Tate JR, Bunk DM, Christenson RH, Barth JH, Katrukha A, Noble JE, Panteghini M, Schimmel H, Wang L, for the IFCC Working Group on Standardization of Cardiac Troponin I (WG-TNI).

Laboratories recognize that due to the lack of standardization, assay-specific decision thresholds are required for the clinical use of cardiac troponin I (cTnI) measurement and these cannot be interchanged between the 24 commercial cTnI assays listed on the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) website. Different assay cutoffs have the potential to confuse physicians leading to misinterpretation of cTnI results; hence the urgency for cTnI standardization.

Several years ago the American Association for Clinical Chemistry (AACC) Troponin I Standardization Subcommittee attempted to standardize cTnI measurements for contemporary assays via use of the troponin Standard Reference Material (SRM) 2921 (1). Due to a lack of commutability in approximately half of the assays on the market at that time, the diluted SRM cTnI material was unsuitable for assay standardization by manufacturers. However, studies showed that serum-based cTnI-positive materials can be used in assay calibration to reduce differences between routine assays (1, 2).

The IFCC Working Group for the Standardization of Cardiac Troponin I (WG-TNI) believes it is possible to standardize cTnI measurement and has evaluated 16 current assays for measurement equivalence and their standardization capability using an initial harmonization approach. At the same time serum pools prepared in various ways from cTnI-positive patient sera were tested for harmonization.

Results of the pilot study showed about a 10-fold difference in cTnI concentrations among assays and that this is largely due to differences in calibration. When these calibration differences were removed by a mathematical recalculation (using regression slope and y-intercept values), the inter-assay variation is typical of External Quality Assessment Scheme results of methods measuring more common analytes. The ability to mathematically recalibrate assays is an indication that the assays are measuring the same analyte despite the diversity of cTnI antibodies in use and the inherent structural variability of the cTnI analyte.

While the 16 assays demonstrated negligible bias after realignment, some samples were still discordant between methods post recalibration and gave large positive or negative biases (> 50%) that contributed to larger inter-assay variability than for the serum pools. The sample-dependent effect appeared to be largely related to antibody configuration and was not observed for pools.

The WG-TNI concluded from the study results that it seems feasible that the observed 10-fold difference between cTnI assays can be markedly reduced by the availability of a cTnI-positive serum pool as a reference material (RM). The pools must be shown to be commutable with patient samples and preliminary evaluation by pair-wise regression analysis suggests the pools are commutable in most assays.

Regarding value assignment of an RM, options are either via a protocol transferring trueness from SRM 2921 using only those commercial assays for which commutable calibrants of SRM 2921 can be produced, or else via an empirical harmonization approach which uses a mathematical recalibration of assays.

The National Institute of Standards and Technology (NIST) in the US will produce the RM and it is anticipated a certified SRM for cTnI will be available to manufacturers within 2 years.

References

  1. Christenson RH, Duh SH, Apple FS, Bodor GS, Bunk DM, Dalluge J, et al. Standardization of cardiac troponin I assays: round robin of ten candidate reference materials. Clin Chem 2001;47:471-7.
  2. Tate JR, Heathcote D, Koerbin G, Thean G, Andriske D, Bonar J, et al. The harmonization of cardiac troponin I measurement is independent of sample time collection but is dependent on the source of calibrator. Clin Chim Acta 2002;324:13-23.

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