Volume 57, Issue 1 - Special Issue: Harmonization in Laboratory Medicine: the Request, the Sample, the Measurement, and the Report – an Update. Part 2 / Editors: Jillian R. Tate, MariaStella Graziani and Mario Plebani

Harmonization initiatives in laboratory medicine seek to eliminate or reduce illogical variations in service to patients, clinicians and other healthcare professionals. Significant effort will be required to achieve consistent application of terminology, units and reporting across laboratory testing providers. Current variations in practice for nomenclature, reference intervals, flagging, units, standardization and traceability between analytical methods, and presentation of cumulative result data are inefficient and inconvenient, or worse yet, patient safety risks. All aspects of laboratory service across the “total testing process” ultimately depend on concise, reliable communication. Clinical terminologies (e.g. SNOMED-CT, LOINC, IFCC/IUPAC NPU) provide a mechanism to correctly identify an analyte or panel of tests within a request for testing and communicate the results back to the clinician or electronic health record (EHR). Electronic systems for requesting and reporting laboratory testing are said to be interoperable when reliable connection and communication of content occur. Modern electronic reports and EHRs will provide greater flexibility and functionality, but also require effective guidelines or standards to ensure consistent representation of laboratory data. Programs to harmonize service in these areas require ongoing local, national and international efforts and should incorporate stakeholders from laboratories, medical staff, information technology and informatics specialists, patient representatives and government. The process of identifying harmonized best practice, then ensuring uptake across many laboratory testing providers, is generally iterative rather than “one off”. New opportunities for additional harmonization will be generated as analytical performance, standardization and traceability, and diagnosis and treatment continue to evolve.

Background: Harmonization of units is an important step to improve the comparability of clinical chemistry results, but few examples exist of successful harmonization efforts. We present the results of a pragmatic approach that was implemented in Belgium from 2012. Methods: After a large consultation and information of stakeholders, preferred units were proposed for 140 assays, including the 23 immunoassays discussed in more detail here. The change occurred in two phases, first involving assays for which there was no change in the numerical result, then changes involving a change in numerical results. Laboratories were invited to participate in this harmonization on a voluntary basis. The project was based on a bottom-up approach, large consultation and the pragmatic choice of the proposed units, including conventional and SI units. Results: The large heterogeneity of units was drastically reduced; adoption of the preferred units increased from 3% (insulin) – 45% (HCG) to 70% (insulin) – 96% (LH and FSH). Adoption of the preferred units was higher if it involved no change in numerical values (90%) than when there was a change (76%). Conclusions: We believe that the harmonization effort has reached its goals. Without aiming at implementing SI units for all parameters, our strategy was successful with a large majority of the laboratories switching to the proposed units. Moreover, the harmonization program is still progressing, with additional laboratories converting to the consensus units.

Reference intervals are a vital part of the information supplied by clinical laboratories to support interpretation of numerical pathology results such as are produced in clinical chemistry and hematology laboratories. The traditional method for establishing reference intervals, known as the direct approach, is based on collecting samples from members of a preselected reference population, making the measurements and then determining the intervals. An alternative approach is to perform analysis of results generated as part of routine pathology testing and using appropriate statistical techniques to determine reference intervals. This is known as the indirect approach. This paper from a working group of the International Federation of Clinical Chemistry (IFCC) Committee on Reference Intervals and Decision Limits (C-RIDL) aims to summarize current thinking on indirect approaches to reference intervals. The indirect approach has some major potential advantages compared with direct methods. The processes are faster, cheaper and do not involve patient inconvenience, discomfort or the risks associated with generating new patient health information. Indirect methods also use the same preanalytical and analytical techniques used for patient management and can provide very large numbers for assessment. Limitations to the indirect methods include possible effects of diseased subpopulations on the derived interval. The IFCC C-RIDL aims to encourage the use of indirect methods to establish and verify reference intervals, to promote publication of such intervals with clear explanation of the process used and also to support the development of improved statistical techniques for these studies.

