Defining a metrologically traceable and sustainable calibration hierarchy of international normalized ratio for monitoring of vitamin K antagonist treatment in accordance with International Organization for Standardization (ISO) 17511:2020 standard: communication from the International Federation of Clinical Chemistry and Laboratory Medicine-SSC/ISTH working group on prothrombin time/international normalized ratio standardization.

Calibration of prothrombin time (PT) in terms of international normalized ratio (INR) has been outlined in "Guidelines for thromboplastins and plasmas used to control oral anticoagulant therapy" (World Health Organization, 2013). The international standard ISO 17511:2020 presents requirements for manufacturers of in vitro diagnostic (IVD) medical devices (MDs) for documenting the calibration hierarchy for a measured quantity in human samples using a specified IVD MD. The objective of this article is to define an unequivocal, metrologically traceable calibration hierarchy for the INR measured in plasma as well as in whole blood samples. Calibration of PT and INR for IVD MDs according to World Health Organization guidelines is similar to that in cases where there is a reference measurement procedure that defines the measurand for value assignment as described in ISO 17511:2020. We conclude that, for PT/INR standardization, the optimal calibration hierarchy includes a primary process to prepare an international reference reagent and measurement procedure that defines the measurand by a value assignment protocol conforming to clause 5.3 of ISO 17511:2020. A panel of freshly prepared human plasma samples from healthy adult individuals and patients on vitamin K antagonists is used as a commutable secondary calibrator as described in ISO 17511:2020. A sustainable metrologically traceable calibration hierarchy for INR should be based on an international protocol for value assignment with a single primary reference thromboplastin and the harmonized manual tilt tube technique for clotting time determination. The primary international reference thromboplastin reagent should be used only for calibration of successive batches of the secondary reference thromboplastin reagent.

Analytical performance specifications and quality assurance of point-of-care testing in primary healthcare.

Point-of-care testing (POCT) is the fastest-growing segment of laboratory medicine. This review focuses on the essential aspects of setting analytical performance specifications (APS) and performing quality assurance for POCT in primary healthcare. In-vitro diagnostic medical devices for POCT are typically small and easy to operate. Users often have little to no laboratory experience and may not necessarily see the value of conducting quality assurance on their devices. Therefore, training, guidance, and motivation should be integral parts of the total quality management system, as they are vital for managing errors and ensuring reliable results. It is common to believe that the analytical quality of POCT should be comparable to that of laboratory testing, and as a result, APS should be the same. This paper challenges this concept. The APS for POCT can often be less stringent compared to those used in a central laboratory because the requester is closer to both the analytical and clinical situation. Point-of-care instruments should be selected based on clinical needs, the required analytical quality and user-friendliness in the intended usage setting.Quality assurance should include both internal quality control (IQC) and external quality assessment (EQA). It is recommended that IQC protocols should be dependent on the complexity of the POCT device. A scoring system to determine how frequent IQC should be analyzed in primary healthcare on different types of POCT devices has been suggested. The main challenge in EQA for POCT involves using suitable control materials that reflect instrument performance on patient samples. Obtaining commutable control materials for POCT is difficult since the matrix often is whole blood. An essential aspect of EQA for POCT is that feedback reports should be easily interpretable. Users should receive advice from the EQA organizer regarding the root causes of deviating results. Quality assurance for POCT is not an easy task and presents numerous challenges. However, there is evidence that quality assurance improves the quality of POCT measurements and, consequently, can enhance patient outcomes.

Using three external quality assurance schemes to achieve equivalent international normalized ratio results in primary and secondary healthcare.

