Mauro Panteghini

Multicenter analytical evaluation of a high-sensitivity troponin T assay.

BACKGROUND High-sensitivity cardiac troponin assays are being introduced clinically for earlier diagnosis of acute myocardial infarction (AMI). We evaluated the analytical performance of a high-sensitivity cardiac troponin T assay (hscTnT, Roche Diagnostics) in a multicenter, international trial. METHODS Three US and 5 European sites evaluated hscTnT on the Modular® Analytics E170, cobas® 6000, Elecsys 2010, and cobas® e 411. Precision, accuracy, reportable range, an inter-laboratory comparison trial, and the 99th percentile of a reference population were assessed. RESULTS Total imprecision (CVs) were 4.6-36.8% between 3.4 and 10.3 ng/L hscTnT. Assay linearity was up to 10,000 ng/L and the limit of blank and detection were 3 and 5 ng/L, respectively. The 99th percentile reference limit was 14.2 ng/L (n=533). No significant differences between specimen types, assay incubation time, or reagent lots existed. A substantial positive bias (76%) exists between the 4th generation and hscTnT assays at the low end of the measuring range (<50 ng/L). hscTnT serum pool concentrations were within 2SD limits of the mean of means in the comparison trial, indicating comparable results across multiple platforms and laboratories. CONCLUSION The Roche hscTnT assay conforms to guideline precision requirements and will likely identify additional patients with myocardial injury suspicious for AMI.

Quality Specifications for Cardiac Troponin Assays

Abstract The objective of this report is to help to improve the quality of immunochemical determinations of cardiac troponins. The guidelines are intended for use by the manufacturers of commercial assays and by clinical laboratories performing troponin analyses. The main goals of the document are that: 1. Manufacturers endorse, or at the minimum, address the enclosed recommendations. 2. All package inserts for troponin immunoassay procedures include information on method design, and on pre-analytical and analytical performance characteristics as outlined in this document. 3. Manufacturers and the scientific community select and design research projects that further the knowledge and the definition of the issues addressed in this document.

Defining analytical performance specifications: Consensus Statement from the 1st Strategic Conference of the European Federation of Clinical Chemistry and Laboratory Medicine.

*Corresponding author: Sverre Sandberg, Norwegian Quality Improvement of Primary Care Laboratories (Noklus), Institute of Global Public Health and Primary Health Care, University of Bergen and Laboratory of Clinical Biochemistry, Bergen, Norway, E-mail: sverre.sandberg@isf.uib.no Callum G. Fraser: Centre for Research into Cancer Prevention and Screening, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK Andrea Rita Horvath: SEALS Department of Clinical Chemistry, Prince of Wales Hospital, Screening and Test Evaluation Program, School of Public Health, University of Sydney, and School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia Rob Jansen: Netherlands Foundation for Quality Assessment of Medical Laboratories (SKML), Radboud University, Nijmegen, The Netherlands Graham Jones: SydPath, St Vincent’s Hospital, Sydney, NSW, Australia Wytze Oosterhuis: Atrium-Orbis, Department of Clinical Chemistry and Haematology, Heerlen, The Netherlands Per Hyltoft Petersen: Norwegian Quality Improvement of Primary Care Laboratories (Noklus), Institute of Global Public Health and Primary Health Care, University of Bergen, Norway Heinz Schimmel: European Commission, Joint Research Centre, Institute for Reference Materials and Measurements (IRMM), Geel, Belgium Ken Sikaris: Sonic Healthcare and Melbourne University, Melbourne, Vic, Australia Mauro Panteghini: Centre for Metrological Traceability in Laboratory Medicine (CIRME), University of Milan, Milan, Italy Consensus Statement

Biochemical markers for prediction of chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use.