Reference intervals (RIs) are fundamental tools used by healthcare and laboratory professionals to interpret patient laboratory test results, ideally enabling differentiation of healthy and unhealthy individuals. Under optimal conditions, a laboratory should perform its own RI study to establish RIs specific for its method and local population. However, the process of developing RIs is often beyond the capabilities of an individual laboratory due to the complex, expensive and time-consuming process to develop them. Therefore, a laboratory can alternatively verify RIs established by an external source. Common RIs can be established by large, multicenter studies and can subsequently be received by local laboratories using various verification procedures. The standard approach to verify RIs recommended by the Clinical Laboratory Standards Institute (CLSI) EP28-A3c guideline for routine clinical laboratories is to collect and analyze a minimum of 20 samples from healthy subjects from the local population. Alternatively, “data mining” techniques using large amounts of patient test results can be used to verify RIs, considering both the laboratory method and local population. Although procedures for verifying RIs in the literature and guidelines are clear in theory, gaps remain for the implementation of these procedures in routine clinical laboratories. Pediatric and geriatric age-groups also continue to pose additional challenges in respect of acquiring and verifying RIs. In this article, we review the current guidelines/approaches and challenges to RI verification and provide a practical guide for routine implementation in clinical laboratories.

The Australasian Association of Clinical Biochemists (AACB) has over the past 5 years been actively working to achieve harmonized reference intervals (RIs) for common clinical chemistry analytes using an evidence-based checklist approach where there is sound calibration and metrological traceability. It has now recommended harmonized RIs for 18 common clinical chemistry analytes which are performed in most routine laboratories and these have been endorsed by the Royal College of Pathologists of Australasia (RCPA). In 2017 another group of analytes including urea, albumin and arterial blood gas parameters were considered and suggested harmonized RIs proposed. This report provides an update of those harmonization efforts.

Background External quality assessment (EQA) programs for general chemistry tests have evolved from between laboratory comparison programs to trueness verification surveys. In the Netherlands, the implementation of such programs has reduced inter-laboratory variation for electrolytes, substrates and enzymes. This allows for national and metrological traceable reference intervals, but these are still lacking. We have initiated a national endeavor named NUMBER (Nederlandse UniforMe Beslisgrenzen En Referentie-intervallen) to set up a sustainable system for the determination of standardized reference intervals in the Netherlands. Methods We used an evidence-based ‘big-data’ approach to deduce reference intervals using millions of test results from patients visiting general practitioners from clinical laboratory databases. We selected 21 medical tests which are either traceable to SI or have Joint Committee for Traceability in Laboratory Medicine (JCTLM)-listed reference materials and/or reference methods. Per laboratory, per test, outliers were excluded, data were transformed to a normal distribution (if necessary), and means and standard deviations (SDs) were calculated. Then, average means and SDs per test were calculated to generate pooled (mean±2 SD) reference intervals. Results were discussed in expert meetings. Results Sixteen carefully selected clinical laboratories across the country provided anonymous test results (n=7,574,327). During three expert meetings, participants found consensus about calculated reference intervals for 18 tests and necessary partitioning in subcategories, based on sex, age, matrix and/or method. For two tests further evaluation of the reference interval and the study population were considered necessary. For glucose, the working group advised to adopt the clinical decision limit. Conclusions Using a ‘big-data’ approach we were able to determine traceable reference intervals for 18 general chemistry tests. Nationwide implementation of these established reference intervals has the potential to improve unequivocal interpretation of test results, thereby reducing patient harm.

The results of medical laboratory testing are only useful if they lead to appropriate actions by medical practitioners and/or patients. An underappreciated component of the medical testing process is the transfer of the information from the laboratory report into the reader’s brain. The format of laboratory reports can be determined by the testing laboratory, which may issue a formatted report, or by electronic systems receiving information from laboratories and controlling the report format. As doctors can receive information from many laboratories, interpreting information from reports in a safe and rapid manner is facilitated by having similar report layouts and formats. Using Australia as an example, there is a wide variation in report formats in spite of a body of work to define standards for reporting. In addition to standardising of report formats, consideration needs to be given to optimisation of report formatting to facilitate rapid and unambiguous reading of the report and also interpretation of the data. Innovative report formats have been developed by some laboratories; however, wide adoption has not followed. The need to balance uniformity of reporting with appropriate innovation is a challenge for safe reporting of laboratory results. This paper discusses the current status and opportunity for improvement in safety and efficiency of the reading of laboratory reports, using current practise and developments in Australia as examples.

