE was significantly higher in patients with diabetes mellitus across all models. Comparisons between patients with good and poor functional outcomes, and multivariate predictions of these outcomes showed the significance of the association between BrainAGE and post-stroke recovery. $\textbf{Conclusion:}$ FL enables accurate age predictions without data centralization. The strong association between BrainAGE, vascular risk factors, and post-stroke recovery highlights its potential for prognostic modeling in stroke care.