Hypothesis

A federated validation pipeline built on homomorphically encrypted complete blood count time-series can reproduce the ranking and calibration of azathioprine myelotoxicity models across decentralized autoimmune registries without sharing raw patient-level laboratory data.

Rationale

Thiopurine safety research is limited by fragmented cohorts, privacy barriers, and small ancestry-specific subgroups. If encrypted CBC trajectories and covariates can be used for model scoring and pooled evaluation, external validation could scale without centralizing identifiable clinical data.

Testable prediction

Compared with conventional centralized pooling, an FHE-based evaluation workflow will preserve clinically meaningful model performance estimates (difference in AUROC <= 0.02 and calibration slope difference <= 0.05) for azathioprine myelotoxicity prediction across at least three independent autoimmune registries.

Proposed study

• Sites: three or more registries with azathioprine exposure and longitudinal CBC data
• Inputs: encrypted CBC trajectories, TPMT/NUDT15 phenotype categories, dose band, renal function band, interacting-drug indicators
• Primary endpoints: agreement in AUROC, calibration slope, Brier score, and subgroup performance by ancestry
• Secondary endpoint: computational overhead and failure rate versus plaintext benchmarking

Falsification

The hypothesis fails if encrypted validation materially distorts discrimination/calibration or becomes operationally infeasible for realistic cohort sizes.

Limitations

Current FHE workflows may impose heavy compute costs, phenotype harmonization across sites may be imperfect, and privacy-preserving feature engineering can reduce granularity.

References

1. Kim M, Song Y, Wang S, Xia Y, Jiang X. Proc IEEE. 2024;112(1):105-128. DOI: 10.1109/JPROC.2023.3336288
2. Blatt M, Gusev A, Polyakov Y, Goldwasser S. Nat Biomed Eng. 2020;4(12):1190-1198. DOI: 10.1038/s41551-020-00640-8
3. Relling MV, Gardner EE, Sandborn WJ, et al. Clin Pharmacol Ther. 2011;89(3):387-391. DOI: 10.1038/clpt.2010.320