Point: Put simply, standardization of cardiac troponin I is complicated.

thyroid-stimulating hormone, and cardiac troponin I (cTnI) is underscored by their routine use in the diagnosis, prognosis, monitoring, and management of disease, and their incorporation into professional guidelines. Standardization is difficult for proteins because there are few reference measurement procedures for these analytes, few primary (pure substance) reference materials (RMs) have been developed, and some of the RMs that are available can be used only for assay calibration with restrictions. In addition, few secondary (matrix-based) RMs with assigned values are available. In fact, the reference measurement system for the majority of clinically relevant proteins fall into the relatively weak Category 4, according to International Organization for Standardization (ISO) document 17511 (1 ). Furthermore, protein reference measurements sometimes appear to belong in a higher category but are in fact subject to analytical artifacts and prone to bias. By the criteria of the recently published “roadmap for harmonization” (2 ), standardization and harmonization of measurement would be regarded as high priority and mission critical for many proteins in laboratory medicine. cTnI is one such protein because its measurement represents the cornerstone for the diagnosis, prognosis, and management of patients with suspected and confirmed acute coronary syndromes (3, 4 ). Standardization is based on the concept of metrological traceability, as described, for instance, in the ISO 17511 document (1 ). According to ISO 17511, standardization-of-measurement results for a substance require the metrological traceability chain outlined in Fig. 1A. This chain begins with a primary reference measurement procedure, which assigns quantity values to a primary RM. Primary RMs are used to assign values to a secondary RM. With this secondary RM (which typically has a matrix equivalent to that of patient samples), a strategy is executed to transfer values to working and product calibrators for the field methods that are designed for routinely quantifying the measurand in patient samples. As illustrated in Fig. 1A, this chain allows values reported for patient care to be traced to a fixed anchor point, i.e., the SI unit. In this way, metrological traceability supports longterm stability and comparability of routine measurement results. Although complicated, standardization has been accomplished successfully for some important heterogeneous proteins. An example is Hb A1c, which is critical for the diagnosis, risk stratification, monitoring, and management of patients in the context of diabetes mellitus (5 ). The effort to standardize Hb A1c assays originated from the work of the National Glycohemoglobin Standardization Program (6 ) and others worldwide directed at harmonizing glycohemoglobin assays. To achieve standardization of Hb A1c measurements, however, required not only a reference measurement procedure but also defining the analyte in a more stringent and clinically meaningful way. Because the hemoglobin protein can react with glucose at multiple molecular locations and the glycohemoglobin measurand is heterogeneous, glycohemoglobin is not intrinsically a well-defined analyte. To pursue standardization of this heterogeneous protein analyte, the IFCC devel1 University of Maryland, Baltimore, MD; 2 National Institute of Standards and Technology, Gaithersburg, MD; 3 European Commission, Joint Research Centre, Institute for Reference Materials and Measurements, Geel, Belgium; 4 Pathology Queensland, Department of Chemical Pathology, Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia. * Address correspondence to this author at: Laboratories of Pathology, University of Maryland School of Medicine, University of Maryland Medical Center, 22 South Greene St., Baltimore, MD 21201. Fax 410-328-5880; e-mail [email protected]. † Members of the IFCC Working Group on Standardization of Troponin I include: Mauro Panteghini, Centre for Metrological Traceability in Laboratory Medicine (CIRME), University of Milan, Milan, Italy; Julian H. Barth, Leeds General Infirmary, Leeds, UK; Aleksei G. Katrukha, HyTest Ltd., Turku, Finland; James E. Noble, National Physical Laboratory, Teddington, Middlesex, UK; Robert A. Porter, National Physical Laboratory, Teddington, Middlesex UK; Lilli Wang, National Institute of Standards and Technology, Gaithersburg, MD. Received July 7, 2011; accepted August 31, 2011. Previously published online at DOI: 10.1373/clinchem.2011.166140 5 Nonstandard abbreviations: Hb A1c, hemoglobin A1c; cTnI, cardiac troponin I; RM, reference material; ISO, International Organization for Standardization; cTnITC, complex of cardiac troponins I, T, and C; cTnIC, complex of cardiac troponins I and C. Clinical Chemistry 58:1 000 – 000 (2012) Point/Counterpoint