All you wanted to know about laboratory tests, but were afraid to ask

1. All you wanted to know about laboratory tests, but were afraid to ask The informed patient meeting the laboratory director Standardization & Traceability The solution By Dietmar Stöckl STT Consulting - 8 -

2. Today The reference measurement system Now it moves forward! All you wanted to know about laboratory tests -8-

3. The reference measurement system • Requirements to obtain–and maintain–a meaningful measurement system • Cali JP. Clin Chem 1973;19:291–3. • Part 1. A rational, self-consistent system of units of measurement (e.g., the SI units). • Part 2. The materials to realize in daily practice the defined units and their derivatives (e.g., the certified Standard Reference Materials produced and issued by NBS = NIST). • Part 3. The availability of accurate methods of measurement, analysis, or test, based on the well-characterized materials of part 2 (these accurate methods are often referred to as "referee methods", "reference methods", or "standard methods"). • Part 4. Field or applied methods of measurement, analysis, or test. • Part 5. A method whereby the long-term integrity of the measurement system is assured. All you wanted to know about laboratory tests -8-

4. The reference measurement system • ISO 17511:2003 • In vitro diagnostic medical devices – Measurement of quantities in biological samples – Metrological traceability of values assigned to calibrators and control materials. June 2002 What did you take so long? All you wanted to know about laboratory tests -8-

5. Uncertainty Measurand/SI Serum/plasma–cortisol; amount-of-substance concentration (nmol/L) Unit realization Cortisol NIST SRM 921 Procedure Material Gravimetry Cortisol calibrator (NIST SRM 921 in ethanol) ID-GC/MS Working calibrator Human sera IRMM/IFCC 451 Assay xyz master procedure Product calibrator 6 calibrators Assay xyz end user’s procedure Routine sample Patient xyz *** nmol/L Traceability chain ISO 17511 All you wanted to know about laboratory tests -8-

6. I type ... ... an idea whose time has come … Cali JP. Clin Chem 1973;19:291–3 36 – Congratulations! All you wanted to know about laboratory tests -8-

7. The next visit Analytical performance goals ... heavy load! All you wanted to know about laboratory tests -8-

8. Resources • My personal opinion is that it is almost certain that the Product Standards soon to be promulgated by the Food and Drug Administration with regard to the labeling requirements of clinical kits, chemicals, and devices will, where applicable, somehow relate to and (or) require the use of referee methods (or state-of-the-art interim methods where referee methods have not yet been developed) to provide the baseline against which other methods or products will be assessed. • Cali JP. An idea whose time has come$. Clin Chem 1973;19:291–3 ($accuracy in clinical chemistry) All you wanted to know about laboratory tests -8-

9. Resources • ISO Guide 2:2004 Standardization and related activities — General vocabulary • 1.1 standardization: activity of establishing, with regard to actual or potential problems, provisions for common and repeated use, aimed at the achievement of the optimum degree of order in a given context; NOTE 1 In particular, the activity consists of the processes of formulating, issuing and implementing standards; NOTE 2 Important benefits of standardization are improvement of the suitability of products, processes and services for their intended purposes, prevention of barriers to trade and facilitation of technological cooperation. • 1.4 state of the art: developed stage of technical capability at a given time as regards products, processes and services, based on the relevant consolidated findings of science, technology and experience. • 2 Aims of standardization • NOTE The general aims of standardization follow from the definition in 1.1. Standardization may have one or more specific aims, to make a product, process or service fit for its purpose. Such aims can be, but are not restricted to, variety control, usability, compatibility, interchangeability, health, safety, protection of the environment, product protection, mutual understanding, economic performance, trade. They can be overlapping. • 2.1 fitness for purpose: ability of a product, process or service to serve a defined purpose under specific conditions. • 2.2 compatibility: suitability of products, processes or services for use together under specific conditions to fulfil relevant requirements without causing unacceptable interactions • 2.3 interchangeability: ability of one product, process or service to be used in place of another to fulfil the same requirements; NOTE The functional aspect of interchangeability is called “functional interchangeability”, and the dimensional aspect “dimensional interchangeability”. • 2.4 variety control: selection of the optimum number of sizes or types of products, processes or services to meet prevailing needs; NOTE Variety control is usually concerned with variety reduction. • 2.5 safety: freedom from unacceptable risk of harm; NOTE In standardization, the safety of products, processes and services is generally considered with a view to achieving the optimum balance of a number of factors, including non-technical factors such as human behaviour, that will eliminate avoidable risks of harm to persons and goods to an acceptable degree. All you wanted to know about laboratory tests -8-

