Traceability In Laboratory Medicine Research Articles

Measurement traceability and US IVD manufacturers: the impact of metrology

A goal of clinical laboratory science is to produce accurate and comparable patient test results for a specimen independent of analytical methodology. The In Vitro Diagnostics Directive in Europe has provided the impetus for the U.S. in vitro diagnostic (IVD) industry to adapt the concepts of Metrology, the science of measurement, including measurement traceability and measurement uncertainty. The joint committee for traceability in laboratory medicine has provided a valuable database of internationally recognized reference materials and methods and reference laboratories. Much of the responsibility for measurement traceability falls on IVD manufacturers, but all global stakeholders, including the clinical laboratory profession, government Regulatory bodies, metrology institutes, and the providers of EQA/PT surveys, must cooperate to progress toward this goal. The adaptation of the concepts of Metrology to the clinical laboratory is an appropriate and logical development and it will continue in the twenty-first century.

Assay Configuration and Analytic Specificity May Have Major Effects on Prediction of Clinical Outcomes— Implications for Reference Standards

In this month’s issue of Clinical Chemistry , Anborgh et al. demonstrate that differences in assay configuration can produce major differences in the association of plasma osteopontin measurements with survival in prostate cancer (1). Prediction of survival was found to be significantly better with assays that have a monoclonal antibody targeted to a specific epitope on the osteopontin molecule. This linkage between assay configuration and clinical utility may have major implications on the way reference materials and reference methods are formulated, because, as this report shows, the reference standards may need to focus on specific forms of the analyte. Various national and international organizations are working to develop reference standards to help harmonize diagnostic assays. The European Union In Vitro Diagnostics Directive (98/79/EC) requires manufacturers marketing in the European Union to provide evidence that the values assigned to calibrators and control materials are traceable, through available reference measurement procedures and reference materials (when available), to standards of a higher metrological order (2)(3). The Joint Committee on Traceability in Laboratory Medicine (JCTLM)1 has helped guide the logistics of traceability with the use of European Committee for Standardization (CEN) and International Organization for Standardization (ISO) standards (4). ISO document 17511 distinguishes 2 broad categories of measurands: type A analytes, which are traceable to International System (SI) units, and type …

Implementation of the concept of traceability in laboratory medicine in external quality assessment

Implementation of the concept of traceability in laboratory medicine in external quality assessment

Traceability as a unique tool to improve standardization in laboratory medicine

The standardization of measurements is of high priority in Laboratory Medicine, its purpose being to achieve closer comparability of results obtained using routine analytical systems. In order to achieve standardization, an approach is required that provides reliable transfer of the measurement values from the highest hierarchical level to methods which are routinely used in the clinical laboratories. Such a structure is presented by the reference measurement system (RS), based on the concepts of metrological traceability. Key elements of a comprehensive RS are the reference measurement procedure and reference materials. Other essential elements include the definition of the measurand in regards to the intended clinical use and the reference laboratories that may collaborate in a network. At present, there is international cooperation in developing RS for analytes of clinical significance. Thanks to the work of the Joint Committee on Traceability in Laboratory Medicine (JCTLM), a list of higher order reference materials and reference methods is now publicly available. JCTLM has also published the list of reference laboratories that are able to deliver a reference measurement service. As soon as a new RS is implemented, clinical validation of the correctly calibrated routine methods (the IVD products sold onto the market) should take place. Other important issues concerning the implementation of a metrologically-correct approach for result standardization are: 1) the clear definition of the clinically allowable error of measurements and 2) the post-market surveillance of the performance of IVD products. These are tasks of our profession through the organization of appropriate External Quality Assessment programs.

State-of-the-Art of Serum Testosterone Measurement by Isotope Dilution–Liquid Chromatography– Tandem Mass Spectrometry

