Despite monumental advances in quality improvement over the past few decades, clinical laboratories are still under increasing pressure to achieve efficiency, timeliness, safety, effectiveness and patient-centered services . Laboratory tests are required for fulfilling the healthcare needs of individual patients and populations; they are critical to predict susceptibility to and prevent disease, to achieve early diagnosis and effective monitoring, and to determine prognosis and personalize treatment to get the best outcomes. They are critical to the management of communicable and noncommunicable diseases, surveillance of emerging infectious threats such as Ebola and Zika viruses, the safe and rational use of essential medicines, including stewardship of anti-infective agents to reduce the likelihood of the development of microbial resistance. Improved access to diagnostics has been shown to double the rate of adequate glycemic control, and to quadruple the number of cases of human deficiency virus infections detected . However, many laboratory test results are still highly variable, poorly standardized and harmonized . But analytical variability is the tip of the iceberg, as clinicians and patients require that laboratory tests performed by different laboratories at different times on the same patient can be compared and consistently evaluated. This, in turn, requires not only the comparability of analytical results but also of the ultimate laboratory information; therefore, all other aspects of the total testing process (TTP), such as terminology, sample and specimen quality, units, reference ranges and decision limits, report formats and criteria for interpretation should be harmonized [4, 5]. If the final goal is that patient treatment based on laboratory information is accurate, timely and safe, a global picture of the harmonization process is required. It has been emphasized that “although the brain-to-brain concept is widely accepted by laboratory professionals, there is little clarity concerning the inter-relationship between the different phases of the cycle, in particular the interdependence between the pre-analytical phase and analytical quality, and the role of post-analytical steps in affecting the quality of the ultimate laboratory information provided” . Anything that interferes with any step in the process will be at least a waste and at most a source of errors. This concept has been defined as “the global picture of harmonization in laboratory medicine” which starts from pre-pre-analytical steps, focuses on analytical aspects and finally closes with post-post-analytical issues [4, 5]. The main reasons for focusing on a global picture of harmonization have been already reported [4, 7], but the great progress experienced in the area of harmonization in the last few years persuaded us to publish another special issue of the Journal dedicated to this topic. In particular, the aim of this special issue is not only to report progress of standardization and harmonization initiatives in the traditional area of clinical chemistry but to take into consideration progresses made in other subspecialties such as hematology, coagulation, microbiology, molecular diagnostics as well as in external quality assessment programs, reference values, terminology and units.
The special issue presents a wide range of papers prepared by international experts in the different disciplines in the field of laboratory medicine and is divided into two parts: the first one includes papers describing the initiatives related to harmonization activities from a global perspective and papers dedicated to specific aspects as well (pre-pre analytical, pre-analytical and analytical phases of the TTP); the second one contains papers dedicated to post- and post-post analytical phases.
Section 1. Current harmonization activities at global level. The section lists 11 papers describing: (i) the need to expand the harmonization activities to cover the different subspecialties of laboratory medicine ; (ii) the necessity to organize harmonized external quality schemes that include all the branches of the clinical laboratory ; (iii) the harmonization activities undertaken by the European Federation of Clinical Chemistry and Laboratory Medicine over the years in Europe and their results as well ; (iv) the need of a global approach (IVD companies included) to achieve test standardization/harmonization ; (v) the bone turnover in osteoporosis as an example of harmonization of the TTP ; the harmonization activities in (vi) hemostasis ; (vii) autoimmunity ; (viii) microbiology ; (ix) the generation and utilization of the biological variation data ; and finally, (x) the harmonized and unifying role of the standard ISO15189 ; and (xi) the external quality assessment programs and ISO15189 .
Section 2. Pre-pre and pre-analytical phases. This section includes two papers: (i) a consensus report from Italy related to the harmonization of the test request in emergency departments ; (ii) the EFLM strategy to harmonize the pre-analytical phase .
