The risk of clinical misinterpretation of HbA1c: Modelling the impact of biological variation and analytical performance on HbA1c used for diagnosis and monitoring of diabetes

Background: The validity of clinical interpretation of HbA1c depends on the analytical performance of the method and the biological variation of HbA1c in patients. The contribution of non-glucose related factors to the bio-logical variation of HbA1c (NGBVA1c) is not known. This paper explores the cumulative impact of analytical errors and NGBVA1c on the risk of misinterpretation.Methods: A model has been developed to predict the risk of misinterpretation of HbA1c for diagnosis and monitoring with variables for analytical performance and levels of NGBVA1c.Results: The model results in probabilities of misinterpretation for a given HbA1c. Example: for an HbA1c 43 mmol/mol (6.1%), bias 1 mmol/mol (0.09%), CV 3% (2%) used for diagnosis, the probabilities of misinter-pretation range from 1 to 19% depending on the contribution of NGBVA1c to the biological variation of HbA1c.Conclusions: In addition to analytical bias and imprecision, NGBVA1c contributes to the risk of misinterpretation, but the relative impact is different per clinical application of HbA1c. For monitoring, imprecision is the pre-dominating factor, for diagnosis both biological variation and analytical bias. Given the increasing use of HbA1c for diagnosis, increase of knowledge on NGBVA1c, decrease of analytical bias, and awareness of the risk of misinterpretation are required.