Vitamin B12 reference intervals on Beckman, Roche and Siemens analytical platforms.

BACKGROUND: Vitamin B12 status is assessed primarily by measuring total serum B12 using competitive binding methods. The lack of availability of a standard material and high-level reference measurement procedure affect the trueness of B12 results; this results in variation between methods. This study aimed to determine the reference intervals for vitamin B12 on three routine analytical platforms. METHOD: A prospective reference population of healthy individuals was recruited according to the IFCC CRIDL criteria. Vitamin B12 samples were measured on Roche, Beckman and Siemens analytical platforms. RESULTS: In total, 300 adult subjects were recruited; the central 95th centile values for B12 for Roche (190-678 ng/mL) and Siemens (181-562 ng/mL) analytical platforms were in a close agreement. Beckman DXi, however, showed a significantly lower reference limit (110-562 ng/mL). All reference intervals are in keeping with previously published data but some are not in agreement with manufacturer provided reference interval. CONCLUSION: As the quality of the reference intervals plays a significant role in clinical outcome, it is of great importance that laboratories use a method-specific reference interval and if possible, locally derived reference intervals until further method standardization occurs.

A proposed Common Training Framework for Specialists in Laboratory Medicine under EU Directive 2013/55/EC (The Recognition of Professional Qualifications).

European Union (EU) Directive 2013/55/EC (The Recognition of Professional Qualifications) allows Member States to decide on a common set of minimum knowledge, skills and competences that are needed to pursue a given profession through a Common Training Framework. To be adopted the framework must combine the knowledge, skills and competences of at least one third of the Member States. Professionals who have gained their qualifications under a Common Training Framework will be able to have these recognised automatically within the Union. The backbone of the European Federation of Clinical Chemistry and Laboratory Medicine's (EFLM) proposed Common Training Framework for non-medical Specialists in Laboratory Medicine is outlined here. It is based on an Equivalence of Standards in education, training, qualifications, knowledge, skills, competences and the professional conduct associated with specialist practice. In proposing the recognition of specialist practice EFLM has identified 15 EU Member States able to meet Equivalence and in whom the profession and/or its training is regulated (an additional EU Commission requirement). The framework supports and contributes to the Directive's enabling goals for increasing professional mobility, safeguarding consumers and ensuring a more equitable distribution of skills and expertise across the Member States. It represents EFLM's position statement and provides a template for professional societies and/or competent authorities to engage with the EU Commission.

The Academy of the European Federation of Clinical Chemistry and Laboratory Medicine and the European Register of Specialists in Laboratory Medicine: guide to the Academy and the Register, version 4 - 2020.

The 4th version of the guide to the Register for European Specialists in Laboratory Medicine (EuSpLM) established by the European Communities Confederation of Clinical Chemistry and Laboratory Medicine describes the transfer of the register to the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) in 2016, the extension in 2018 of the Register beyond the European Union to Europe and the benefits of membership of the EFLM Academy to which the Register transferred on the Academy's launch in 2019. The Academy offers EuSpLM registrants access to benefits that include reduced registration rates at selected conferences and free subscription to Clinical Chemistry and Laboratory Medicine. With effect from 2020 eligibility was extended to anyone with an interest in laboratory medicine. The updated guide describes the electronically driven processes for individual membership and block enrolment from national societies/organisations, and the stepping stones to recognition as an EuSpLM within the Academy. Whilst eligibility for recognition as an EuSpLM remains largely unchanged new expectations across Europe in education, training, professional regulation and qualifications are reflected in updated criteria. The continuing driver for establishing the Academy and growing the EFLM Register reflects the federation's leadership role in the harmonisation of high quality education and training for those with an interest in laboratory medicine as well as ongoing initiatives to establish a Common Training Framework for Specialists in Laboratory Medicine under EU Directive 2013/55/EC (The Recognition of Professional Qualifications).

The European Federation of Clinical Chemistry and Laboratory Medicine syllabus for postgraduate education and training for Specialists in Laboratory Medicine: version 5 - 2018.