OBJECTIVES: Accurate prothrombin time international normalized ratio (INR) results are essential for safe anticoagulation treatment. Patients are treated both in primary and secondary healthcare, therefore equivalence of INR results from point-of-care (POC) and hospital measurement procedures (MPs) are important. It is not possible to evaluate this equivalence in traditional external quality assessment (EQA). The aim of this paper is to describe a special quality assurance system consisting of three different EQA schemes to monitor the harmonization of INR results in Norway. METHODS: The EQA scheme for hospital laboratories uses commutable control materials and evaluates participant performance and the equivalence of hospital MPs. The EQA scheme for primary healthcare laboratories uses non-commutable control materials and evaluates participant performance. A third EQA scheme for selected primary healthcare laboratories uses native patient split samples and evaluates the equivalence between POC and hospital MPs. RESULTS: The relationship between the three EQA schemes is presented. The split sample EQA scheme provides a link between the hospital scheme and the scheme for primary healthcare. Results from 2017 to 2022 are presented for all three schemes. When aberrant EQA results occur Noklus takes actions to be able to have a sustainable equivalence between INR results. CONCLUSIONS: All three EQA schemes are important for monitoring the harmonization of INR results in Norway. This quality assurance system, including help and guidance of the participants, will reduce the risk of harm to patients due to non-equivalence of results from different MPs.

Point-of-care testing in primary healthcare: a scoring system to determine the frequency of performing internal quality control.

OBJECTIVES: Internal quality control (IQC) plays an important role in quality assurance in laboratory medicine. However, there is no universal consensus or guideline on when and how IQC should be analyzed on point-of-care testing (POCT) devices. The aim of this study was to develop a scoring system to determine how often IQC should be analyzed in primary healthcare on the various POCT devices. METHODS: Based on a systematic literature review and a thorough process involving the whole Noklus, a nationwide POC organization, a scoring system for when to analyze IQC was developed. Four factors were considered to significantly impact IQC frequency: The importance of the analyte in diagnosing and monitoring patients, type of POCT device, user-friendliness, and number of patient samples. For each POCT device, the first three factors were given a score, and the sum of the scores determined the general recommended IQC frequency. The number of patient samples determined whether and how to adjust these frequencies in each individual general practice. RESULTS: The scoring system was applied to 17 analytes and 134 different POCT devices (153 analyte-device combinations). Most of the devices analyzing high-risk analytes (71 out of 74) obtained daily or weekly IQC frequency. For example, all blood-cell counters and all glucose meters should undergo IQC daily and weekly, respectively. CONCLUSIONS: This study presents a consensus-based scoring system for differentiated and device-specific recommendations for IQC frequency on POCT devices in primary healthcare. The scoring system can easily be adopted to other local environments and is easy to use.

A national surveillance program for evaluating new reagent lots in medical laboratories.

OBJECTIVES: Differences between laboratory results attributable to the use of different reagent lots can potentially affect the diagnosis and monitoring of patients. To minimize patient risks, all laboratories should verify that new reagent lots meet agreed analytical performance specifications (APS). We propose a simplified, pragmatic approach for laboratories that involves compilating results into a national surveillance program, and present the first results obtained when applying this approach to troponins, glycated hemoglobin (HbA1c), prostate-specific antigen (PSA) and D-dimer. METHODS: In the surveillance program we have (i) determined APS for selected analytes, (ii) implemented a simplified procedure for lot evaluation with patient samples used in laboratories across Norway and (iii) performed central processing of the results from the participating laboratories. RESULTS: Over a one-year period, 27 Norwegian laboratories returned results from 28 lot changes for troponin I, 11 for troponin T, and 29 for HbA1c, PSA and D-dimer. The mean difference between two reagent lots was 4.5% for troponin I (for a concentration interval of 20-32 ng/L), 5.1% for troponin T (10.7-17.5 ng/L), 2.2% for HbA1c (40-50 mmol/mol), 3.7% for PSA (3-5 µg/L) and 5.5% for D-dimer (0.4-1.0 mg/L FEU). CONCLUSIONS: A novel procedure for reagent lot evaluation is proposed in which information about multiple lot changes from different medical laboratories can be accumulated nationally. Sharing this information allows simplification of lot evaluations in individual laboratories and provides real-world data about lot-to-lot variations.

