Upper reference limit, analytical quality specifications and clinical use of haemoglobin A1C

Haemoglobin A1c (HbA1c) is now the key component for monitoring glycaemic control in diabetes mellitus (DM), especially for its close relation to diabetes complications. However, treatment goals in terms of HbA1c concentrations have been difficult to define and compare because of lack of international standardization and lack of common reference values of HbA1c concentrations. The aims of our study were to document our HbA1c analysis and make it traceable to international reference laboratories with the aid of current reference preparations, to establish a reference interval based on a low-risk population, and to evaluate the analytical quality specifications, which could meet clinical needs. The s(analytical) of our method (Tosoh) was < 0.3 HbA1c%, and the mean bias as estimated from Dr Cas Weykamp's reference preparation was below 0.3 HbA1c. This was the same as that for participating Scandinavian and international reference laboratories. The concentrations were made traceable to results from the Diabetes Control and Complication Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS). Risk groups for DM were ruled out from a randomly selected population in Vejle County, which isolated a "low-risk" reference population. The 97.5 reference interval in this population (N=430) was from 5.07 HbA1c% (95% CI: 5.02-5.11) to 6.24 HbA1c% (95% CI: 6.19-6.30), and the 99.9 centile was 6.62 HbA1c% (95%) CI 6.55-6.71). Body mass index, age and gender contributed marginally to the level of HbA1c concentrations. A 10% delta risk estimate of DM complications was detectable with a probability of Type I error of 40%, while adoption of a significance level of 95% and consideration to biological variation needed a risk difference of at least 33% to be detected. The critical difference was 11% for changes in either direction at s(analytical) < or = 0.2 HbA1c% and a s(biological) of 0.3 HbA1c%. Based on criteria for sharing common reference intervals and clinical utility, we accepted that the bias and s(analytical) should both be < 0.3 HbA1c% at the level of 7.0 HbA1c%.