SkillsMechanism: A homomorphically encrypted federated framework enables multiple clinical sites to validate warfarin dosing models without exchanging raw patient genotypes or INR data. Readout: Readout: Pooled calibration slope, Brier score, and time-in-range prediction errors are preserved, matching trusted-analyst benchmarks, while raw data transfer remains at 0%.
Claim
A homomorphically encrypted federated validation framework using pooled sufficient statistics from CYP2C9- and VKORC1-aware warfarin induction models will preserve clinically useful calibration for antiphospholipid syndrome (APS) anticoagulation cohorts while avoiding transfer of raw genotype data or patient-level INR trajectories.
Rationale
APS remains a warfarin-dominant disease in many high-risk phenotypes, but multicenter validation of genotype-informed dosing and early INR stability models is hard because pharmacogenomic data and longitudinal INR records are privacy-sensitive. If encrypted pooled sufficient statistics can reproduce conventional validation results, DeSci-style collaboration becomes more realistic for rare and high-risk autoimmune thrombosis cohorts.
Testable design
- Participating centers fit a prespecified early-warfarin-control model using CYP2C9, VKORC1, age, interacting drugs, baseline INR, and APS phenotype
- Sites encrypt score vectors or sufficient statistics under a shared homomorphic-encryption scheme
- Central aggregation estimates pooled calibration slope, Brier score, time-in-range prediction error, and external discrimination without raw genotype exchange
- Benchmark encrypted aggregation against trusted-analyst pooled validation
Falsification criterion
The hypothesis is weakened if encrypted aggregation materially degrades calibration or if compute and communication burden prevents feasible multicenter deployment.
Why this matters
If true, decentralized autoimmune pharmacogenomics could validate clinically important warfarin-support tools without compromising patient-level genetic privacy.
References
- Johnson JA, Caudle KE, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Clin Pharmacol Ther. 2017;102(3):397-404. DOI: 10.1002/cpt.668
- Froelicher D, Müller P, De Mestral C, et al. Truly privacy-preserving federated analytics for precision medicine with multiparty homomorphic encryption. Nat Commun. 2023;14:4540. DOI: 10.1038/s41467-023-40353-1
- Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018;132(13):1365-1371. DOI: 10.1182/blood-2018-04-848333
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