A Trust-Network-Based Federated Learning Framework for Multi-Center Aging Clock Prediction

$\textbf{Objective:}$ 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.

Federated learning (FL) enables collaborative model training across distributed clients while keeping data local. A central challenge is determining which client updates are beneficial for aggregation with respect to each client's target domain. Existing methods typically address this problem in parameter space by comparing model parameters or gradients. However, parameter-space similarity can be a poor proxy for predictive behavior, especially under heterogeneous, non-IID data. Consequently, updates that are misaligned with a client's target domain, including those caused by heterogeneous data or malfunctioning clients, may degrade local model performance. We propose Local Inference Guided Aggregation for Heterogeneous Training Environments to Yield Enhancement Through Agreement and Regularization (LIGHTYEAR), a federated learning framework that performs update selection in function space. LIGHTYEAR uses an NTK-based agreement score to characterize predictive behavior and determine a personalized aggregation set for each client. By relating model parameters to local predictive responses, the Neural Tangent Kernel (NTK) provides a more expressive criterion for update selection than parameter-space similarity alone. Because function-space information is not available before aggregation in conventional centralized FL, LIGHTYEAR uses a peer-to-peer (P2P) topology in which clients exchange updates directly and evaluate incoming models on private validation data. Each client selects only updates that are beneficial for its own target domain and aggregates them using a regularized rule that improves stability under heterogeneity. Across five datasets and nine baseline methods, LIGHTYEAR consistently outperforms centralized FL baselines and existing P2P approaches.

Federated learning enables collaborative training without sharing patient-level data, but most studies remain simulations. Based on five requirements derived from the literature, we analyzed 14 FL frameworks and found that none fully satisfied these requirements. We present FL-Net, a novel federated clinical research framework to fulfill all requirements. It integrates modular data harmonization, data discovery, disclosure control, securely built versioned FL-Net-Tools and containerized federated workflow execution into a persistent network. It enables the re-use of harmonized data and workflows across studies. FL-Net's end-to-end capabilities were evaluated through harmonization, cross-study patient discovery across MIMIC and US-130, and reproducible, audited federated workflows with up to 50 concurrent clients. FL-Net is being developed within the dAIbetes and Microb-AI-ome EU projects and will cover over 800,000 patients across 10 hospitals in 9 countries covering longitudinal and single point in time data, FL-Net provides a practical foundation for interoperable, reproducible, and privacy-preserving multicenter clinical research.