Chemotherapy is a well-established therapeutic approach for several malignancies, but its clinical efficacy is often limited by its related cardiotoxicity, which leads to cardiomyopathy, possibly evolving into heart failure. To detect cardiac damage, the adopted diagnostic approach is the estimation of left ventricular ejection fraction by echocardiography. This approach shows low sensitivity toward early prediction of cardiomyopathy, when the possibilities of appropriate treatments could still improve the patients outcome. Cardiac troponins, however, show high diagnostic efficacy as early as 3 months before the clinical onset of cardiomyopathy. The increase in their concentrations is correlated with disease severity and may predict the new onset of major cardiac events during follow-up. Negative troponin concentrations may identify patients with a very low risk of cardiomyopathy (negative predictive value, 99%). Concerning cardiac natriuretic peptides, definitive evidence in regard to a diagnostic or prognostic role in predicting chemotherapy-induced cardiomyopathy is still lacking.

IFCC primary Reference Procedures for the Measurement of Catalytic Activity Concentrations of enzymes at 37 °C. Part 3. Reference procedure for the measurement of catalytic concentration of lactate dehydrogenase

Abstract This paper is the second in a series dealing with reference procedures for the measurement of catalytic activity concentrations of enzymes at 37°C and the certification of reference preparations. Other parts deal with: Part 1. The Concept of Reference Procedures for the Measurement of Catalytic Activity Concentrations of Enzymes; Part 3. Reference Procedure for the Measurement of Catalytic Concentration of Lactate Dehydrogenase; Part 4. Reference Procedure for the Measurement of Catalytic Concentration of Alanine Aminotransferase; Part 5. Reference Procedure for the Measurement of Catalytic Concentration of Aspartate Aminotransferase; Part 6. Reference Procedure for the Measurement of Catalytic Concentration of γ-Glutamyltransferase; Part 7. Certification of Four Reference Materials for the Determination of Enzymatic Activity of γ-Glutamyltransferase, Lactate Dehydrogenase, Alanine Aminotransferase and Creatine Kinase at 37°C. A document describing the determination of preliminary reference values is also in preparation. The procedure described here is deduced from the previously described 30°C IFCC reference method (1). Differences are tabulated and commented on in Appendix 3.

Use of Biochemical Markers in Acute Coronary Syndromes. IFCC Scientific Division, Committee on Standardization of Markers of Cardiac Damage

Abstract This paper presents evidence and suggestions from the IFCC Committee on “Standardization of Markers of Cardiac Damage” (C-SMCD) on the use of biochemical markers for the triage diagnosis of acute coronary syndromes. There is general agreement that both ‘early’ and ‘definitive’ biochemical markers of myocardial damage are necessary and that these assays must be available with a turnaround time of 1 h or less. Currently, myoglobin is the marker that most effectively fits the role as an ‘early’ marker, whereas ‘definitive’ markers are cardiac troponins. Since the sensitivity of the initial electrocardiogram is only 50 % for detecting myocardial infarction, the use of biochemical markers may significantly contribute to the early diagnosis and become relevant when the electrocardiogram is not diagnostic. In addition, new sensitive biochemical markers, particularly the cardiac troponins, are presently the best to detect the presence of minor myocardial cell damage. With regard to this, two decision limits are probably needed for the optimal use of troponins: a low abnormal value suggesting the presence of myocardial damage and a higher value suggesting the diagnosis of myocardial infarction according to traditionally used criteria. Properly designed studies should be performed to establish limits for each commercially available troponin assay. Finally, it is recognized that there is no need for the use of any biochemical marker when the clinical diagnosis is unequivocal, other than for diagnosing reinfarction, estimating the infarct size, and monitoring thrombolytic therapy.

IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 degrees C. International Federation of Clinical Chemistry and Laboratory Medicine. Part 5. Reference procedure for the measurement of catalytic concentration of aspartate aminotransferase.

