Claim A homomorphically encrypted validation pipeline using pooled sufficient statistics from baseline QTc, potassium, magnesium, eGFR, concomitant QT-active drugs, and hydroxychloroquine exposure will preserve clinically useful external calibration of hydroxychloroquine QT-safety models across decentralized autoimmune cohorts without sharing patient-level ECG or laboratory data.

Rationale Hydroxychloroquine is broadly used in lupus and other autoimmune disease, but arrhythmic risk is highly context dependent and many single-center datasets are too small for robust external validation. Multicenter aggregation is difficult because ECG-linked lab data are privacy sensitive. If calibration-relevant summary statistics can be combined under homomorphic encryption, external validation could become feasible without exposing raw traces or patient-level records.

Testable design

• Sites independently fit the same prespecified logistic or survival model for short-horizon QT prolongation or clinically relevant monitoring thresholds.
• Each site exports encrypted sufficient statistics or encrypted gradient/Hessian terms rather than patient-level data.
• Central aggregation reconstructs calibration slope, intercept, Brier score, and AUROC under encrypted or privacy-preserving computation.
• Compare encrypted pooled validation against conventional secure in-house pooled analysis as a reference standard.
• Success criterion: calibration slope/intercept and AUROC differ by less than a clinically negligible margin from raw-data pooled validation.

Falsification The hypothesis fails if encrypted aggregation materially degrades calibration estimates, requires impractical computational overhead, or cannot handle heterogeneous ECG-lab timing across sites.

Why it matters This would offer a concrete path to privacy-preserving pharmacovigilance for cardiovascular drug-safety questions in autoimmune medicine and could generalize to other ECG-linked toxicities.

References

1. Jankelson L, Karam G, Becker ML, Chinitz LA, Tsai MC. QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine. Circulation. 2020;142(1):3-5. DOI: 10.1161/CIRCULATIONAHA.120.047521
2. Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT interval prolongation associated with hydroxychloroquine with or without concomitant azithromycin. JAMA Cardiol. 2020;5(9):1036-1041. DOI: 10.1001/jamacardio.2020.1834
3. Froelicher D, Troncoso-Pastoriza JR, Sousa JS, et al. Truly privacy-preserving federated analytics for precision medicine with multiparty homomorphic encryption. Nat Commun. 2021;12:5910. DOI: 10.1038/s41467-021-25972-y