Compliance to specifications in an external quality assurance program: did new biological variation estimates of the European Federation of Laboratory Medicine (EFLM) affect the quality of laboratory results?

Objectives: The results of external quality assurance schemes are evaluated against specifications generally based on biological variation (BV) data. This study was carried out to determine whether new BV values affected the level of compliance to specifications. Our secondary objective was to identify the conditions that would be compromised as a result of poor analytical performance in disease associated markers. Methods: This study was based on the results of the SEQCML External Quality Assurance scheme for the 2015-2022 period. Deviation of the individual result from the target value was estimated. Additionally, we calculated the percentage of results that met the pre-established specification. Results: In 97 of the 133 analytes, the level of compliance was maintained in 80-90 % of the results obtained in the two study periods. In 23 analytes, the level of compliance ranged from 51 to 79 % in the two study periods. In ALT, AST and sodium, the level of compliance was ≤50 % of the results obtained in the first study period, with sodium being the only analyte that maintained this poor level of compliance in the second study period. Conclusions: The level of compliance to specifications remained independent from the specification used (SEQCML or EFLM) for the majority of the analytes. The results for sodium ion were below the target value, which may lead to misdiagnosis of hyponatremia. Non-compensated alkaline picrate methods overestimate creatinine, which may produce false information suggestive of kidney failure.

Internal quality control - past, present and future trends.

Objectives: This paper offers an historical view, through a summary of the internal quality control (IQC) models used from second half of twentyth century to those performed today and wants to give a projection on how the future should be addressed. Methods: The material used in this work study are all papers collected referring IQC procedures. The method used is the critical analysis of the different IQC models with a discussion on the weak and the strong points of each model. Results: First models were based on testing control materials and using multiples of the analytical procedure standard deviation as control limits. Later, these limits were substituted by values related with the intended use of test, mainly derived from biological variation. For measurands with no available control material methods based on replicate analysis of patient' samples were developed and have been improved recently; also, the sigma metrics that relates the quality desired with the laboratory performance has resulted in a highly efficient quality control model. Present tendency is to modulate IQC considering the workload and the impact of analytical failure in the patent harm. Conclusions: This paper remarks the strong points of IQC models, indicates the weak points that should be eliminated from practice and gives a future projection on how to promote patient safety through laboratory examinations.

External quality control in laboratory medicine. Progresses and future.

Objectives: An external quality control program distributes same control samples to various laboratories and evaluates results obtained with a common criterion. The aim of this work is to summarize the evolution of various types of external programs, to point out the progresses ant to preclude practical consequences of the participant laboratories. Content: The material consists on a brief revision of the different types of external programs that have been used for the last forty years. The method is the critical analysis of the strong and weak points of each program model, from the light of our experience. External quality assessment (EQA) programs were initiated at half the XX century, evidencing big discrepancies among laboratory results. EQA were developed in various countries and some mechanisms to harmonize them were proposed: to establish common performance specifications derived from biological variation, to use EQS as educational tool. Since the 2000 important advances were seen: to focus EQA to assure the adequate clinical use of laboratory tests, to use commutable controls, to harmonize the different EQA models, to promote a forum for co-operation and exchange of knowledge on quality-related matters for EQA organizers. Summary and Outlook: To participate in an EQA with commutable-reference method assigned values controls allows to know the real inaccuracy of results and their impact on patient' samples. To participate in a EQA with non commutable controls allows to know whether the individual laboratory performance agrees with that from other laboratories using same analytical method.

Critical appraisal and meta-analysis of biological variation estimates for kidney related analytes.

