Use of routine clinical laboratory data to define reference intervals

Ann Clin Biochem 2008;45:467-475
© 2008 Association for Clinical Biochemistry



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Original Articles

Brian Shine

Department of Clinical Biochemistry, John Radcliffe Hospital, Oxford, 0X3 9DU, UK

Corresponding author: Brian Shine. Email: brian.shine{at}

Background: Reference intervals are used to distinguish between healthyand diseased state. Ideally, they are defined using specimensonly from ‘healthy’ individuals, but this is oftendifficult or impossible. In order to use routine clinical laboratorydata, outliers must be removed before the underlying distributionand changes related to age and sex can be modelled. This paperillustrates the process for plasma alkaline phosphatase (ALP).ALP levels are high in infancy and childhood, peak in adolescence,are stable from the early 20s and rise after the fourth decade.Three types of normalizing transformations (Logarithmic, Box-Coxand Cole’s LMS) are compared.

Methods: Single ALP results from 75,328 individuals aged 0–80 yearswere binned by sex and age. The normalizing transformationswere applied to each bin, outliers were removed and the normalizingtransformations were reapplied to the remaining data. The normalityof the transformed data was assessed by normal score plots andthe Kolmogorov-Smirnov test. Fractional polynomials were usedto model the underlying parameters of the transformations andthe derived parametric reference intervals (mean ± 1.96standard deviations), separately for each sex as a whole andpartitioned into two or three age ranges, with overlapping togive smooth transitions.

Results: All transformations yielded acceptably normal data, but theLMS method gave the closest approximation to normal. Outlierrates were similar for each method. The derived reference rangeswere similar for all the three methods. Splitting the data-setinto several segments resulted in a better fit with the peakseen in adolescence.

Conclusion: Routine clinical laboratory specimens can be used to derivereference intervals.

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