Section 3. Analytical phase. This section lists 17 papers. The first two are related to general activities dedicated to the harmonization and standardization of the clinical laboratory results: (i) a report from the International Consortium for harmonization  and (ii) a report from the Dutch Calibration 2.000 program . A number of the articles (n=6) describe the harmonization activities and the respective results (positive or negative) related to a specific test or group of tests: (iii) 17 hydroxyprogesterone , (iv) international normalized ratio , (v) antithrombin , (vi) thiopurine drugs , (vii) PCR-based detection of intestinal pathogens , (viii) albuminuria . A huge number of papers (n=9) is dedicated to the harmonization of autoimmune testing, starting from (ix) a general perspective of the feasibility of this possibility , and continuing with the specific activities addressing specific tests: (x) testing for rheumatic diseases , (xi) rheumatoid factor , (xii) anti-neutrophil cytoplasmic antibodies , (xiii) anti-nuclear antibodies , (xiv) autoimmune thyroid diagnostics , (xv) anti-nuclear antibodies patterns , (xvi) anti-mitochondrial and anti-rods/rings autoantibodies . (xvii) A Letter to the Editor closes this section: it is related to the definition of negative patterns of anti-nuclear antibody testing .
Section 4. The post- and post-post analytical phase. The post-analytical part (16 papers) is mainly related to the laboratory report. The first two papers examine the issue from a general point of view: (i) a call for harmony  and (ii) a critical analysis on how deep we should go in harmonizing laboratory reports . The following six papers are related to the harmonization of units, terminology and reference intervals: (iii) a Belgian approach to the harmonization of units , (iv) a recommendation by the IFCC Committee on reference intervals and decision limits , (v) another paper recommending how the clinical laboratory should determine reference intervals in practice  and finally three papers reporting on different initiatives on reference intervals, from (vi) Australasia , (vii) the Netherlands , and (viii) Canada . The next papers inform (ix) about the experience on critical results alert in Australia and New Zealand  and (x) about the harmonization in the molecular diagnostics . (xi) An interesting paper from the Italian Society of Clinical Chemistry about the harmonization of interpretative comments in hematology reports is following . The last papers of this section report about the different experience in harmonization of the laboratory report based on external quality assessment activities in (xii) Italy  and (xiii) Norway , and in (xiv) proficiency testing in hemostasis . The post-post-analytical phase includes two papers: (xv) one about the need of using extra-analytical quality indicators  and (xvi) the second one illustrating how laboratory medicine can cooperate with patients and physicians for a better collaborative healthcare .
We are confident that this wide range of papers covering all the phases of the TTP of the clinical laboratory and including different branches of laboratory medicine will be useful for the CCLM readership in understanding how we are and where we should go to pursue the pivotal project of harmonization in our discipline with the ultimate goal to assure better outcomes for the patients and the population we serve.
Kilpatrick ES, Sandberg S. An overview of EFLM harmonisation activities in Europe. Clin Chem Lab Med (in print). Google Scholar
Cobbaert C, Smit N, Gillery P. Metrological traceability and harmonization of medical tests: a quantum leap forward is needed to keep pace with globalization and stringent IVD-regulations in the 21st century! Clin Chem Lab Med 2018;56:1598–602. CrossrefPubMedGoogle Scholar
Damoiseaux J, Olschowka N, Shoenfeld Y. EASI – European Autoimmunity Standardisation Initiative: facing the challenges of diagnostics in autoimmunity. Clin Chem Lab Med 2018;56:1620–3. PubMedCrossrefGoogle Scholar