The goal of harmonizing laboratory testing is contributing to improving the quality of patient care and ultimately ameliorating patient outcome. The complete blood and leukocyte differential counts are among the most frequently requested clinical laboratory tests. The morphological assessment of peripheral blood cells (PB) through microscopic examination of properly stained blood smears is still considered a hallmark of laboratory hematology. Nevertheless, a variable inter-observer experience and the different terminology used for characterizing cellular abnormalities both contribute to the current lack of harmonization in blood smear revision. In 2014, the Working Group on Diagnostic Hematology of the Italian Society of Clinical Chemistry and Clinical Molecular Biology (WGDH-SIBioC) conducted a national survey, collecting responses from 78 different Italian laboratories. The results of this survey highlighted a lack of harmonization of interpretative comments in hematology, which prompted the WGDH-SIBioC to develop a project on “Harmonization of interpretative comments in the laboratory hematology report”, aimed at identifying appropriate comments and proposing a standardized reporting system. The comments were then revised and updated according to the 2016 revision of the World Health Organization classification of hematologic malignancies. In 2016, the Working Group on Diagnostic Hematology of the Italian Society of Clinical Chemistry and Clinical Molecular Biology (WGDH SIBioC) published its first consensus based recommendation for interpretative comments in laboratory hematology reporting whit the purpose of evaluating comments and the aim to (a) reducing their overall number, (b) standardizing the language, (c) providing information that could be easily comprehended by clinicians and patients, (d) increasing the quality of the clinical information, and (e) suggesting additional diagnostic tests when necessary. This paper represents a review of the recommendations of the former document.

Background: The International Organization for Standardization (ISO) 15189 standard provides recommendations for the postexamination reporting phase to enhance quality in clinical laboratories. The purpose of this study was to encourage a broad discussion on current reporting practices for molecular diagnostic tests by conducting a global survey of such practices. Methods: The International Federation of Clinical Chemistry and Laboratory Medicine’s Committee for Molecular Diagnostics (IFCC C-MD) surveyed laboratories on selected ISO 15189 recommendations and topics. The survey addressed the following aspects: (1) laboratory demographics, (2) report format, (3) result reporting/layout, (4) comments in report and (5) interpretation and clinical decision-making information. Additionally, participants indicated categories needing standardization. Results: Sixteen responses from laboratories located in Asia, Europe, the Middle East, North America and South America were received. Several categories yielded 100% agreement between laboratories, whereas other categories had less than or equal to 50% concordance. Participants scored “nomenclature” and “description of methodologies” as the two most frequently cited aspects needing standardization. Conclusions: The postexamination phase requires extensive and consistent communication between the laboratory, the healthcare provider and the end user. Surveyed laboratories were most likely to follow explicit ISO 15189 recommendations vs. recommendations when the term(s) “where appropriate or where applicable” was used. Interpretation and reporting of critical values varied among participants. Although the outcome of this study may not fully represent the practices of all molecular testing laboratories in countries around the world, the survey identified and specified several recommendations that are requirements for harmonized reporting in molecular diagnostics.

Individual laboratories are required to compose an alert list for identifying critical and significant risk results. The high-risk result working party of the Royal College of Pathologists of Australasia (RCPA) and the Australasian Association of Clinical Biochemists (AACB) has developed a risk-based approach for a harmonized alert list for laboratories throughout Australia and New Zealand. The six-step process for alert threshold identification and assessment involves reviewing the literature, rating the available evidence, performing a risk analysis, assessing method transferability, considering workload implications and seeking endorsement from stakeholders. To demonstrate this approach, a worked example for deciding the upper alert threshold for potassium is described. The findings of the worked example are for infants aged 0–6 months, a recommended upper potassium alert threshold of >7.0 mmol/L in serum and >6.5 mmol/L in plasma, and for individuals older than 6 months, a threshold of >6.2 mmol/L in both serum and plasma. Limitations in defining alert thresholds include the lack of well-designed studies that measure the relationship between high-risk results and patient outcomes or the benefits of treatment to prevent harm, and the existence of a wide range of clinical practice guidelines with conflicting decision points at which treatment is required. The risk-based approach described presents a transparent, evidence- and consensus-based methodology that can be used by any laboratory when designing an alert list for local use. The RCPA-AACB harmonized alert list serves as a starter set for further local adaptation or adoption after consultation with clinical users.

