A clinical algorithm to identify people with the glucose-6-phosphate dehydrogenase p.Val68Met variant at risk for diabetes undertreatment.

Purpose: To develop an algorithm using routine clinical laboratory measurements to identify people at risk for systematic underestimation of glycated hemoglobin (HbA1c) due to p.Val68Met glucose-6-phosphate dehydrogenase (G6PD) deficiency. Methods: We analyzed 122,307 participants of self-identified Black race across four large cohorts with blood glucose, HbA1c, and red cell distribution width measurements from a single blood draw. In UK Biobank, we used recursive partitioning to develop criteria for possible and likely G6PD deficiency. We validated the algorithm in NIH All of Us, Vanderbilt BioVU, and the Million Veterans Program. In Vanderbilt's Synthetic Derivative, we created a cohort of 48,031 participants with type 2 diabetes and no genetic data to test whether predicted risk for G6PD deficiency was associated with incident diabetic retinopathy. Results: G6PD deficiency predictions in hemizygous males showed precision/recall of 31%/81% for possible and 81%/10% for likely deficiency. In homozygous females, precision/recall was 6%/76% for possible and 34%/13% for likely deficiency. Diabetic patients with predicted possible deficiency demonstrated 1.4-fold higher 20-year retinopathy rates (14.3% vs 11.2%, P=0.003). Conclusion: We report a simple clinical algorithm that enables healthcare systems to identify people who may benefit from G6PD genotyping and glucose-based diabetes monitoring.