Evaluation of systematic and random factors in measurements of fasting plasma glucose as the basis for analytical quality specifications in the diagnosis of diabetes. 3. Impact of the new WHO and ADA recommendations on diagnosis of diabetes mellitus

On behalf of the Danish Society of Clinical Endocrinology and the Danish So ciety of Clinical Chemistry we were commissioned to evaluate the influence of analytical and pre-analytical systematic and random factors on the diagn osis of diabetes, in order to provide a tool for conclusions on the analyti cal quality specifications needed to diagnose diabetes. A systems analysis was performed in accordance with the principles for evaluation of analytica l quality specifications. The clinical setting was defined-diagnosis of dia betes in accordance with the WHO and ADA criteria with determination of fas ting plasma glucose concentration (FPG) greater than or equal to7.0 mmol/L in two independent samples-with well-documented data on 1n (log(e))-Gaussia n distribution of reference values from a low-risk population and values fo r within-subject biological variation taken from the literature. An investi gation was made of the consequences for the clinical setting of assumed err ors related to the measurement of FPG. Four approaches were investigated fo r a single sampling and measurement and also for two independent samples: o ne showing the percentage of healthy individuals who had values greater tha n or equal to7.0 mmol/L, one illustrating the origin of biological set-poin ts for results greater than or equal to7.0 mmol/L, one showing the risk of being measured greater than or equal to7.0 mmol/L when the biological set-p oint is known, and one showing the combined bias and imprecision for assume d percentages of false-positive (FP), defined as measurements greater than or equal to7.0 mmol/L for the low-risk population and false-negative (FN), defined as measurements <6.4 mmol/L (the upper reference limit) for diabeti cs. This leaves a "grey zone" which includes the upper part of low-risk ind ividuals, and defined by ADA and WHO as "impaired fasting glucose" (IFG). I n the analysis, increasing systematic and random errors (combined analytica l and pre-analytical) were assumed, and for each error condition the fracti ons of FP and FN were calculated. This gave plots from which the combined a llowable systematic and random errors could be read off for pre-determined clinically acceptable fractions of FP and FN. The analysis does not disting uish between pre-analytical and analytical errors, as specified information on one of these is needed for specification of the other. The investigatio n provides a reliable basis for estimation of the needed analytical quality , and thereby for decisions about analytical quality specifications for ana lysis of FPG in relation to diagnosis of diabetes under optimized pre-analy tical and analytical conditions. Consequences of deviations from these idea l conditions are illustrated in the figures, and should be considered for t he different approaches with different performance conditions.