Validate, Transfer or Establish: What Are You Doing with Your Reference Intervals?

Reference intervals are absolutely necessary for proper interpretation of laboratory tests, and yet obtaining appropriate reference intervals can be the bane of the laboratory. I mentioned establishing, validating or transferring reference intervals in an earlier blog post, but didn’t talk about exactly what these are and when to use which one.

Establishing a reference interval is exactly what it says. A reference interval must be established if a new assay has never been performed in the lab and there is no current reference interval to start with. Most often, laboratory developed tests (LDTs) that are developed from scratch will require the establishment of a reference interval. To do this, ideally 120 samples from healthy individuals for each sub-population (gender or age sub-group) is used, although there are methods available using smaller sample sizes. Samples used to establish reference intervals may be collected a priori, meaning they are collected from individuals for the express purpose of establishing a reference interval, with well-defined inclusion or exclusion criteria used, or a posteriori, meaning they are samples collected and analyzed first, with exclusion criteria applied after statistical analysis.

Validating a reference interval is the easiest way to obtain one, and is what is hoped for when a new method is introduced. Validation is usually used when a new instrument or method replaces an old one, and reference intervals are currently in place. A patient correlation study is done using at least 20 patients. The data is analyzed with regression, bias and correlation statistics. If the bias and regression are acceptable, the reference interval that is currently in place will also work with the new assay. The interval has been validated and can be used with the new method.

When a validation study is done for a new method and the results of the data analysis are NOT acceptable to validate the assay, then a transference study is necessary. A transference study is simply an extended correlation. More than 20 patients are used, enough to determine the amount of bias between the two methods. Then the old reference interval is adapted to fit the new method, using the amount of bias determined. For example if the new method measures 15 percent higher than the old method, the reference intervals will be increased 15 percent across the board. Transference is recommended to be performed once. If another new method is brought in for that analyte, rather than transfer the reference interval again, a new interval should be established.

All three of these methods for obtaining reference intervals are useful in the right situations. It is important to know when to use which method.

 

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-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

2 thoughts on “Validate, Transfer or Establish: What Are You Doing with Your Reference Intervals?”

  1. I’m not aware of an online link to read more about this topic. Two source of additional information are: Contemporary Practice in Clinical Chemistry, Chapter 3: Reference Intrervals. by Dr Endres, published in 2011 by AACC Press and also the Clinical and Laboratory Standards Institute (CLSI) document: Defining, establishing and verifying reference intervals in the clinical laboratory. Approved Guideline, 3rd ed. CLSI document EP28-A3c.

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