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Laboratory tests provide valuable information necessary to evaluate a patient’s condition and to monitor recommended treatment. Chemistry and hematology test results are compared with those of healthy individuals or those undergoing similar therapeutic treatment to determine clinical status and progress. In the past, the term normal ranges relayed some ambiguity because statistically the term normal also implied a specific (Gaussian or normal) distribution, and epidemiologically it implied the state of the majority, which is not necessarily the desirable or targeted population. This is most apparent in cholesterol levels, where values greater than 200 mg/dL are common, but not desirable. Use of the term reference range or reference interval is therefore recommended by the International Federation of Clinical Chemistry (IFCC) and the Clinical and Laboratory Standards Institute (CLSI) to indicate that the values relate to a reference population and clinical condition.

Reference ranges are established for a specific age, sex, and sexual maturity; they are also defined for a specific pharmacologic status, dietary restrictions, and stimulation protocol. Similarly, diurnal variation is a factor as is degree of obesity. Some reference ranges are particularly meaningful when combined with other results (eg, parathyroid hormone and calcium) or when an entire set of analytes is evaluated.

Laboratory tests are becoming more specific and measure much lower concentrations than ever before. Therefore, reference ranges should reflect the analytical procedure as well as reagents and instrumentation used for a specific analysis. As test methodology continues to evolve, reference ranges are modified and updated.


The pediatric environment is particularly challenging for the determination of reference intervals since growth and developmental stages do not have a distinct and finite boundary by which test results can be tabulated. Furthermore, adult reference ranges are not always appropriate for pediatric patients. Reference ranges may overlap and, in many cases, complicate diagnosis and treatment. Collection and allocation of test results by age for the purpose of establishing a reference range is a convenient and manageable way to report them, but caution is needed in their interpretation and clinical correlation. Additionally, ethical concerns may exist related to blood draws in infants and young children to establish these reference ranges. Despite these challenges, there have been multicenter studies to improve the reference ranges for laboratory testing in pediatrics.

A particular difficulty lies in establishing reference ranges for analytes whose levels are changed under scheduled stimulation conditions. The common glucose tolerance test is such an example, but more complex endocrinology tests require skill and extensive experience to interpret. Reference ranges for these serial tests are established over a long period of time and are not easily transferable between test methodologies.

Adeli  K: Special issue on laboratory reference intervals. eJIFCC. September 2008.
C28A3: Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory: Approved Guideline...

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