The recent interest of clinical laboratories in developing serum testosterone assays based on isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) stems from the lack of accuracy of direct immunoassays. In this study, we assessed the accuracy and state of standardization (traceability) of 4 published ID-LC-MS/MS procedures in a method comparison with an ID-gas chromatography (GC)-MS reference measurement procedure listed in the database of the Joint Committee for Traceability in Laboratory Medicine. The study used 58 specimens from different patient categories. Each specimen was measured in triplicate (ID-LC-MS/MS) and quadruplicate (ID-GC-MS) in independent runs. The testosterone concentrations by ID-GC-MS were 0.2-4.4 nmol/L (women), 0.2-2.0 nmol/L (hypogonadal man), and 10.1-31.3 nmol/L (normogonadal men). For ID-GC-MS, the CV was nearly constant, with a median of 1.0%; for ID-LC-MS/MS, it was concentration-dependent, with a median of up to 8%. Weighted Deming regression gave mean slopes, intercepts, and correlation coefficients of 0.90-1.11, -0.055-0.013 nmol/L, and 0.993-0.997, respectively. The % difference plot showed between 7% and 26% of the results outside a total error limit of 14%, with median deviations from ID-GC-MS between -9.6 and 0.4%. This study demonstrated fairly good accuracy and standardization of the tested ID-LC-MS/MS procedures. Performance differences between procedures were evident in some instances, due to improper calibration and between-run calibration control. This emphasizes the need for thorough validation, including traceability, of new ID-LC-MS/MS procedures.

What's in a name? Standardisation of HbA1c: a response

W. Garry John, Gunnar Nordin and Mauro Panteghini* 1 Clinical Biochemistry, Norfolk and Norwich University Hospital, and School of Medicine, Health Policy and Practice, UEA, Norwich, NR4 7UY, UK 2 External Quality Assurance in Laboratory Medicine in Sweden, Uppsala, Sweden 3 Centre for Metrological Traceability in Laboratory Medicine (CIRME) and Department of Clinical Sciences ‘‘Luigi Sacco’’, University of Milan, Milan, Italy

Analytical performance evaluation of the Cobas 6000 analyzer – special emphasis on trueness verification

Consolidation of analyzers is an emerging issue in clinical chemistry. We evaluated the analytical performance of the Cobas 6,000 analyzer (Roche Diagnostics), which is considered a candidate for replacement of current Hitachi 917 analyzers and for consolidation of chemistry and immunochemistry. The precision, accuracy, linearity and correlation with current field methods were evaluated according to Clinical and Laboratory Standards Institute protocols EP5, EP9 and EP10. A total of 31 routine chemistry assays and 18 immunoassays were studied. Accuracy and linearity were verified for 24 chemistry parameters using value-assigned trueness controls from the Dutch External Quality Assessment Scheme organizers. In addition, traceability to methods endorsed by the Joint Committee of Traceability in Laboratory Medicine was examined. All analytes met allowable precision criteria, apart from the low level for sodium and folate. Total coefficients of variation ranged between 0.6% and 4.4% for routine chemistry and between 0.8% and 5.8% for immunochemistry, apart from folate (12% at the low end). The correlation coefficients for comparison to current field methods were >0.975, except for magnesium and for six out of 18 immunochemistries. Recovery experiments indicated high recovery for most of the 24 routine chemistry assays. Considering the excellent precision data and the result equivalence for most assays, it can be concluded that Cobas 6,000 accommodates robust chemistry and immunochemistry, and has good potential for workstation consolidation in medium-sized laboratories.

Proposal of a candidate international conventional reference measurement procedure for free thyroxine in serum

In the present paper the IFCC WG-STFT recommends and provides the rationale to establish metrological traceability of serum free thyroxine (FT4) measurements to a candidate international conventional reference measurement procedure. It is proposed that this procedure be based on equilibrium dialysis combined with determination of thyroxine in the dialysate with a trueness-based reference measurement procedure. The measurand is thus operationally defined as "thyroxine in the dialysate from equilibrium dialysis of serum prepared under defined conditions". With regard to the trueness-based reference measurement procedure, the WG-STFT recommends use of an isotope dilution-liquid chromatography/tandem mass spectrometry (ID-LC/tandem MS) procedure for total thyroxine that has been optimized towards measurement at picomolar concentration levels and that is listed in the database of the Joint Committee for Traceability in Laboratory Medicine (JCTLM). For calibration, the purified thyroxine material IRMM-468 (resulting from a project funded by the European Commission and recently submitted to the JCTLM) is proposed. The WG-STFT stresses that according to this recommendation it is a prerequisite to strictly adhere to the defined equilibrium dialysis procedure, whereas it is permissible to introduce variants in the ID-LC/tandem MS procedure.

