Batch effects can impair federated learning in multi-center omics studies

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.

Multi-center clinical studies and biomedical research collaborations increasingly seek to utilize data across centers to build models that generalize beyond any single center. This creates two distinct challenges: data protection regulations may restrict the sharing of raw patient data across institutions, while centers may collect only partially overlapping sets of features under different protocols. Federated learning enables collaborative model training without centralizing raw data. However, existing federated imputation methods rarely evaluate feature-level missingness, in which entire features are unobserved at some centers. To address this setting, we adapt the ReMasker masked autoencoder to federated learning (Fed-ReMasker), enabling centers to impute features never observed locally by leveraging knowledge learned across collaborating centers. We evaluate Fed-ReMasker in a benchmark spanning synthetic datasets with linear and nonlinear relationships and real-world tabular datasets, including clinical data. The benchmark varies the number of centers, the missingness ratios, and client heterogeneity. Fed-ReMasker achieves the lowest imputation error in 93.2% of value-level and 96.7% of feature-level scenarios in the homogeneous benchmark. It also remains robust to client heterogeneity using simple federated averaging, outperforming all baselines in all 36 value-level scenarios and each baseline in at least 35 of 36 feature-level scenarios, and comes within 3.0% on average of a centralized model trained on the pooled data.

Single-cell ATAC-seq (scATAC-seq) enables high-resolution mapping of chromatin accessibility, yet privacy regulations and data size constraints hinder multi-institutional sharing. Federated learning (FL) offers a privacy-preserving alternative, but faces three fundamental barriers in scATAC-seq analysis: ultra-high dimensionality, extreme sparsity, and severe cross-institutional heterogeneity. We propose FL-Sailer, the first FL framework designed for scATAC-seq data. FL-Sailer integrates two key innovations: (i) adaptive leverage score sampling, which selects biologically interpretable features while reducing dimensionality by 80%, and (ii) an invariant VAE architecture, which disentangles biological signals from technical confounders via mutual information minimization. We provide a convergence guarantee, showing that FL-Sailer converges to an approximate solution of the original high-dimensional problem with bounded error. Extensive experiments on synthetic and real epigenomic datasets demonstrate that FL-Sailer not only enables previously infeasible multi-institutional collaborations but also surpasses centralized methods by leveraging adaptive sampling as an implicit regularizer to suppress technical noise. Our work establishes that federated learning, when tailored to domain-specific challenges, can become a superior paradigm for collaborative epigenomic research.