Although laboratory medicine practise varies across the European Union's (EU) member states, the extent of overlap in scope is such that a common syllabus describing the education and training associated with high-quality, specialist practise can be identified. In turn, such a syllabus can help define the common set of skills, knowledge and competence in a Common Training Framework (CTF) for non-medical Specialists in Laboratory Medicine under EU Directive 2013/55/EU (The recognition of Professional Qualifications). In meeting the requirements of the directive's CTF patient safety is particularly enhanced when specialists seek to capitalise on opportunities for free professional migration across EU borders. In updating the fourth syllabus, the fifth expands on individual discipline requirements, new analytical techniques and use of statistics. An outline structure for a training programme is proposed together with expected responsibilities of trainees and trainers; reference is provided to a trainee's log book. In updating the syllabus, it continues to support national programmes and the aims of EU Directive 2013/55/EU in providing safeguards to professional mobility across European borders at a time when the demand for highly qualified professionals is increasing in the face of a disparity in their distribution across Europe. In support of achieving a CTF, the syllabus represents EFLM's position statement for the education and training that underpins the framework.

Comparison of method-related reference intervals for thyroid hormones: studies from a prospective reference population and a literature review.

Introduction Reference intervals are dependent on the reference population, the analytical methods and the way the data are handled statistically. Individual method-related differences have been studied but the comparative differences in reference intervals have not. Methods We studied a reference population of healthy adult subjects and measured free thyroxine and thyroid-stimulating hormone by the four most commonly used analytical platforms used in the UK. Subjects were excluded if they were > 65 years or had positive thyroid peroxidase antibodies. We also performed a systematic literature review of thyroid hormone reference interval studies in non-pregnant adults. Results In total, 303 subjects were recruited and 42 excluded. The central 95th centile values for thyroid-stimulating hormone (mIU/L) were Abbott Architect (0.51-3.67); Beckman Unicel DxI (0.57-3.60); Roche Cobas (0.60-4.31) and Siemens Advia Centaur XP (0.63-4.29). The 95th centile values for thyroxine (pmol/L) were Abbott Architect (10.6-15.5); Beckman Unicel DxI (7.9-13.0); Roche Cobas (12.5-19.6) and Siemens Advia Centaur XP (11.8-19.0). We identified 55 papers describing thyroid reference intervals in male and non-pregnant female adults. The values for upper and lower reference intervals by manufacturer varied but were not significantly different for thyroid-stimulating hormone but were for thyroxine. Discussion Our study demonstrates clearly that there are marked variations in the reference intervals for thyroid hormones between analytical platforms. There is an urgent need for standardization of thyroid hormone assays to permit transferability of results. Until then, guidelines will need to reflect this method-related difference.

A practical tool for monitoring the performance of measuring systems in a laboratory network: report of an ACB Working Group.

Background A logical consequence of the introduction of robotics and high-capacity analysers has seen a consolidation to larger units. This requires new structures and quality systems to ensure that laboratories deliver consistent and comparable results. Methods A spreadsheet program was designed to accommodate results from up to 12 different instruments/laboratories and present IQC data, i.e. Levey-Jennings and Youden plots and comprehensive numerical tables of the performance of each item. Input of data was made possible by a 'data loader' by which IQC data from the individual instruments could be transferred to the spreadsheet program on line. Results A set of real data from laboratories is used to populate the data loader and the networking software program. Examples are present from the analysis of variance components, the Levey-Jennings and Youden plots. Conclusions This report presents a software package that allows the simultaneous management and detailed monitoring of the performance of up to 12 different instruments/laboratories in a fully interactive mode. The system allows a quality manager of networked laboratories to have a continuous updated overview of the performance. This software package has been made available at the ACB website.

Analytical performance of 17 general chemistry analytes across countries and across manufacturers in the INPUtS project of EQA organizers in Italy, the Netherlands, Portugal, United Kingdom and Spain.

BACKGROUND: Optimum patient care in relation to laboratory medicine is achieved when results of laboratory tests are equivalent, irrespective of the analytical platform used or the country where the laboratory is located. Standardization and harmonization minimize differences and the success of efforts to achieve this can be monitored with international category 1 external quality assessment (EQA) programs. METHODS: An EQA project with commutable samples, targeted with reference measurement procedures (RMPs) was organized by EQA institutes in Italy, the Netherlands, Portugal, UK, and Spain. Results of 17 general chemistry analytes were evaluated across countries and across manufacturers according to performance specifications derived from biological variation (BV). RESULTS: For K, uric acid, glucose, cholesterol and high-density density (HDL) cholesterol, the minimum performance specification was met in all countries and by all manufacturers. For Na, Cl, and Ca, the minimum performance specifications were met by none of the countries and manufacturers. For enzymes, the situation was complicated, as standardization of results of enzymes toward RMPs was still not achieved in 20% of the laboratories and questionable in the remaining 80%. CONCLUSIONS: The overall performance of the measurement of 17 general chemistry analytes in European medical laboratories met the minimum performance specifications. In this general picture, there were no significant differences per country and no significant differences per manufacturer. There were major differences between the analytes. There were six analytes for which the minimum quality specifications were not met and manufacturers should improve their performance for these analytes. Standardization of results of enzymes requires ongoing efforts.

