Quality Requirements and Standards

In 2009, US laboratories were reporting surges in the number of vitamin D tests being ordered - increases of 50% to even 100%. But beyond the growth in testing and usage, what's the quality required by this type of testing?

Everyone in the US laboratory community has noted the explosive growth in Vitamin D testing. In July 2009, Clinical Laboratory News reported that a survey of labs where "[m]ore than 50% of respondents indicated that the volume of 25-hydroxyvitamin D (25-OH-D) testing in their labs had increased by at least 50% in the past year, with 27% indicating that volume had gone up by more than 100%."[1]

Vitamin D is not new to the testing world, but in previous times, it was thought the only utility for vitamin D testing was in prevention of rickets and osteomalacia. The modern era has brought increased interest in the appropriate levels of vitamin D in the population - in parallel with many studies that reveal its role in bone health, diabetes, autoimmune diseases, immune regulation, infections, cancer and cardiovascular disease [2]

But what hasn't been asked very often is, How good are vitamin D assays? Given all the new uses for the test, are the methods performing to the needed quality? Indeed what quality is required by a vitamin D test?

Thankfully, Stockl, Sluss, and Thienpont have examined those issues  in their recent paper:

Dietmar Stockl, Patrick M. Sluss, Linda M. Thienpont, Specifications for trueness and precision of a reference measurement system for serum/plasma 25-hydroxyvitamin D analysis. Clinical Chimica Acta, 408 (2009): 8-13.[3]

In this paper, they apply four different approaches for setting quality specifications for a S/P-25(OH)D test, following the guidance from the 1999 Stockholm consensus conference on quality specifications. [4]

"1)We analyzed the impact of bias and analytical imprecision on interpretation of clinical results, more in particular for diagnosis of vitamin D deficiency or insufficiency based on test value decision points, 2) we used the model that relates analytical performance to the intra- and inter-individual biological variation of S/P-25 (OH)D, 3) we considered performance goals set by expert opinion for a widely used proficiency testing program, and 4) we evaluated the literature on currently used measurement procedures for S/P-25(OH)D analysis [e.g. immunoassay, HPLC, and liquid chromatography (LC)/tandem mass spectrometry] with documented trueness/recovery and precision."[3]

This is a remarkable paper, not only for the rigorous approach but for the multiple methods used to find an answer. Not only did they calculate the quality required by reference measurement procedures (the stated goal of the paper), but they also calculated the quality required by routine laboratory measurement performance, and the quality required by certified reference materials. We believe this study creates a useful template for future papers on quality requirements - for any analyte.

Without giving too much away, the results are dramatic. It turns out that "where you stand depends on where you sit" - each model produces very different recommendations. The biggest difference is between the expert opinion model and the biologic variation model. The quality requirement for routine method performance by the expert opinions is more than 5 times as high as the requirement calculated from known biologic variation (22% CV vs 4% CV, respectively).

More striking still is the survey of the "state of the art". Stockl et al looked at 14 different studies of methods - and only one method was close to achieving the performance required by the most stringent model  (the performance required based on knowledge of within-subject biologic variation: 4% CV and 2.6% Bias).

Ultimately, Stockl et al recommended using a slightly less strict biologic variation approach (called the Gowan model), which works out to recommendations of CV < 10% and Bias < 5% for routine testing and  CV < 5% and Bias < 1.7% for reference measurements.  The requirements are challenging, but Stock et al believe the laboratory community is up to the challenge:

"Naturally, it will be a challenge for metrological institutes and reference laboratories to demonstrate their capability not only to comply with the specifications, but also to offer that quality on a continuous basis. Networking of reference laboratories will be an adequate approach to this."[3]

The entire paper is worth a serious read.

References

1. Genna Rollins, Vitamin D Testing—What’s the Right Answer? Labs Grapple with Confusing Analytics, Evidence, Clinical Laboratory News,
   http://www.aacc.org/publications/cln/2009/july/Pages/CovStory1July09.aspx Last Accessed November 17, 2009.
2. Etienne Cavalier, Pierre Delanaye, Jean-Paul Chapelle, and Jean-Claude Souberbielle, Vitamin D: current status and perspectives, Clin Chem Lab Med 2009:47(2):120-127.
3. Dietmar Stockl, Patrick M. Sluss, Linda M. Thienpont, Specifications for trueness and precision of a reference measurement system for serum/plasma 25-hydroxyvitamin D analysis. Clinical Chimica Acta, 408 (2009): 8-13.
4. PH Petersen, CG Fraser, A Kallner, D Kenney, eds., Strategies to Set Global Analytical Quality Specifications in Laboratory Medicine.  Scand J Clin Lab Invest  1999;59:475-585.