Implementation of haemoglobin A1c results traceable to the IFCC reference system: the way forward

Mauro Panteghini* and W. Garry John on behalf of the IFCC Scientific Division 1 Centre for Metrological Traceability in Laboratory Medicine (CIRME), University of Milan, Milan, Italy 2 Department of Clinical Sciences ‘‘Luigi Sacco’’, University of Milan, Milan, Italy 3 Clinical Biochemistry, Norfolk and Norwich University Hospital, and School of Medicine Health Policy and Practice, UEA, Norwich, UK

Establishing reference laboratories in laboratory medicine

The concept of measurement traceability provides probably the most important strategy to achieve standardization in laboratory medicine aimed at comparable measurement results regardless of the method, the measurement procedure (test kit) and of the laboratory where analyses are carried out. Establishing networks of reference laboratories is - in addition to reference measurement procedures and reference materials - one of the biggest challenges in implementing the concept of measurement traceability. With respect to these requirements, the Joint Committee on Traceability in Laboratory Medicine (JCTLM), established by the BIPM, the IFCC and the ILAC, has launched two projects in its working groups. WG-1 has to date published tables of reference materials and reference procedures on the BIPM web-sites, whereas WG-2 is identifying reference measurement laboratories. There is general agreement now that reference laboratories should be identified - according to the metrological level of the procedures applied where the principle of measurement is the most important criterion, - on the basis of accreditation or at least compliance with ISO 15195 or ISO 17025 as calibration laboratory, and - on the basis of their ability to demonstrate performance in regular inter - laboratory comparisons (ring trials). To date, a data base on candidate reference laboratories has been collected containing information on the laboratory identity, the metrological level of the procedures and on the status of accreditation and the participation in networks or ring trials. The data base currently contains the addresses of about 60 laboratories. On average, each of the laboratories reported measurement capabilities for six different measurands resulting in about 360 entries. The IFCC has recently launched a ring trial program for reference laboratories for some thirty different measurands. Ring trial results not only demonstrate the competence of individual laboratories, but also reveal the equivalence or bias of different reference procedures. .

Traceability in laboratory medicine

In laboratory medicine meaningful measurements are essential for diagnosis, risk assessment, treatment and monitoring of patients. Thus methods applied in diagnostic measurements must be accurate, precise, specific and comparable among laboratories. Inadequate or incorrect analytical performance has consequences for the patients, the clinicians, and the health care system. One key element of metrology is the traceability of a measurement result to the SI system ensuring comparable results. This principle is described in the ISO/TC 212/WG2 N65 prEN 17511 Standard. In addition to the principles of metrology, the clinical usefulness, the diagnostic needs, and the biological and disease associated variations in patients' specimens have to be considered when the analytical biases for diagnostic purposes are defined. It must be the general goal of diagnostic laboratories to produce results that are true and comparable worldwide. The recent European in vitro diagnostic (IVD) Directive 98/79 EC follows the above mentioned standard of the International Organization for Standardization (ISO) and the European Committee for Standardization (CEN) requesting its application for all IVD reagents used within the European Union. This new European legislation will have a worldwide impact on manufacturers and clinical laboratories and will be implemented in 2003. It states that "traceability of values assigned to calibrators and/or control materials must be assured through available reference measurement procedures and/or available reference materials of a higher order". Thus a worldwide reference system needs to be established by collaboration and mutual recognition between the United States National Institute of Standards and Technology (NIST), European Metrology Institutes (EUROMET), regulatory bodies (e.g. United States Food and Drug Administration, FDA) the IVD industry and professional organizations (e.g. International Federation of Clinical Chemistry and Laboratory Medicine, IFCC). In June 2002, in Paris, representatives of international and regional organizations and institutions decided to form the "Joint Committee on Traceability for Laboratory Medicine" (JCTLM), which will support industry in registration and licensing of the "CE" label to test systems conforming to the IVD Directive.

Metrological traceability in laboratory medicine

Metrological traceability in laboratory medicine

Quality specifications for reference methods

Reference methods are a key element to the objective of traceability in laboratory medicine. However, to serve this purpose adequately, minimum analytical quality specifications are required. Here, possible strategies for deriving such specifications are presented, being based on concepts developed before by a European Working Group. Distinction is made between ?genuine requirements? for reference methods (direct calibration with primary reference materials; absence of sample-related effects) and ?performance specifications? (limits for random, systematic and total error, the latter in association with the number of measurements). While the former requirements are considered as conditio sine-qua-non, the latter specifications should be variable, which means that they should be tailored to the specific application of the methods. In general, it is advocated to derive performance specifications for reference methods from desirable specifications of routine methods (analyte-related), although other models should not be ruled out beforehand. Further, it is recommended that reference laboratories make special efforts to demonstrate and maintain a uniform level of quality of reference methods.