Predicting C282Y Homozygote Genotype for Hemochromatosis Using Serum Ferritin and Transferrin Saturation Values from 44,809 Participants of the HEIRS Study

INTRODUCTION: The simultaneous interpretation of serum ferritin level and transferrin saturation has been used as a clinical guide to diagnose genetic hemochromatosis. The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 101,168 North American participants for serum ferritin level and transferrin saturation, and C282Y genotyping for the HFE gene. METHODS: Logistic regression involving a subsample of Caucasians (n=44,809) was used to predict individual probabilities of HFE C282Y homozygosity using serum ferritin and transferrin saturation values. Men (n=17,323) and women (n=27,486) were analyzed separately. Regression equations were evaluated using area under the curve from ROC analysis and variance explained by Nagelkerke's pseudo R-squared. An Android smartphone App and website application were developed to provide physicians with easy access to predicting C282Y homozygosity of the HFE gene. RESULTS: The logistic equation had an area under the ROC curve of 0.91 for men and 0.89 for women. The pseudo R-squared was 0.44 for men and 0.34 for women. An example analysis was a Caucasian man with a transferrin saturation of 50% and a ferritin level of 500 µg⁄L, who had a 1.3% (95% CI 1.1% to 8.8%) probability of being a C282Y homozygote. CONCLUSIONS: A large primary care-based sample of 44,809 participants contributed to the development of a new computer⁄smartphone tool that predicts the probability of being a C282Y homozygote of the HFE gene from serum ferritin and transferrin saturation values.