Feasibility for aggregation of commutable external quality assessment results to evaluate metrological traceability and agreement among results.

Objectives: External quality assessment (EQA) with commutable samples is used for assessing agreement of results for patients' samples. We investigated the feasibility to aggregate results from four different EQA schemes to determine the bias between different measurement procedures and a reference target value. Methods: We aggregated EQA results for creatinine from programs that used commutable EQA material by calculating the relative difference between individual participant results and the reference target value for each sample. The means and standard errors of the means were calculated for the relative differences. Results were partitioned by methods, manufacturers and instrument platforms to evaluate the biases for the measurement procedures. Results: Data aggregated for enzymatic methods had biases that varied from -8.2 to 3.8% among seven instrument platforms for creatinine at normal concentrations (61-85 µmol/L). EQA schemes differed in the evidence provided about the commutability of their samples, and in the amount of detail collected from participants regarding the measurement procedures which limited the ability to sub-divide aggregated data by instrument platforms and models. Conclusions: EQA data could be aggregated from four different programs using different commutable samples to determine bias among different measurement procedures. Criteria for commutability for EQA samples as well as standardization of reporting the measurement methods, reagents, instrument platforms and models used by participants are needed to improve the ability to aggregate the results for optimal assessment of performance of measurement procedures. Aggregating data from a larger number of EQA schemes is feasible to assess trueness on a global scale.

Harmonising EQA schemes the next frontier: challenging the status quo.

There is a focus on standardisation and harmonisation of laboratory results to reduce the risk of misinterpretation of patient results assayed in different laboratories. External quality assessment (EQA) is critical to assess the need for harmonisation and to monitor the success of procedures to achieve harmonisation. However, EQA providers are being stretched to meet the needs of their participants with proven commutable material with reference method targets, a range of clinically significant levels of the materials, detailed and customised data analysis, and educational support. The path ahead for harmonisation of EQA schemes will require leadership from an organisation that has the support and confidence of EQA providers, like the European Organisation for External Qualily Assurance Providers in Laboratory Medicine.

Performance of Afinion HbA1c measurements in general practice as judged by external quality assurance data.

Background It has been debated whether point-of care (POC) glycated hemoglobin (HbA1c) measurements methods can be used for diagnosing persons with diabetes mellitus. The aim of this study was to evaluate the analytical performance of the POC Afinion HbA1c system in the hands of the users, and to investigate which predictors that were associated with good participant performance. Methods External quality assurance (EQA) data from seven surveys in 2017-2018 with a total of 5809 Afinion participants from a POC total quality system in Norway were included in this study (response rate 90%). The control materials were freshly drawn pooled EDTA whole blood. Each participant was evaluated against the analytical performance specification of ±6% from the target value, while the Afinion system was evaluated against the pooled within-laboratory CV <2%, the between-laboratory CV <3.5%, and bias <0.3%HbA1c. Logistic regression analyses were used to investigate which factors were associated with good participant performance. Results The participant pass rates for each survey varied from 98.2% to 99.7%. The pooled within-laboratory CV varied from 1.3% to 1.5%, the between-laboratory CV varied from 1.5% to 2.1%, and bias varied between -0.17 and -0.01 %HbA1c in all surveys. Reagent lot was the only independent factor to predict good participant performance. Conclusions Afinion HbA1c fulfilled the analytical performance specifications and is robust in the hands of the users. It can therefore be used both in diagnosing and monitoring persons with diabetes mellitus, given that the instrument is monitored by an EQA system.

Pre-analytical practices for routine coagulation tests in European laboratories. A collaborative study from the European Organisation for External Quality Assurance Providers in Laboratory Medicine (EQALM).