Abstract This paper is the fourth in a series dealing with reference procedures for the measurement of catalytic activity concentrations of enzymes at 37°C and the certification of reference preparations. Other parts deal with: Part 1. The Concept of Reference Procedures for the Measurement of Catalytic Activity Concentrations of Enzymes; Part 2. Reference Procedure for the Measurement of Catalytic Concentration of Creatine Kinase; Part 3. Reference Procedure for the Measurement of Catalytic Concentration of Lactate Dehydrogenase; Part 5. Reference Procedure for the Measurement of Catalytic Concentration of Aspartate Aminotransferase; Part 6. Reference Procedure for the Measurement of Catalytic Concentration of γ-Glutamyltransferase; Part 7. Certification of Four Reference Materials for the Determination of Enzymatic Activity of γ-Glutamyltransferase, Lactate Dehydrogenase, Alanine Aminotransferase and Creatine Kinase at 37°C. A document describing the determination of preliminary upper reference limits is also in preparation. The procedure described here is deduced from the previously described 30°C IFCC reference method (1). Differences are tabulated and commented on in Appendix 2.

Cardiac troponin elevations in chronic renal failure: prevalence and clinical significance.

OBJECTIVES The aim of the study was investigate the prevalence of abnormal values of cardiac troponin T (cTnT) and cardiac troponin I (cTnI) in patients with chronic renal failure (CRF) and their clinical significance. DESIGN AND METHODS We investigated the concentrations of cTnT and cTnI in 49 CRF patients without heart disease or diabetes. Cardiac TnT values were measured with a second generation immunoassay and cTnI with two immunoassays with different analytical sensitivity. All CRF patients underwent regular clinical follow-up over a 18-month period. RESULTS No patients with CRF had elevated values of cTnI when measured with one assay and only 2 patients displayed minimally elevated values with the second assay. In contrast, 23 CRF patients (47%) displayed cTnT concentrations elevated above the upper reference limit. The elevated cTnT values observed were below the values detected in acute myocardial infarction and were not associated with adverse cardiac events during follow-up. CONCLUSIONS Mildly elevated cTnT concentrations are common in patients with CRF and do not appear to be associated with adverse coronary events.

Reference intervals: the way forward

New facts have recently enhanced interest in the topic of reference intervals. In particular, the International Organization for Standardization standard 15189, requesting that ‘biological reference intervals shall be periodically reviewed’, and the directive of the European Union on in vitro diagnostic medical devices asking manufacturers to provide detailed information on reference intervals, have renewed interest in the subject. This review presents an update on the topic, discussing the theoretical aspects and the most critical issues. The basic approach to the definition of reference intervals proposed in the original International Federation of Clinical Chemistry documents still remain valid. The use of data mining to obtain reference data from existing databases has severe limitations. New statistical approaches to discard outliers and to compute reference limits have been recommended. On the other hand, perspectives opened by the improvement in standardization through the implementation of the concept of traceability suggest new models to define ‘common’ reference intervals that can be transferred and adopted by different clinical laboratories in order to decrease the proliferation of different reference intervals not always justified by differences in population characteristics or in analytical methodology.

National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: Analytical Issues for Biomarkers of Heart Failure

### A. Background In 2005, the IFCC C-SMCD recommended analytical and pre-analytical quality specifications for natriuretic peptide and their related co-metabolites assays.1 The objectives developed were intended to guide manufacturers of commercial assays and clinical laboratories that utilize these assays. The overall goal was to establish uniform criteria so that the analytical qualities and clinical performance of assays natriuretic peptide and their related co-metabolites could be evaluated objectively. As B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) become more heavily integrated into clinical practice as diagnostic and prognostic biomarkers, understanding the differences between individual assays becomes important. Further, the influence of clinical, analytical and preanalytical factors on the growing number of BNP and NT-proBNP assays commercially available begs for a better understanding of how to interpret findings of different studies predicated on BNP or NT-proBNP concentrations monitored by different assays. The Laboratory Medicine community must also work closely with the in vitro diagnostics companies to assist in defining all of the assay characteristics,1 a process that was poorly orchestrated during the developmental phase of cardiac troponin assays. When BNP or NT-proBNP assays are used as biomarkers for diagnosis, therapy decisions, and prognosis, or used in clinical trials or studies, they should be well characterized, as suggested by the list of recommendations that follow. We recommend that when designing studies that will use BNP or NT-proBNP assays, investigators …