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Clinical Chemistry and Laboratory Medicine (CCLM)

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A plea for intra-laboratory reference limits. Part 2. A bimodal retrospective concept for determining reference limits from intra-laboratory databases demonstrated by catalytic activity concentrations of enzymes

Farhad Arzideh1 / Werner Wosniok2 / Eberhard Gurr3 / Wilhelm Hinsch4 / Gerhard Schumann5 / Nicodemo Weinstock6 / Rainer Haeckel7

1Institut für Statistik, Universität Bremen, Bremen, Germany

2Institut für Statistik, Universität Bremen, Bremen, Germany

3Klinikum Links der Weser, Bremen, Germany

4Reinhard-Nieter-Krankenhaus, Wilhelmshaven, Germany

5Medizinische Hochschule Hannover, Hannover, Germany

6Diagnostic Center Wagner Stibbe, Göttingen, Germany

7Diagnostic Center Wagner Stibbe, Göttingen, Germany

Corresponding author: Prof. Dr. Rainer Haeckel, Diagnostic Center Wagner Stibbe, Werner-von-Siemens Str. 10, 37077 Göttingen, Germany Phone: +49-421-273446,

Citation Information: Clinical Chemical Laboratory Medicine. Volume 45, Issue 8, Pages 1043–1057, ISSN (Online) 14374331, ISSN (Print) 14346621, DOI: 10.1515/CCLM.2007.250, August 2007

Publication History



Background: The current recommendations for establishing intra-laboratory reference limits (RLs) cannot be fulfilled by most laboratories because of the expense involved. In the current study, a bimodal method was developed to derive RLs from data stored in a laboratory information system without any assumption concerning the distribution of the diseased subgroup.

Methods: A smoothed kernel density function (Dmix) was estimated for the distribution of combined data for non-diseased and diseased adult subjects. It was assumed that the “central” part of the distribution represents the non-diseased population, which was defined and used to estimate a Gaussian distribution of either the original values or Box-Cox transformed data. This normal distribution was now considered the distribution of the non-diseased subgroup (Dnd). Percentiles were calculated to obtain retrospective RLs. The density function of the diseased subgroup (Dd) was calculated by subtracting the non-diseased density function from Dmix (Dd=Dmix–Dnd). The intersection point of the Dnd and Dd curves identified the RL with the highest diagnostic efficiency.

Results: The model was applied to catalytic activity concentrations of several enzymes with data from different laboratories. The RLs obtained were similar to recently published consensus values. Differences between laboratories were small but significant. Gender stratification was necessary for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutymaltransferse (γ-GT), not significant for lipase and amylase and inconsistent among the laboratories for alkaline phosphatase (AP) and lactate dehydrogenase (LDH). Age stratification was only tested for two groups (18–49 and ≥50 years) and was significant for AST (females only), γ-GT and lipase, not significant for amylase and inconsistent for AP, LDH and ALT. For γ-GT, further stratification for age in decades was necessary for males. Creatine kinase MB (CK-MB) values were not stratified owing to the low number of data available.

Conclusions: Retrospective RLs derived from intra-laboratory data pools for the catalytic activity concentration of enzymes using a modified procedure plausibly agreed with published consensus values. However, most RLs varied significantly among laboratories, thus supporting the “old” plea for intra-laboratory RLs.

Clin Chem Lab Med 2007;45:1043–57.

Keywords: decision limits; enzyme catalytic activity concentrations; reference limits

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