10. Resources • More definitions of standardization • Merriam Webster's Online Dictionary • Standardization (main entry: standardize) • Standardize • 1 : to compare with a standard • 2 : to bring into conformity with a standard • NATO definition of standardization • "The development and implementation of concepts, doctrines, procedures, and designs to achieve and maintain the required levels of compatibility, interchangeability or commonality in the operational, procedural, materiel, technical and administrative fields to attain interoperability. Note: the three levels of standardization in ascending order are: compatibility, interchangeability and commonality (AAP 6 4/10/2000)". All you wanted to know about laboratory tests -8-

11. Resources (VIM) metrological traceability property of a measurement result whereby the result can be related to a reference through a documented unbroken chain of calibrations, each contributing to the measurement uncertainty NOTE 1 For this definition, a ‘reference’ can be a definition of a measurement unit through its practical realization, or a measurement procedure including the measurement unit for a non-ordinal quantity, or a measurement standard. NOTE 2 Metrological traceability requires an established calibration hierarchy. measurement standard (etalon) realization of the definition of a given quantity, with stated quantity value and associated measurement uncertainty, used as a reference. commutability of a reference material property of a reference material, demonstrated by the closeness of agreement between the relation among the measurement results for a stated quantity in this material, obtained according to two given measurement procedures, and the relation obtained among the measurement results for other specified materials NOTE 1 The reference material in question is usually a calibrator and the other specified materials are usually routine samples. NOTE 2 The measurement procedures referred to in the definition are the one preceding and the one following the reference material (calibrator) in question in a calibration hierarchy (see ISO 17511). All you wanted to know about laboratory tests -8-

12. Resources • In vitro diagnostic medical device directive 98/79/EC • (and related CEN TC 140 and ISO TC 212 activities) • http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:1998:331:0001:0037:EN:PDF • http://www.newapproach.org/Directives/DirectiveList.asp • http://www.cen.eu/newapproach/cen/stdlist.asp?dir_area=98/79/EC&prod_fam=CEN/TC%20140 • http://www.iso.org/iso/iso_catalogue/catalogue_tc/catalogue_tc_browse.htm?commid=54916&published=on • JCTLM (Joint committee for traceability in laboratory medicine) • http://www.bipm.org/en/committees/jc/jctlm/ • IFCC working groups and committees related to standardization • http://www.ifcc.org/index.asp?cat=Scientific_Activities&scat=Working_Groups&rif=4&dove=1 • http://www.ifcc.org/index.asp?cat=Scientific_Activities&scat=Committees&rif=4&dove=1 • Centers for disease control and prevention • (activities related to standardization in laboratory medicine) • http://www.cdc.gov/nceh/dls/ • Interdipartimental Center of Metrological Traceability in Laboratory Medicine • http://users.unimi.it/cirme/home/index.php • Clinical and laboratory standards institute (CLSI) • http://www.clsi.org All you wanted to know about laboratory tests -8-

13. Resources • Reference materials • https://www-s.nist.gov/srmors/BrowseMaterials.cfm?subkey=5&category=1 (NIST) • http://irmm.jrc.ec.europa.eu/html/homepage.htm (IRMM) • http://www.reccs.or.jp/e_activities.html • http://www.nibsc.ac.uk/ (NIBSC, merged into the HPA) • Established standardization activities • Lipids: http://www.cdc.gov/labstandards/lsp.htm • Steroids: http://www.cdc.gov/nceh/dls/hormone_standardization.htm • Creatinine and other kidney markers: http://www.nkdep.nih.gov/labprofessionals/ • HbA1c: http://www.ngsp.org/prog/index.html; http://www.ifcchba1c.net/ All you wanted to know about laboratory tests -8-

14. Resources • References • Cali JP. An idea whose time has come. Clin Chem 1973;19:291–3. • Vesper HW, Thienpont LM. Traceability in laboratory medicine [Review]. Clin Chem 2009;55. • Thienpont LM. Accuracy in clinical chemistry - who will kiss Sleeping Beauty awake? Clin Chem Lab Med 2008;46:1220-2. • Thienpont LM, Van Uytfanghe K, De Leenheer AP. Reference measurement systems in clinical chemistry [Review]. Clin Chim Acta 2002;323:73-87. • Stöckl D, Franzini C, Kratochvíla J, Middle J, Ricós C, Thienpont LM. Current stage of standardization of measurements of specific polypeptides and proteins discussed in light of steps needed towards a comprehensive measurement system. Eur J Clin Chem Clin Biochem 1997;35:719-32. All you wanted to know about laboratory tests -8-