Aarsand AK, Røraas T, Bartlett WA, Coşkun A, Carobene A, Fernandez-Calle P, et al., on behalf of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group on Biological Variation. Harmonization initiatives in the generation, reporting and application of biological variation data. Clin Chem Lab Med 2018;56:1629–36. CrossrefPubMedGoogle Scholar
Lippi G, Panteghini M, Bernardini S, Bonfanti L, Carraro P, Casagranda I, et al. Laboratory testing in the emergency department: an Italian Society of Clinical Biochemistry and Clinical Molecular Biology (SIBioC) and Academy of Emergency Medicine and Care (AcEMC) consensus report. Clin Chem Lab Med 2018;56:1655–9. CrossrefPubMedGoogle Scholar
Lippi G, Simundic A-M., on behalf of the European Federation for Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for Preanalytical Phase (WG-PRE). The EFLM strategy for harmonization of the preanalytical phase. Clin Chem Lab Med 2018;56:1660–6. CrossrefPubMedGoogle Scholar
Myers GL, Miller WG. The roadmap for harmonization: status of the International Consortium for Harmonization of Clinical Laboratory Results. Clin Chem Lab Med 2018;56:1667–72. CrossrefPubMedGoogle Scholar
Jansen RT, Cobbaert CM, Weykamp C, Thelen M. The quest for equivalence of test results: the pilgrimage of the Dutch Calibration 2.000 program for metrological traceability. Clin Chem Lab Med 2018;56:1673–84. CrossrefPubMedGoogle Scholar
Greaves RF, Ho CS, Loh TP, Chai JH, Jolly L, Graham P, et al., on behalf of Working Group 3 “Harmonisation of Laboratory Assessment” European Cooperation in Science and Technology (COST) Action BM1303 “DSDnet”. Current state and recommendations for harmonization of serum/plasma 17-hydroxyprogesterone mass spectrometry methods. Clin Chem Lab Med 2018;56:1685–97. CrossrefPubMedGoogle Scholar
Meijer P, Kynde K, van den Besselaar AM, Van Blerk M, Woods TA. International normalized ratio (INR) testing in Europe: between-laboratory comparability of test results obtained by Quick and Owren reagents. Clin Chem Lab Med 2018;56:1698–703. CrossrefPubMedGoogle Scholar
Ruhaak LR, Romijn FP, Smit NP, van der Laarse A, Pieterse MM, de Maat MP, et al. Detecting molecular forms of antithrombin by LC-MRM-MS: defining the measurands. Clin Chem Lab Med 2018;56:1704–14. CrossrefPubMedGoogle Scholar
Robijns K, Luin M, Jansen R, Neef C, Touw D. Introduction of a new design for external quality assessment for the analysis of thiopurine drugs. Clin Chem Lab Med (in print). Google Scholar
Schuurs TA, Koelewijn R, Brienen EA, Kortbeek T, Mank TG, Mulder B, et al. Harmonization of PCR-based detection of intestinal pathogens: experiences from the Dutch external quality assessment scheme on molecular diagnosis of protozoa in stool samples. Clin Chem Lab Med 2018;56:1722–7. PubMedCrossrefGoogle Scholar
Ćwiklińska A, Dąbrowska H, Kowalski R, Kuchta A, Kortas-Stempak B, Fijałkowska A, et al. Harmonization of urine albumin/creatinine ratio (ACR) results: a study based on an external quality assessment program in Polish laboratories. Clin Chem Lab Med 2018;56:1728–33. CrossrefPubMedGoogle Scholar
Falkenburg WJ, von Richthofen HJ, Koers J, Weykamp C, Schreurs MW, Bakker-Jonges LE, et al. Clinically relevant discrepancies between different rheumatoid factor assays. Clin Chem Lab Med 2018;56:1749–58. CrossrefPubMedGoogle Scholar
Damoiseaux J, Heijnen I, Van Campenhout C, Eriksson C, Fabien N, Herold M, et al. An international survey on anti-neutrophil cytoplasmic antibodies (ANCA) testing in daily clinical practice. Clin Chem Lab Med 2018;56:1759–70. PubMedCrossrefGoogle Scholar
Pérez D, Gilburd B, Cabrera-Marante Ó, Martínez-Flores JA, Serrano M, Naranjo L, et al. Predictive autoimmunity using autoantibodies: screening for anti-nuclear antibodies. Clin Chem Lab Med 2018;56:1771–7. CrossrefPubMedGoogle Scholar
Andrade LE, Klotz W, Herold M, Conrad K, Rönnelid J, Fritzler MJ, et al. International consensus on antinuclear antibody patterns: definition of the AC-29 pattern associated with antibodies to DNA topoisomerase I. Clin Chem Lab Med 2018;56:1783–8. PubMedCrossrefGoogle Scholar
Calise SJ, Zheng B, Hasegawa T, Satoh M, Isailovic N, Ceribelli A, et al., the IUIS Autoantibody Standardization Committee. Reference standards for the detection of anti-mitochondrial and antirods/rings autoantibodies. Clin Chem Lab Med 2018;56:1789–98. CrossrefGoogle Scholar