OBJECTIVES: Kidney markers are some of the most frequently used laboratory tests in patient care, and correct clinical decision making depends upon knowledge and correct application of biological variation (BV) data. The aim of this study was to review available BV data and to provide updated BV estimates for the following kidney markers in serum and plasma; albumin, creatinine, cystatin C, chloride, potassium, sodium and urea. CONTENT: Relevant studies were identified from a historical BV database as well as by systematic literature searches. Retrieved publications were appraised by the Biological Variation Data Critical Appraisal Checklist (BIVAC). Meta-analyses of BIVAC compliant studies with similar design were performed to deliver global estimates of within-subject (CVI) and between-subject (CVG) BV estimates. Out of the 61 identified papers, three received a BIVAC grade A, four grade B, 48 grade C, five grade D grade and one was not appraised as it did not report numerical BV estimates. Most studies were identified for creatinine (n=48). BV estimates derived from the meta-analysis were in general lower than previously reported estimates for all analytes except urea. For some measurands, BV estimates may be influenced by age or states of health, but further data are required. SUMMARY: This review provides updated global BV estimates for kidney related measurands. For all measurands except for urea, these estimates were lower than previously reported. OUTLOOK: For the measurands analyzed in this review, there are sufficient well-designed studies available to publish a trustworthy estimate of BV. However, for a number of newly appearing kidney markers no suitable data is available and additional studies are required.

Models to estimate biological variation components and interpretation of serial results: strengths and limitations.

Biological variation (BV) has multiple applications in a variety of fields of clinical laboratory. The use of BV in statistical modeling is twofold. On the one hand, some models are used for the generation of BV estimates (within- and between-subject variability). Other models are built based on BV in combination with other factors to establish ranges of normality that will help the clinician interpret serial results for the same subject. There are two types of statistical models for the calculation of BV estimates: A. Direct methods, prospective studies designed to calculate BV estimates; i. Classic model: developed by Harris and Fraser, revised by the Working Group on Biological Variation of the European Federation of Laboratory Medicine. ii. Mixed-effect models. iii. Bayesian model. B. Indirect methods, retrospective studies to derive BV estimates from large databases of results. Big data. Understanding the characteristics of these models is crucial as they determine their applicability in different settings and populations. Models for defining ranges that help in the interpretation of individual serial results include: A. Reference change value and B. Bayesian data network. In summary, this review provides an overview of the models used to define BV components and others for the follow-up of patients. These models should be exploited in the future to personalize and improve the information provided by the clinical laboratory and get the best of the resources available.

Critical appraisal and meta-analysis of biological variation studies on glycosylated albumin, glucose and HbA1c.

Objectives: Numerous biological variation (BV) studies have been performed over the years, but the quality of these studies vary. The objectives of this study were to perform a systematic review and critical appraisal of BV studies on glycosylated albumin and to deliver updated BV estimates for glucose and HbA1c, including recently published high-quality studies such as the European Biological Variation study (EuBIVAS). Methods: Systematic literature searches were performed to identify BV studies. Nine publications not included in a previous review were identified; four for glycosylated albumin, three for glucose, and three for HbA1c. Relevant studies were appraised by the Biological Variation Data Critical Appraisal Checklist (BIVAC). Global BV estimates were derived by meta-analysis of BIVAC-compliant studies in healthy subjects with similar study design. Results: One study received BIVAC grade A, 2B, and 6C. In most cases, the C-grade was associated with deficiencies in statistical analysis. BV estimates for glycosylated albumin were: CVI=1.4% (1.2-2.1) and CVG=5.7% (4.7-10.6), whereas estimates for HbA1c, CVI=1.2% (0.3-2.5), CVG=5.4% (3.3-7.3), and glucose, CVI=5.0% (4.1-12.0), CVG=8.1% (2.7-10.8) did not differ from previously published global estimates. Conclusions: The critical appraisal and rating of BV studies according to their methodological quality, followed by a meta-analysis, generate robust, and reliable BV estimates. This study delivers updated and evidence-based BV estimates for glycosylated albumin, glucose and HbA1c.

Modelos para estimar la variación biológica y la interpretación de resultados seriados: bondades y limitaciones.

