The Effect of Analytical Error and Individual Biological Variation of Hemoglobin A1c on the Risk of Misclassification of Diabetes and Pre-Diabetes American Diabetes Association Diagnostic Criteria

Background & Aims: While HbA1c methods have improved, commercial methods continue to have ±5%bias (e.g. For a target of 53.5 mmol/mol: 50.8 to 56.2; For a target of 7.0%: 6.65 to 7.35%) in proficiency testing programs. The aim of this study was to evaluate the influence of HbA1c analytical error on misclassification of patients using diagnostic criteria outlined by the American Diabetes Association (ADA). Methods: NHANES 2015 HbA1c dataset was used as a population sample (n=6326) for simulation studies: prevalence of 11.0% diabetics by HbA1c. HbA1c results were categorized using ADA criteria as healthy, pre-diabetic or diabetic. HbA1c concentrations were then modified in a statistical model by addition of bias, imprecision and biological variation. The fraction of modified HbA1c results misclassified between ADA healthy, pre-diabetic and diabetic groups was assessed. Results: The fractions of HbA1c results misclassified as functions of bias and precision were determined. Representative results were: (A) Biologic variation of HbA1c alone misclassified: 7% of Healthy values as Pre-diabetics, 15% of Pre-diabetics as Healthy, 1 % of Pre-diabetics as Diabetic, and 2% of Diabetic as Pre-diabetics. (B) Addition of 2% precision and -5% bias misclassified: 62% of Pre-diabetics as Healthy and 16% of Diabetics as Pre-diabetics. (C) Addition of 2% precision and +5% bias misclassified: 25% of Healthy patients as Pre-diabetics and 17% of Pre-diabetics as Diabetic. Conclusions: This simulation model demonstrated significant risk of misclassification errors of diabetics, pre-diabetics and healthy patients due to bias of HbA1c methods and demonstrated minor influence of precision.