Herold M, Klotz W, Andrade LE, Conrad K, Cruvinel WM, Damoiseaux J, et al. International Consensus on Antinuclear Antibody Patterns: defining negative results and reporting unidentified patterns. Clin Chem Lab Med 2018;56:1799–802. PubMedCrossrefGoogle Scholar
Jones GR, Legg M. Report formatting in laboratory medicine – a call for harmony. Clin Chem Lab Med 2018. doi: 10.1515/cclm-2017-1165. [Epub ahead of print]. Google Scholar
Demarteau M, Cammaert P, Vandevelde NM, Callewaert N, Coucke W, China B, et al. A pragmatic bottom-up approach to harmonize the units of clinical chemistry tests among Belgian clinical laboratories, focused on immunoassays. Clin Chem Lab Med 2018. doi: 10.1515/cclm-2017-0824. [Epub ahead of print]. Google Scholar
Jones GR, Haeckel R, Loh TP, Sikaris K, Streichert T, Katayev A, et al. IFCC Committee on Reference Intervals and Decision Limits. Indirect methods for reference interval determination – review and recommendations. Clin Chem Lab Med 2018. doi: 10.1515/cclm-2018-0073. [Epub ahead of print]. PubMedGoogle Scholar
Ozarda Y, Higgins V, Adeli K. Verification of reference intervals in routine clinical laboratories: practical challenges and recommendations. Clin Chem Lab Med 2018. doi: 10.1515/cclm-2018-0059. [Epub ahead of print]. PubMedGoogle Scholar
Koerbin G, Sikaris K, Jones GR, Flatman R, Tate JR; AACB Harmonization Committee for Common Reference Intervals. An update report on the harmonization of adult reference intervals in Australasia. Clin Chem Lab Med 2018. doi: 10.1515/cclm-2017-0920. [Epub ahead of print]. PubMedGoogle Scholar
den Elzen WP, Brouwer N, Thelen MH, Le Cessie S, Haagen I-A, Cobbaert CM. Standardized reference intervals in the Netherlands using a ‘big data’ approach. Clin Chem Lab Med (in print). Google Scholar
Parker ML, Adeli K, CSCC Working Group on Reference Interval Harmonization. Pediatric and adult reference interval harmonization in Canada: an update. Clin Chem Lab Med 2018. doi: 10.1515/cclm-2017-0965. [Epub ahead of print]. Google Scholar
Campbell CA, Lam Q, Horvath AR. An evidence- and risk-based approach to a harmonized laboratory alert list in Australia and New Zealand. Clin Chem Lab Med 2018. doi: 10.1515/cclm-2017-1114. [Epub ahead of print]. PubMedGoogle Scholar
Payne DA, Baluchova K, Russomando G, Ahmad-Nejad P, Mamotte C, Rousseau F, et al. IFCC Committee on Molecular Diagnostics. Toward harmonization of clinical molecular diagnostic reports: findings of an international survey. Clin Chem Lab Med 2018. doi: 10.1515/cclm-2017-1080. [Epub ahead of print]. PubMedGoogle Scholar
Buoro S, Da Rin G, Fanelli A, Lippi G. Harmonization of interpretative comments in laboratory hematology report: the recommendations of Working Group on Diagnostic Hematology of the Italian Society of Clinical Chemistry and Clinical Molecular Biology (WGDH-SIBioC). Clin Chem Lab Med 2018. doi: 10.1515/cclm-2017-0972. [Epub ahead of print]. Google Scholar
Secchiero S, Sciacovelli L, Plebani M. Harmonization of units and reference intervals of plasma proteins: state of the art from an External Quality Assessment Scheme. Clin Chem Lab Med 2018. doi: 10.1515/cclm-2017-1172. [Epub ahead of print]. PubMedGoogle Scholar
Stavelin A, Sandberg S. Harmonization activities of Noklus – a quality improvement organization for point-of-care laboratory examinations. Clin Chem Lab Med 2018. doi: 10.1515/cclm-2018-0061. [Epub ahead of print]. PubMedGoogle Scholar
Favaloro EJ, Jennings I, Olson J, Van Cott EM, Bonar R, Gosselin R, et al. Towards harmonization of external quality assessment/proficiency testing in hemostasis. Clin Chem Lab Med 2018. doi: 10.1515/cclm-2018-0077. [Epub ahead of print]. PubMedGoogle Scholar
Aita A, Sciacovelli L, Plebani M. Extra-analytical quality indicators – where to now? Clin Chem Lab Med 2017. doi: 10.1515/cclm-2017-0964. [Epub ahead of print]. Google Scholar
About the article
Published Online: 2018-07-09
Published in Print: 2018-09-25
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.