Background: The need to harmonize laboratory information is particularly intense in the field of plasma proteins, considering their clinical impact and relevance in monitoring diseases. Methods: We evaluated units and reference intervals (RIs) utilized by participants of the External Quality Assessment Scheme (EQAS) for plasma proteins of the Centre of Biomedical Research. Moreover, we evaluated inter-laboratory analytical variability from 2001 to 2017. Results: The census of participants’ units employed in 2017 showed that for albumin (ALB), ~66% of laboratories still used dL instead of L, and for most other proteins, ~70% still expressed the results in mg/dL. Laboratories primarily used the RIs reported in the packaging inserts of their analytical systems, but for each protein, there was a wide variability of RIs, also among laboratories using the same analytical method. Mean CVs% of the 13 certified proteins in the last five EQA cycles ranged from 3.8% of haptoglobin (HPT) to 12.4% of α 1 -antitrypsin (AAT) and decreased from 2001 to 2017 for most of them, in particular for C3, ALB, α 2 -macroglobulin (A2M), HPT and transferrin (TRF). Conclusions: In the face of a reduction in inter-laboratory variability for a lot of proteins, there has not been a substantial change in the units and in the RIs used by the participants. To change old habits is difficult and requires coordination and collaboration. The EQAS plays an important role in the assessment and monitoring of all elements that contribute to the formulation of laboratory information and may be useful to contribute to their harmonization.

Noklus is a non-profit quality improvement organization that focuses to improve all elements in the total testing process. The aim is to ensure that all medical laboratory examinations are ordered, performed and interpreted correctly and in accordance with the patients’ needs for investigation, treatment and follow-up. For 25 years, Noklus has focused on point-of-care (POC) testing in primary healthcare laboratories and has more than 3100 voluntary participants. The Noklus quality system uses different tools to obtain harmonization and improvement: (1) external quality assessment for the pre-examination, examination and postexamination phase to monitor the harmonization process and to identify areas that need improvement and harmonization, (2) manufacturer-independent evaluations of the analytical quality and user-friendliness of POC instruments and (3) close interactions and follow-up of the participants through site visits, courses, training and guidance. Noklus also recommends which tests that should be performed in the different facilities like general practitioner offices, nursing homes, home care, etc. About 400 courses with more than 6000 delegates are organized annually. In 2017, more than 21,000 e-learning programs were completed.

Quality in diagnostic testing represents a key target of laboratory medicine, for which an assurance around the quality of testing is expected from all involved in the process. Laboratories attempt to assure the quality of their testing by various processes, but especially by performance of internal quality control and external quality assessment (EQA). This is especially true for tests of hemostasis and coagulation. EQA in general provides information on test accuracy and on evaluation of long-term laboratory performance. EQA providers support laboratory performance by various means, including distribution of material for testing of analytes (“proficiency testing”), educational support through expert advice, distribution of publications or case series. Participation in EQA is often a laboratory accreditation requirement. This review aims to identify some of the strengths and weaknesses of EQA, and targets attempts towards harmonization of EQA practice, in order to achieve the best outcome for participant laboratories and, thus, for patients and their clinical care providers.

A large body of evidence collected in recent years demonstrates the vulnerability of the extra-analytical phases of the total testing process (TTP) and the need to promote quality and harmonization in each and every step of the testing cycle. Quality indicators (QIs), which play a key role in documenting and improving quality in TTP, are essential requirements for clinical laboratory accreditation. In the last few years, wide consensus has been achieved on the need to adopt universal QIs and common terminology and to harmonize the management procedure concerning their use by adopting a common metric and reporting system. This, in turn, has led to the definition of performance specifications for extra-analytical phases based on the state of the art as indicated by data collected on QIs, particularly by clinical laboratories attending the Model of Quality Indicators program launched by the Working Group “Laboratory Errors and Patient Safety” of the International Federation of Clinical Chemistry and Laboratory Medicine. Harmonization plays a fundamental role defining not only the list of QIs to use but also performance specifications based on the state of the art, thus providing a valuable interlaboratory benchmark and tools for continuous improvement programs.

Healthcare delivery and responsibility is changing. Patient-centered care is gaining international acceptance with the patient taking greater responsibility for his/her health and sharing decision making for the diagnosis and management of illness. Laboratory medicine must embrace this change and work in a tripartite collaboration with patients and with the clinicians who use clinical laboratory services. Improved communication is the key to participation, including the provision of educational information and support. Knowledge management should be targeted to each stakeholder group. As part of collaborative healthcare clinical laboratory service provision needs to be more flexible and available, with implications for managers who oversee the structure and governance of the service. Increased use of managed point of care testing will be essential. The curriculum content of laboratory medicine training programs will require trainees to undertake practice-based learning that facilitates interaction with patients, clinicians and managers. Continuing professional development for specialists in laboratory medicine should also embrace new sources of information and opportunities for collaborative healthcare.