Privacy-Preserving Detection of Rare Disease-Associated Cell Subsets via Secure Multi-Party Computation

The detection of rare disease-associated cell subsets from high-dimensional single-cell measurements is critical for understanding diseases such as leukaemia and viral infections. CellCnn, a convolutional neural network (CNN) designed for this task, has demonstrated the ability to identify phenotype-associated cell populations at frequencies as low as 0.01\%. Training such models reliably requires patient cohorts that are larger and more diverse than any single institution can typically assemble, and the underlying single-cell data is too sensitive to share across institutional boundaries under existing privacy regulations. We propose a secure multi-party computation (MPC) framework that enables the training and inference of CellCnn entirely on secret-shared data. This ensures that neither the participants nor the computing servers ever observe raw patient data or intermediate values. Evaluated on benchmark single-cell datasets for cytomegalovirus infection (CMV) and acute myeloid leukaemia (AML), our implementation preserves accuracy close to its plaintext counterpart while outperforming the prior privacy-preserving baseline. In contrast to earlier privacy-preserving approaches that removed components such as ReLU activations and bias terms, our method retains these key parts of the CellCnn architecture and supports accurate analysis without exposing raw patient data.

Do ECG Foundation Models Transfer to Rare Cardiac Diseases? Evidence from Brugada Syndrome Detection

Background: Foundation models (FMs) trained on large-scale unlabeled physiological data have emerged as a promising paradigm for medical artificial intelligence. Their ability to capture clinically meaningful, transferable representations for rare diseases remains largely unproven. This study investigates whether FM pre-training provides genuine clinical generalization benefits beyond improved optimization for rare electrocardiographic (ECG) phenotypes. Methods: We systematically evaluated nine publicly available ECG FMs for Brugada syndrome detection on the BrSwiss cohort (294 patients, 87 cases) and the independent external HUCA cohort (363 patients, 76 cases), under three strategies (from-scratch training, linear probing, full fine-tuning) across several configurations, including a 3% data ablation and zero-shot cross-site transfers. Results: Pre-training was necessary for high-capacity architectures unable to converge from scratch (AUC gain up to 0.411, p < 0.05), but gave no significant gain for compact architectures already converged on labeled data alone. On full BrSwiss, the best fine-tuned FM (ECG-CPC, AUC = 0.962) only marginally exceeded the strongest supervised baseline (ECG-CPC from scratch, AUC = 0.932; p = 0.091). At matched training-set size, the data-efficiency advantage on BrSwiss-3% (AUC gain = 0.055, p < 0.01) did not replicate on HUCA. Under zero-shot cross-site transfer, FM-based pipelines did not generalize better than supervised baselines, all approaching chance-level performance. Conclusion: For Brugada syndrome detection, FM pre-training is mechanical rather than semantic, providing optimization stability rather than transferable clinical knowledge. These findings challenge the assumption that large-scale pre-training inherently encodes clinically meaningful representations, highlighting the central role of model architecture and data-domain alignment.