Background Correct handling and storage of blood samples for coagulation tests are important to assure correct diagnosis and monitoring. The aim of this study was to assess the pre-analytical practices for routine coagulation testing in European laboratories. Methods In 2013-2014, European laboratories were invited to fill in a questionnaire addressing pre-analytical requirements regarding tube fill volume, citrate concentration, sample stability, centrifugation and storage conditions for routine coagulation testing (activated partial thromboplastin time [APTT], prothrombin time in seconds [PT-sec] and as international normalised ratio [PT-INR] and fibrinogen). Results A total of 662 laboratories from 28 different countries responded. The recommended 3.2% (105-109 mmol/L) citrate tubes are used by 74% of the laboratories. Tube fill volumes ≥90% were required by 73%-76% of the laboratories, depending upon the coagulation test and tube size. The variation in centrifugation force and duration was large (median 2500 g [10- and 90-percentiles 1500 and 4000] and 10 min [5 and 15], respectively). Large variations were also seen in the accepted storage time for different tests and sample materials, for example, for citrated blood at room temperature the accepted storage time ranged from 0.5-72 h and 0.5-189 h for PT-INR and fibrinogen, respectively. If the storage time or the tube fill requirements are not fulfilled, 72% and 84% of the respondents, respectively, would reject the samples. Conclusions There was a large variation in pre-analytical practices for routine coagulation testing in European laboratories, especially for centrifugation conditions and storage time requirements.

Commutability of a Whole-Blood External Quality Assessment Material for Point-of-Care C-Reactive Protein, Glucose, and Hemoglobin Testing.

BACKGROUND: The optimal situation in external quality assessment (EQA) is to use commutable materials. No previous study has examined the commutability of a whole-blood material for point-of-care (POC) testing. The aim of this study was to determine the commutability of the Norwegian Quality Improvement of Laboratory Examinations (Noklus) organization's "in-house" whole-blood EQA material for C-reactive protein (CRP), glucose, and hemoglobin for frequently used POC instruments in Norway and to determine the possibility of using a common target value for each analyte. METHODS: The study was performed according to the Clinical and Laboratory Standards Institute guidelines. The EQA material was pooled stabilized EDTA venous whole-blood containing different concentrations of the analytes. The EQA material and native routine patient samples were analyzed using 17 POC and 3 hospital instruments. The commutability was assessed using Deming regression analysis with 95% prediction intervals for each instrument comparison. RESULTS: The EQA material was commutable for all CRP and hemoglobin POC instruments, whereas for glucose the material was commutable for all POC instruments at the lowest concentration analyzed [126.0 mg/dL (7.0 mmol/L)] and for 3 POC instruments at all of the concentrations analyzed. CONCLUSIONS: Noklus EQA participants using CRP and hemoglobin POC instruments now receive results that are compared with a reference target value, whereas the results for participants using glucose POC instruments are still compared with method-specific target values. Systematic deviations from a reference target value for the commutable glucose POC instruments can be calculated, and this additional information can now be offered to these participants and to the manufacturers.

Harmonization activities of Noklus - a quality improvement organization for point-of-care laboratory examinations.

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.

Analytical performance specifications for external quality assessment - definitions and descriptions.

External Quality Assurance (EQA) is vital to ensure acceptable analytical quality in medical laboratories. A key component of an EQA scheme is an analytical performance specification (APS) for each measurand that a laboratory can use to assess the extent of deviation of the obtained results from the target value. A consensus conference held in Milan in 2014 has proposed three models to set APS and these can be applied to setting APS for EQA. A goal arising from this conference is the harmonisation of EQA APS between different schemes to deliver consistent quality messages to laboratories irrespective of location and the choice of EQA provider. At this time there are wide differences in the APS used in different EQA schemes for the same measurands. Contributing factors to this variation are that the APS in different schemes are established using different criteria, applied to different types of data (e.g. single data points, multiple data points), used for different goals (e.g. improvement of analytical quality; licensing), and with the aim of eliciting different responses from participants. This paper provides recommendations from the European Federation of Laboratory Medicine (EFLM) Task and Finish Group on Performance Specifications for External Quality Assurance Schemes (TFG-APSEQA) and on clear terminology for EQA APS. The recommended terminology covers six elements required to understand APS: 1) a statement on the EQA material matrix and its commutability; 2) the method used to assign the target value; 3) the data set to which APS are applied; 4) the applicable analytical property being assessed (i.e. total error, bias, imprecision, uncertainty); 5) the rationale for the selection of the APS; and 6) the type of the Milan model(s) used to set the APS. The terminology is required for EQA participants and other interested parties to understand the meaning of meeting or not meeting APS.

