Hypothesis

A Bayesian model that combines TPMT/NUDT15 phenotype, baseline WBC, planned azathioprine dose, and week-1 to week-2 CBC slope will predict clinically relevant azathioprine leukopenia better than genotype-alone screening in autoimmune disease.

Rationale

Pharmacogenetic status captures a major part of thiopurine intolerance, but it does not explain all early leukopenia. Baseline marrow reserve, dose intensity, and early blood-count kinetics likely add substantial information. A dynamic model should therefore outperform static genotype-only triage.

Testable prediction

In a prospective multicenter autoimmune cohort starting azathioprine, a hierarchical Bayesian model using genotype + early CBC kinetics will show better discrimination and calibration for grade >=3 leukopenia within 12 weeks than a genotype-only classifier.

Proposed study

• Population: adults with autoimmune disease initiating azathioprine
• Exposure variables: TPMT phenotype, NUDT15 phenotype, dose mg/kg, baseline WBC, week-1 and week-2 CBC values, renal function, interacting drugs
• Primary outcome: grade >=3 leukopenia or drug cessation for hematologic toxicity within 12 weeks
• Analysis: temporal external validation, AUROC, AUPRC, calibration slope, decision-curve analysis

Falsification

The hypothesis is weakened if genotype alone performs equivalently after external validation or if early CBC slopes add negligible net benefit.

Limitations

Event rates may be low, ancestry-specific allele distributions may shift performance, and center-level monitoring practices could confound apparent gains.

References

1. Relling MV, Gardner EE, Sandborn WJ, et al. Clin Pharmacol Ther. 2011;89(3):387-391. DOI: 10.1038/clpt.2010.320
2. Yang SK, Hong M, Baek J, et al. Nat Genet. 2014;46(9):1017-1020. DOI: 10.1038/ng.3060
3. Moriyama T, Nishii R, Perez-Andreu V, et al. Nat Genet. 2016;48(4):367-373. DOI: 10.1038/ng.3508