Post-standardization of routine creatinine assays: are they suitable for clinical applications.

Introduction Reliable serum creatinine measurements are of vital importance for the correct classification of chronic kidney disease and early identification of kidney injury. The National Kidney Disease Education Programme working group and other groups have defined clinically acceptable analytical limits for creatinine methods. The aim of this study was to re-evaluate the performance of routine creatinine methods in the light of these defined limits so as to assess their suitability for clinical practice. Method In collaboration with the Dutch External Quality Assurance scheme, six frozen commutable samples, with a creatinine concentration ranging from 80 to 239 µmol/L and traceable to isotope dilution mass spectrometry, were circulated to 91 laboratories in four European countries for creatinine measurement and estimated glomerular filtration rate calculation. Two out of the six samples were spiked with glucose to give high and low final concentrations of glucose. Results Results from 89 laboratories were analysed for bias, imprecision (%CV) for each creatinine assay and total error for estimated glomerular filtration rate. The participating laboratories used analytical instruments from four manufacturers; Abbott, Beckman, Roche and Siemens. All enzymatic methods in this study complied with the National Kidney Disease Education Programme working group recommended limits of bias of 5% above a creatinine concentration of 100 µmol/L. They also did not show any evidence of interference from glucose. In addition, they also showed compliance with the clinically recommended %CV of ≤4% across the analytical range. In contrast, the Jaffe methods showed variable performance with regard to the interference of glucose and unsatisfactory bias and precision. Conclusion Jaffe-based creatinine methods still exhibit considerable analytical variability in terms of bias, imprecision and lack of specificity, and this variability brings into question their clinical utility. We believe that clinical laboratories and manufacturers should work together to phase out the use of relatively non-specific Jaffe methods and replace them with more specific methods that are enzyme based.

Persistently raised aspartate aminotransferase (AST) due to macro-AST in a rheumatology clinic.

Macrocomplexes between immunoglobins and aspartate aminotransferase (macro-AST) may result in persistently increased AST concentration. The presence of macro-AST in patients has been implicated in unnecessary investigations of abnormal liver function tests. We report the case of a 44-year-old female who presented to the rheumatology clinic with a 12-months' history of constant widespread pain affecting her limbs and was found to have an elevated AST concentration. Further information from her GP revealed a 14-years' history of elevated AST with otherwise normal liver function. Previous abdominal ultrasound and two liver biopsies carried out 2 years apart were normal. This prompted further analytical investigation by the biochemistry department which identified macro-AST as the cause. This case illustrates that persistently raised isolated AST concentration with no other abnormal indices may warrant macroenzyme analysis potentially avoiding unnecessary invasive investigations.

A category 1 EQA scheme for comparison of laboratory performance and method performance: An international pilot study in the framework of the Calibration 2000 project.

INTRODUCTION: In the modern healthcare service, patients receive care in multiple hospitals and healthcare settings. Therefore, harmonization of results from different methods and instruments, both between and within laboratories, is of the utmost importance. The present pilot study aims to test the use of a Category 1 EQA scheme across four European countries by assessing the current level of equivalence of test results. METHOD: This work was led by the Dutch External Quality Assurance Scheme SKML and involved 28 laboratories from three regions in the UK, Spain and Portugal, and 120 laboratories from The Netherlands. A set of six commutable samples, targeted with reference methods, were circulated and 18 biochemistry analytes were tested. RESULTS AND CONCLUSIONS: The Total Error (TE) score, defined as the probability (%) that results are within the Total Error Acceptable (TEA) limits, for the eighteen analytes was calculated. Our data show that there is a need for further harmonization of laboratory data, in particular for electrolytes (calcium, chloride, magnesium, sodium), enzymes (ALT, amylase, AST, LDH), lipids (HDL-cholesterol), and for substrates (creatinine, total protein). Lack of performance consistency between instruments was seen for most analytes. The lack of harmonization is still present despite manufacturer claims of established traceability.

Can current analytical quality performance of UK clinical laboratories support evidence-based guidelines for diabetes and ischaemic heart disease?--A pilot study and a proposal.