An overview of the European Organization for External Quality Assurance Providers in Laboratory Medicine (EQALM).

The European Organisation for External Quality Assurance Providers in Laboratory Medicine (EQALM) was founded in 1996 and currently has members from 29 European countries and 6 countries from outside Europe. EQALM provides a forum for co-operation and exchange of knowledge on quality-related matters in laboratory medicine, especially with regard to external quality assessment (EQA) programs in Europe. In addition, EQALM represent the EQA providers in laboratory medicine at European level vis-r-vis political, professional, scientific and other bodies, including patients' organisations. To this end EQALM promotes activities such as organizing meetings with scientific and practical themes for members and other interested parties, issuing scientific publications, developing EQA projects and representing laboratory medicine EQA activities within other organisations and networks. EQALM is active in scientific and educational activity in different fields such as survey frequency, haematology, haemostasis, microbiology, nomenclature, virtual microscopy, traceability, accreditation, and quality assurance of the total testing process. The aim of this paper is to give an overview of the EQALM organisation.

Essential aspects of external quality assurance for point-of-care testing.

External quality assurance (EQA) or proficiency testing for point-of-care (POC) testing is in principle similar to EQA for larger hospital laboratories, but the participants are different. The participants are usually health care personnel with little or no knowledge of laboratory medicine. The implication of this is that the EQA provider has to a) convince the participants that participation in EQA schemes are important, b) be able to circulate materials with reasonable time intervals, c) produce feedback reports that are understandable, and d) offer help and guidance to the participants when needed. It is also important that EQA for POC testing e) address the pre-examination, the examination and the post-examination processes, and f) that schemes for measurement procedures using interval or ordinal scale are offered. The aim of the present paper is to highlight important issues of these essential aspects of EQA for POC testing.

Effect of Participating in a Quality Improvement System over Time for Point-of-Care C-Reactive Protein, Glucose, and Hemoglobin Testing.

BACKGROUND: Users of point-of-care testing (POCT) in Norway participate in a quality improvement system that includes education and guidance in safe laboratory management along with participation in external quality assurance schemes (EQAS).The aim of this study was to identify the effect on the analytical performance of POCT C-reactive protein (CRP), glucose, and hemoglobin (Hb) with the use of a quality improvement system over time and to identify which factors are associated with good performance. METHODS: Participants' results from 19 EQAS for CRP, glucose, and Hb from 2006 to 2015 along with information on the instruments used and different practice characteristics were analyzed. Logistic regression analysis was used to evaluate the factors associated with good laboratory performance. An instrument evaluation and comparison for CRP determination was performed by using commutable EQA material. RESULTS: The mean number of participants in each EQAS was 2134, 2357, and 2271 for CRP, glucose, and Hb, respectively. The percentage of good participant performances increased gradually whereas that of poor performances decreased with participation in a quality improvement system over 9 years for all 3 analytes. Independent factors associated with good performance were type of instrument, the number of times performing EQA, performing internal QC weekly, performing 10 or more tests weekly, and having laboratory-qualified personnel perform the tests. Considering CRP instrument performance, Afinion and QuikRead exhibited the lowest systematic deviation. CONCLUSIONS: The analytical quality of CRP, glucose, and Hb testing is improved by systematic participation in a quality improvement system over time.

