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Detecting rare diseases often requires data from multiple institutions due to the scarcity of cases at individual hospitals. Centralizing data is not feasible due to privacy, consent, and jurisdictional issues. Federated learning enables model training across hospitals without transferring raw data, but it lacks formal privacy guarantees. Model updates can still leak information, and aggregation servers may compromise privacy if they handle unprotected data. This article presents a conceptual framework combining federated learning, differential privacy, and secure multi-party computation for rare disease detection across 50+ international hospitals. The system addresses data scarcity, regulatory fragmentation, and network heterogeneity. Each hospital trains a local model, applies differential privacy to updates, and shares encrypted updates via an aggregation protocol. Non-colluding servers compute global updates without accessing plaintext data. Differential privacy reduces the impact of individual patient data, while secure multi-party computation ensures privacy at the aggregation layer. These methods enable a privacy-preserving approach to federated learning for rare disease collaboration. The proposed framework enables multi-continental rare disease detection without centralizing patient data, offering a privacy-preserving model for future consortia.

Rare pediatric tumors like sarcomas, neuroblastoma, medulloblastoma, and retinoblastoma pose a challenge for developing deep learning models due to the limited availability of histopathology images, which are distributed across multiple institutions. This scarcity is compounded by privacy concerns, as whole-slide images often contain sensitive clinical and genomic data, and generative adversarial networks (GANs) risk memorizing and leaking training samples. To address this, a differentially private GAN framework is proposed for synthesizing high-resolution histopathology patches of rare pediatric cancers. The framework incorporates a generator for image synthesis, a discriminator for realism assessment, per-sample gradient clipping, Gaussian noise injection, and a privacy accountant, ensuring provable privacy guarantees during the training process. The synthetic images generated can aid in data augmentation, model pre-training, and benchmarking without exposing identifiable pathology data, offering a privacy-preserving solution for dataset augmentation while emphasizing the importance of clinical validation.

Federated and decentralized machine learning offer the potential to extract valuable healthcare insights from siloed data without requiring the centralization of sensitive patient records, addressing long-standing privacy and governance challenges. This critical review assesses federated learning in healthcare through three lenses: privacy-preserving technologies, incentive mechanisms, and regulatory compliance frameworks. It examines whether the claims in existing literature are substantiated by real-world evidence from healthcare settings. The review reveals considerable enthusiasm for federated learning but identifies gaps, including incomplete implementation of privacy technologies, theoretical incentive mechanisms, and regulatory compliance often assumed but not validated. Additionally, real-world deployments are limited in scale and duration. The review concludes that the gap between federated learning's theoretical potential and clinical application remains significant, with overstated privacy claims and a lack of established frameworks for incentives and compliance.