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Multicenter Study
. 2013 Feb;56(3):367-73.
doi: 10.1093/cid/cis900. Epub 2012 Oct 24.

An international multicenter performance analysis of cytomegalovirus load tests

Hans H Hirsch  1 , Irmeli Lautenschlager, Benjamin A Pinsky, Laura Cardeñoso, Shagufta Aslam, Bryan Cobb, Regis A Vilchez, Alexandra Valsamakis
Affiliations
Multicenter Study

An international multicenter performance analysis of cytomegalovirus load tests

Hans H Hirsch et al. Clin Infect Dis. 2013 Feb.

Abstract

Background: Quantification of cytomegalovirus (CMV) load is central to the management of CMV infections in immunocompromised patients, but quantitative results currently differ significantly across methods and laboratories.

Methods: The COBAS AmpliPrep/COBAS TaqMan CMV Test (CAP/CTM CMV test), developed using the first World Health Organization CMV standard in the calibration process, was compared to local assays used by 5 laboratories at transplant centers in the United States and Europe. Blinded plasma panels (n = 90) spiked with 2.18-6.7 log(10) copies/mL and clinical plasma samples from immunocompromised patients (n = 660) were tested.

Results: Observed mean panel member concentrations by site and 95% confidence intervals (CIs) of the data combined across sites were narrower for CAP/CTM CMV test compared with local assays. The 95% CI in log(10) copies/mL of the combined data per panel member for CAP/CTM CMV test vs comparator assays was .17 vs 1.5 at 2.18 log(10) copies/mL; .14 vs .52 at 2.74 log(10) copies/mL; .16 vs .6 at 3.3 log(10) copies/mL; .2 vs 1.11 at 4.3 log(10) copies/mL; .21 vs 1.13 at 4.7 log(10) copies/mL; and .18 vs 1.4 at 6.7 log(10) copies/mL. In clinical specimens, constant and variable quantification differences between the CAP/CTM CMV test and comparator assays were observed.

Conclusions: High interlaboratory agreement and precision of CAP/CTM CMV test results across 5 different laboratories over 4 orders of magnitude suggest that this assay could be valuable in prospective studies identifying clinical viral load thresholds for CMV treatment.

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Figures

Figure 1.
Figure 1.
Comparability of quantitative data across laboratory sites. A dilution series of cytomegalovirus (CMV) AD-169 was prepared using cytomegalovirus-seronegative plasma. Geometric means of tested replicates are plotted. Numerical ranges indicate 95% confidence intervals of the means of each panel member at each site. A, COBAS AmpliPrep/COBAS TaqMan CMV data. Dashed line indicates assay lower limit of quantification. B, Data from 5 comparator polymerase chain reaction assays. Abbreviations: CAP/CTM CMV, COBAS AmpliPrep/COBAS TaqMan CMV Test; CMV, cytomegalovirus.
Figure 2.
Figure 2.
Reproducibility of quantitative data across laboratory sites. Standard deviations of replicates from cytomegalovirus (CMV) AD-169 dilution series are plotted. A, COBAS AmpliPrep/COBAS TaqMan CMV Test precision by study site. Quantifiable replicates at 2.18log10 copies/mL: site 2, n = 2; site 3, n = 0; site 4, n = 6; site 5, n = 1; site 6, n = 4. Standard deviations at 2.18log10 copies/mL were not calculated for sites 3 and 5. At 2.74log10 copies/mL, all replicates were quantifiable at all sites except site 6 (11/15 quantifiable). B, Precision for the 5 comparator polymerase chain reaction assays. Replicates of each panel member tested at site 2, n = 12; at sites 3–6, n = 15. Quantifiable replicates at 2.18log10 copies/mL: site 2, n = 2; site 3, n = 15; site 4, n = 11; site 5, n = 0; site 6, n = 10. Standard deviation at 2.18log10 copies/mL was not calculated for site 3. At 2.74log10 copies/mL, all replicates were quantifiable at all sites except site 4 (0/15 quantifiable) and site 5 (9/15 quantifiable). Abbreviation: CAP/CTM CMV, COBAS AmpliPrep/COBAS TaqMan CMV Test.
Figure 3.
Figure 3.
Agreement in cytomegalovirus (CMV) DNA load measurement between the COBAS AmpliPrep/COBAS TaqMan CMV Test (CAP/CTM CMV) and 5 comparator polymerase chain reaction (PCR) assays in plasma samples from immunocompromised individuals. Left-hand panels, agreement plots with Deming regression lines; dashed line indicates 100% agreement level. Right-hand panels, Bland-Altman plots (difference in quantification between the CAP/CTM CMV test and comparator PCR assays vs mean of the 2 measurements). Solid line, least squares regression; dashed lines, mean differences of +0.5/0/−0.5 log10 copies/mL. Abbreviation: CAP/CTM CMV, COBAS AmpliPrep/COBAS TaqMan CMV Test.
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