The Importance of Reagent Lot Registration in External Quality Assurance/Proficiency Testing Schemes.

BACKGROUND: Providers of external quality assurance (EQA)/proficiency testing schemes have traditionally focused on evaluation of measurement procedures and participant performance and little attention has been given to reagent lot variation. The aim of the present study was to show the importance of reagent lot registration and evaluation in EQA schemes. METHODS: Results from the Noklus (Norwegian Quality Improvement of Primary Care Laboratories) urine albumin/creatinine ratio (ACR) and prothrombin time international normalized ratio (INR) point-of-care EQA schemes from 2009-2015 were used as examples in this study. RESULTS: The between-participant CV for Afinion ACR increased from 6%-7% to 11% in 3 consecutive surveys. This increase was caused by differences between albumin reagent lots that were also observed when fresh urine samples were used. For the INR scheme, the CoaguChek INR results increased with the production date of the reagent lots, with reagent lot medians increasing from 2.0 to 2.5 INR and from 2.7 to 3.3 INR (from the oldest to the newest reagent lot) for 2 control levels, respectively. These differences in lot medians were not observed when native patient samples were used. CONCLUSIONS: Presenting results from different reagent lots in EQA feedback reports can give helpful information to the participants that may explain their deviant EQA results. Information regarding whether the reagent lot differences found in the schemes can affect patient samples is important and should be communicated to the participants as well as to the manufacturers. EQA providers should consider registering and evaluating results from reagent lots.

Self-management of warfarin therapy.

BACKGROUND: Clinical studies from other countries show that self-management of warfarin therapy may reduce the risk of mortality, thromboembolism and complications when compared to conventional therapy. The purpose of this study was to train patients in self-management and compare the results with conventional therapy in Norway. METHOD: A total of 23 patients who had previously been given conventional therapy by their GPs were instructed in how to measure INR (using the CoaguChek XS device) and administer warfarin dosage through a structured training programme over the course of 27 weeks. The participants continued with self-management for a further 28 weeks after the end of the training period. The time in the therapeutic range (TTR, measured as a percentage) was calculated and the TTR for conventional therapy and self-management were compared. RESULTS: No significant difference in average TTR was found when comparing conventional therapy (70% (95% confidence interval (CI) 62-78)) with the self-management period (75% (95% CI 69-81, p = 0.24)). The percentage of extreme INR values (< 1.5 or > 5.0) was higher during conventional therapy than during self-management (6.8% vs. 1.0%, p < 0.001). INTERPRETATION: No significant difference in TTR was found when comparing self-management and conventional warfarin therapy in our study, but for self-management there was a lower percentage of extreme INR values compared to conventional warfarin therapy.

The influence of coagulation factors on the in-treatment biological variation of international normalized ratio for patients on warfarin.

BACKGROUND: Biological variation is usually estimated in healthy individuals during steady-state conditions. The aim of this study was to estimate the in-treatment biological variation of the International normalised ratio (INR) and to investigate to what extent the different levels of coagulation factors could explain this variation. METHODS: Blood samples were collected from randomly included patients on warfarin treatment. INR was determined on a laboratory instrument (STA Compact(®)) and on three point-of-care instruments (Simple Simon(®)PT, CoaguChek(®)XS and INRatio(™)). The level of fibrinogen, and the activity of coagulation factors II, V, VII and X were determined. RESULTS: The in-treatment within- and between-subject coefficients of variation of INR were dependent on the method and varied between 18 and 24% and 13 and 19%, respectively, and were reduced to 3.9-5.1% and 2.3-5.8%, after correction for coagulation factors which could explain 91-95% of the variance of INR. CONCLUSIONS: The in-treatment biological variation of INR was higher than reported for healthy individuals as well as patients in a steady-state condition, but by correcting for appropriate coagulation factors it was reduced. The association between INR and coagulation factors was different for the different PT methods mainly due to different sensitivity towards FII and FVII.