CLSI Releases Guidelines for Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory

Market Wire, December, 2008

A measured or observed laboratory test result from a person (usually a patient) is compared with a reference interval for the purpose of making a medical diagnosis, therapeutic management decision, or other physiological assessment. It is important to develop reference intervals using a systematic process that takes into account the various influences on the measured laboratory test results.

Clinical and Laboratory Standards Institute (CLSI) recently published a document, "Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline -- Third Edition" (C28-A3), which offers a protocol for determining reference intervals that meet the minimum requirements for reliability and usefulness.

Gary L. Horowitz, MD, Director of Clinical Chemistry, Beth Israel Deaconess Medical Center, and chairholder of the working group that developed the document, says, "Reference intervals accompany most, if not all, laboratory test results. Physicians rely on the accuracy of those reference intervals to interpret their patients' results. What could be more important than ensuring that the reference intervals themselves are correct?"

The guideline focuses on health-associated reference values as they relate to quantitative clinical laboratory tests. Included are various requirements for studies to determine reference values for a new analyte or a new analytical method of a previously measured analyte. Also discussed is the transfer of established reference values from one laboratory to another.

This document replaces the second approved edition of the guideline, C28-A2, which was published in 2000, and includes the following updates:

--  for some analytes, reference intervals have been replaced by decision
    limits, established by national (or international) consensus;
--  reaffirmation of the recommendation that reference intervals are
    established by collecting samples from a sufficient number of qualified
    reference individuals to yield a minimum of 120 samples for analysis, by
    nonparametric means, for each partition (eg, sex, age range);
--  new emphasis on the ability of every individual laboratory to verify
    reference intervals established elsewhere, a process requiring samples from
    as few as 20 reference individuals; and
--  introduction of recommendations regarding multicenter studies (to make
    it easier to collect large numbers of reference samples) and robust
    statistical methods (to make possible generation of reliable reference
    intervals with fewer than 120 samples).
    

Dr. Horowitz adds, "One of the working group's goals was to make the document practical to the average laboratory. There are concrete, practical examples that help illustrate the concepts. To establish reference intervals, you need to be able to put data in concentration order. To verify reference intervals established elsewhere, you need to establish that no more than 2 of 20 samples from reference individuals are outside the proposed limits."

This document is intended for diagnostic laboratories and diagnostic test manufacturers.

For additional information on CLSI or for further information regarding this release, visit the CLSI website at www.clsi.org or call 610.688.0100.

CLSI, formerly NCCLS, is a global, nonprofit, membership-based organization dedicated to developing standards and guidelines for the health care and medical testing community. CLSI's unique consensus process facilitates the creation of standards and guidelines that are reliable, practical, and achievable for an effective quality system.

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