Abstract

Reference intervals are recommended for naturally occurring quantities and required in the evaluation of new components in order to provide clinically useful information.

The aim of the present study is to present a method for selecting reference individuals for the determination of fasting venous plasma glucose (f-vPG) reference intervals and ways to determine if disease groups can share reference intervals with an ideal reference population.

Reference subjects were randomly selected, eligibility was judged according to predetermined inclusion and exclusion criteria. Using the literature we selected risk indicators for diabetes mellitus (DM) and used these indicators to rule out high-risk individuals in order to obtain a reference distribution of f-vPG determined using individuals with low risk of DM. The distributions of f-vPG in the high-risk individuals was compared with that determined for the low-risk group. We then estimated the ability of the high-risk individuals to share the reference interval of the low risk individuals, and calculated the fraction that was outside this interval. Distributions were also investigated for linearity in the cumulated frequency rankit distribution of ln-values. The allowable difference between two reference limits could not exceed 0.375 times the population biological variation.

Most risk indicators were powerful predictors of high f-vPG values. Subgroups with these risk indicators should not be included in the homogeneous ln-normally distributed reference distribution. Distributions of f-vPG concentrations in individuals with risk factors were not homogeneous and varying percentages of individuals were outside the reference distribution, having f-vPG greater than 7.0 mmol/l.

We conclude that randomisation is only useful to recruit candidate reference subjects. To rule out subjects according to clinical risk factors for diabetes, it is necessary to identify a reference population with low risk of exhibiting increased f-vPG concentrations. This method may be used to validate a reference interval for a particular analyte with respect to an investigated disease, and to stratify risk factors of importance.