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Variability of Lipoprotein-Associated Phospholipase A2 Measurements

Department of Laboratory Medicine and Pathology and Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN

^aAddress correspondence to this author at: Department of Laboratory Medicine and Pathology Mayo Clinic Hilton 310-A 200 First ST SW Rochester, MN 55905 Fax (507) 266-2888 e-mail mcconnell.joseph{at}mayo.edu

To the Editor:

We read with interest the recent report in this journal by Khuseyinova and colleagues regarding the variability of serial lipoprotein-associated phospholipase A2 (Lp-PLA2) measurements in postmyocardial infarction patients(1). Because Lp-PLA2 plays a role in inflammation but, unlike other inflammatory proteins, is not an acute-phase reactant(2), nonspecificity issues associated with acute-phase reactants may be averted. Indeed, recent reviews verify that several epidemiologic studies have demonstrated a strong association between Lp-PLA2 and ischemic events(2)(3)(4). Thus, as indicated by Khuseyinova and colleagues, Lp-PLA2 appears to be a promising emerging biomarker for coronary heart disease and stroke. We applaud the effort of this group to evaluate the performance of Lp-PLA2 measurements.

With all assay development, multiple iterations of assays are often developed before a given analyte is ready to be measured on a widespread basis, and Lp-PLA2 is a good example. It is important to keep these multiple iterations separate because they tend to differ. We too have had consistent results with the second-generation assay, the one reported by Khuseyinova and colleagues. This second-generation assay is no longer commercially available, however, and a third-generation assay has replaced it. We have completed extensive evaluations of both the second- and third-generation assay methods for Lp-PLA2. In our hands, the third-generation assay behaved quite differently from the second, with much greater variability and lot-to-lot variation, and values that were very different from those obtained with the second-generation assay for some patient samples. A comparison of the 2 iterations in 476 patient samples yielded the following correlation data [3^rdGen = (0.557 x 2^rdGen) + 67.0; R² = 0.712]. As a result of analytic problems and our inability to get the third generation assay to perform to reasonable specifications, we delayed and actually stopped reporting values obtained with the third-generation assay. In particular, results obtained while performing the assay in a manual format did not match values obtained using a Triturus® automated immunoassay analyzer. Thus, both the method and instrumentation used to perform the method should be considered during method validation. Although these issues were ultimately resolved and we did institute the third-generation assay in a manual format, we still monitor this assay very carefully and go through several steps to verify the performance of each new lot of reagents.

A fourth-generation assay has recently been cleared by the FDA for use and we have evaluated it in our laboratory. This automated method is more user friendly and has performance characteristics more similar to and perhaps even better than those of the second-generation assay. We found the automated method to be linear down to 30 µg/L (y = 1.052x + 9.6, R² = 0.998). Interassay CVs ranged from 6.6% to 10.4% for 6 samples over the concentration range of 94–441 µg/L (n = 11 replicates per sample). Discrepancies were observed when we compared the automated and third-generation assays [automated = (1.20 x 3^rdGen) + 3.4; R² = 0.4808; n = 65], further demonstrating differences that may be observed from one iteration to the next. We are optimistic about the long-term success of the automated method, but areas of fine tuning are needed before it is ready for wider dissemination. The important conclusion to draw from this situation is that from the research and the clinical perspectives, care must be exercised in documenting what iteration of a given assay is being used, especially when comparing values over time. We do include a comment about this concern in all of our reports.

Acknowledgments

Grant/Funding Support: JPM has received research grant funds from diaDexus in the past.

Financial Disclosures: ASJ is or has been a consultant for most of the major diagnostic companies.

Acknowlegments: We acknowledge Shannon D. Hodel-Hanson, Stacy J. Hartman, and Jennie N. Ward for their work in validation of the diaDexus Lp-PLA2 methods.

References

1. Khuseyinova N, Greven S, Rückerl R, Trischler G, Loewel H, Peters A, Koenig W. Variability of serial lipoprotein-associated phospholipase A2 measurements in post-myocardial infarction patients: results form the AIRGENE Study Center Augsburg. Clin Chem 2008;54:124-130.[Abstract/Free Full Text]
2. McConnell JP, Hoefner DM. Lipoprotein-associated phospholipase A(2). Clin Lab Med 2006;26:679-697.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Caslake MJ, Packard CJ. Lipoprotein-associated phospholipase A2 as a biomarker for coronary disease and stroke. Nat Clin Pract Cardiovasc Med 2005;2:529-535.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. Carlquist JF, Muhlestein JB, Anderson JL. Lipoprotein-associated phospholipase A2: a new biomarker for cardiovascular risk assessment and potential therapeutic target. Expert Rev Mol Diagn 2007;7:511-517.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

The following articles in journals at HighWire Press have cited this article:

				J. P. McConnell and A. S. Jaffe The Spin Stops Here: Inhibition of Lipoprotein-Associated Phospholipase A2-- A Promising Target but a Negative Initial Trial? Clin. Chem., January 1, 2009; 55(1): 21 - 23. [Full Text] [PDF]

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