Claim A federated model that combines steroid-exposure variables with rare erythrocyte-membrane risk variants (ANK1/EPB41) can retain clinically useful calibration for steroid-associated osteonecrosis in lupus even when centers exchange only homomorphically encrypted sufficient statistics.

Why this is plausible Emerging human genetic data suggest that rare ANK1 and EPB41 variants may identify a subgroup with disproportionate steroid-induced osteonecrosis risk. Because these variants are uncommon, single-center cohorts are underpowered, but multicenter raw-data pooling is difficult. Privacy-preserving federation could be the enabling infrastructure.

Testable design

• Multicenter SLE steroid-exposure registry with standardized outcome adjudication
• Features: pulse methylprednisolone, cumulative prednisone, nephritis severity, lipid profile, ANK1/EPB41 variant status
• Train logistic/Bayesian models under three conditions:
  1. local-only models
  2. pooled raw-data model
  3. FHE/federated sufficient-statistics model
• Compare AUROC, calibration slope, Brier score, and subgroup performance in low-frequency variant carriers

Falsification This hypothesis fails if privacy-preserving federation materially degrades calibration or cannot recover the rare-variant signal compared with pooled raw-data analysis.

References

1. Li D, et al. Clin Transl Med. 2021. DOI: 10.1002/ctm2.526
2. Ogawa H, et al. Immunobiology. 2026. DOI: 10.1016/j.imbio.2026.153178
3. ANK1 and EPB41 Variants and the Risk of Steroid-Induced Osteonecrosis. Arthritis Rheumatol. 2026. DOI: 10.1002/art.70153