BACKGROUND: The implementation of national and international guidelines is beginning to standardise clinical practice. However, since many guidelines have decision limits based on laboratory tests, there is an urgent need to ensure that different laboratories obtain the same analytical result on any sample. A scientifically-based quality control process will be a pre-requisite to provide this level of analytical performance which will support evidence-based guidelines and movement of patients across boundaries while maintaining standardised outcomes. We discuss the finding of a pilot study performed to assess UK clinical laboratories readiness to work to a higher grade quality specifications such as biological variation-based quality specifications. METHODS: Internal quality control (IQC) data for HbA1c, glucose, creatinine, cholesterol and high density lipoprotein (HDL)-cholesterol were collected from UK laboratories participating in the Bio-Rad Unity QC programme. The median of the coefficient of variation (CV%) of the participating laboratories was evaluated against the CV% based on biological variation. RESULTS: Except creatinine, the other four analytes had a variable degree of compliance with the biological variation-based quality specifications. More than 75% of the laboratories met the biological variation-based quality specifications for glucose, cholesterol and HDL-cholesterol. Slightly over 50% of the laboratories met the analytical goal for HBA1c. Only one analyte (cholesterol) had a performance achieving the higher quality specifications consistent with 5σ. CONCLUSIONS: Our data from IQC do not consistently demonstrate that the results from clinical laboratories meet evidence-based quality specifications. Therefore, we propose that a graded scale of quality specifications may be needed at this stage.

Calcium adjustment equations in neonates and children.

BACKGROUND: Calcium exists in human blood in a free form and in a form bound to plasma proteins, principally albumin. Since it is the ionized form that is biologically active, it has long been common practice to present calcium adjusted on the basis of serum albumin concentration. The concept of adjusted calcium has only been evaluated in adults. In this study, we evaluated the use of the adult-adjusted equation to report calcium in children. METHODS: We searched the laboratory information system over three teaching hospitals for young patients aged between newborn and 18 years old with a request for calcium and albumin analysis but with no evidence of disturbances of calcium homeostasis. These data were organized on the basis of age and was separated into four age groups (birth to 1 month old, 1 month to 1 year old, 1 to 5 years old and 5 to 18 years old). These data were subjected to regression analysis to derive the calcium-adjusted equation for each age group. RESULTS: There is an inverse relationship between the bias value and the age. The younger the age, the higher the difference between the adjusted calcium calculated by the adult equation and that calculated by the age-specific equation. This pattern was maintained on all sites. CONCLUSION: For all sites, the adult-adjusted calcium equation may be used to calculate the adjusted calcium for children aged one year old and above.

The implementation of a system for managing analytical quality in networked laboratories.

BACKGROUND: In a network of laboratories analytical variability between instruments, even of the same type, may exist for reasons beyond the control of laboratory staff. Controlling variability is a prerequisite for the application of shared reference ranges and for ensuring the transferability of patient test results. Controlling variability requires a robust, non-conventional quality system to detect poor performance of analysers that are geographically distant. Essential to this quality system is a set of well-defined quality specifications. METHODS: The approach used in our study started with (1) selection of a model for quality specifications based on biological variation; the 'three-level model' (TLM) was selected on the basis of its flexibility to accommodate various levels of analytical performance; (2) determination of the performance characteristics of the 71 analytes measured in core biochemistry in terms of imprecision and bias; (3) defining quality requirements in the form of imprecision, bias and total error for 71 analytes measured routinely in core biochemistry; and (4) developing software to assist a consistent wide application of the quality specifications and to monitor analytical indices to the common quality specifications. RESULTS: In this paper we describe how we have implemented this model across our network. Forty-six of the 71 analytes in our core laboratory repertoire were allocated to the TLM. We were able to demonstrate equivalence of results on all analysers, for 42 out of 46 analytes allocated to this model. CONCLUSIONS: We propose that other networked laboratories should investigate the suitability of this quality system for use in their network.

Transient rise in alkaline phosphatase activity in adults.

Benign transient hyperphosphatasia (BTH) is a condition that occurs mainly in infants and children and is characterised by a transient increase of serum alkaline phosphatase (ALP) activity up to several fold the adult upper reference limit (URL). The present report concerns BTH in 2 patients, aged 59 and 52 years old, who showed no evidence of bone or liver disease but had an increase in ALP activity up to 20-fold and 13-fold the adult URL, respectively. The diagnosis of BTH in the first case was made retrospectively, and after excluding liver and bone disease. However, in the second case the diagnosis was made early in the course of the disease, by performing an ALP isoenzyme electrophoresis test. Lengthy and extensive investigations were avoided in the second case. These cases highlight the occurrence of this condition in adulthood as well as in infancy and childhood.