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Determining Laboratory Reference Intervals: CLSI Guideline Makes the Task Manageable

DOI: http://dx.doi.org/10.1309/LMEHV3HP39QOFJPA 75-76 First published online: 1 February 2009

Recently, a publication in the American Heart Journal1 stated that the reference interval for creatine kinase (CK), a test commonly performed to monitor statin therapy, could be off by as much as a factor of 3. As a result, many patients are advised, incorrectly, to discontinue their medications, causing their cholesterol levels to return to their original abnormal levels and putting them at increased risk for coronary heart disease.

To be sure that your laboratory’s reference intervals for all tests, including CK, are appropriate for your patient population, refer to Clinical and Laboratory Standards Institute’s (CLSI) newly revised document Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline—Third Edition (C28-A3), published in November 2008. The document provides the laboratory with guidance to define criteria for selecting a healthy reference population, determine how many subjects are needed, identify outliers, and perform the calculations necessary to generate a valid reference interval.

The 1,500 individuals tested for the CK reference range study noted above were of different sexes, ages, and races who met multiple criteria, including not exercising for three days and not taking any medications (specifically, statins). “For most laboratories, including mine, testing to this extent isn’t practical,” said Gary L. Horowitz, MD, member of the CLSI subcommittee that completed the revision of C28-A3.

As a result of the CK study, which followed the reference interval verification protocol exactly as defined in C28-A2, it was determined that the reference intervals recommended by the manufacturer in question were three to five times too low. For example, 60% of normal black males would have been deemed abnormal if the package insert data provided by …

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