La variación biológica (VB) tiene múltiples aplicaciones en diversos campos del laboratorio clínico. Hay dos formas de relacionar el concepto de VB y los modelos estadísticos. Por un lado existen modelos para el cálculo de estimados de VB (intra e inter individual) y por otro, existen modelos que tienen en cuenta la VB y otros factores para la definición de rangos que ayudan a la interpretación de resultados seriados en un mismo individuo. Dentro de los modelos estadísticos dirigidos al cálculo de los estimados de VB existen dos tipos: A. Métodos directos. Estudios prospectivos, diseñados exclusivamente para el cálculo de estimados de VB: i. Modelo clásico: desarrollado por Harris y Fraser, revisado por EFLM-BVWG. ii. Modelos de efectos mixtos iii. Modelo bayesiano. B. Métodos indirectos. Estudios retrospectivos basados en extraer estimados de VB a partir de resultados que provienen de grandes bases de datos. Big-data. Ambos tipos presentan una serie de características que es importante conocer porque pueden condicionar su aplicabilidad en diferentes situaciones o poblaciones. Entre los modelos para definir rangos que ayudan a la interpretación de resultados seriados en un individuo encontramos: A. Valor de referencia del cambio (VRC). B. Red de datos bayesiana. En resumen, esta revisión pretende dar un enfoque general sobre los modelos para definir los componentes de VB así como otros para aplicarlos en el seguimiento de pacientes, que deberían ser explorados en el futuro para personalizar y mejorar la información aportada por el laboratorio clínico, aprovechando al máximo los recursos disponibles.

Impact of implementing a category 1 external quality assurance scheme for monitoring harmonization of clinical laboratories in Spain.

Background: The objective of the present study was to examine the evolution of the analytical performance specifications (APS) used in External Quality Assurance (EQA) schemes, as well as the efficacy of a category 1 EQA scheme in monitoring the harmonization of clinical laboratory results in Spain. Methods: A review of the literature on the types of quality specifications used in schemes in other countries and their evolution was performed. In addition, a comparative analysis of the potential impact that different APS from eight countries had on clinical decision-making was made based on three measurands: sodium, thyroid-stimulating hormone (TSH), and activated partial thromboplastin time (aPTT). Results: Harmonization of analytical methods was demonstrated by assessing whether average results deviated from the certified reference value of control materials within the APS derived from biological variation (BV). The APS used in EQA have evolved from state-of-the-art models to BV. Poor clinical decision-making would occur if the results accepted by some APS were applied. Conclusions: In Spain, only 2 of the 18 measurands studied are considered to be well harmonized. Closer collaboration between laboratories and analytical system providers would be required to resolve discrepancies.

Spanish society of laboratory medicine external quality assurance programmes: evolution of the analytical performance of clinical laboratories over 30 years and comparison with other programmes.

The purpose of this study is to understand the evolution of the analytical performance of the laboratories participating in the Spanish society of laboratory medicine (SEQCML) external quality assurance (EQA) programmes during its 30 years of operation and to compare it with the performance of other EQA programmes to establish whether the results are similar. The results obtained during this period are evaluated by applying the biological variability (BV) and state of the art-derived quality specifications. In addition, the results are compared with those obtained by other EQA programme organisations. It is noted that the laboratories participating in the EQA-SEQCML programmes have improved their performance over 30 years of experience and that the specifications derived from biological variation are achievable. It is difficult to compare EQA programmes, due to lack of accessibility and the differences in the design of these programmes (control materials, calculations used and analytical specifications established). The data from this study show that for some biological magnitudes the results obtained by the programmes are not yet harmonised, although efforts are being made to achieve this. Organisers of EQA programmes should also join the harmonisation effort by providing information on their results to enable comparison.

Systematic review and meta-analysis of within-subject and between-subject biological variation estimates of 20 haematological parameters.

Background Interpretation of the complete blood count (CBC) parameters requires reliable biological variation (BV) data. The aims of this study were to appraise the quality of publications reporting BV data for CBC parameters by applying the BV Data Critical Appraisal Checklist (BIVAC) and to deliver global BV estimates based on BIVAC compliant studies. Methods Relevant publications were identified by a systematic literature search and evaluated for their compliance with the 14 BIVAC criteria, scored as A, B, C or D, indicating decreasing compliance. Global CVI and CVG estimates with 95% CI were delivered by a meta-analysis approach using data from BIVAC compliant papers (grades A-C). Results In total, 32 studies were identified; four received a BIVAC grade A, 2 B, 20 C and 6 D. Meta-analysis derived CVI and CVG estimates were generally lower or in line with those published in a historical BV database available online. Except for reticulocytes, CVI estimates of erythrocyte related parameters were below 3%, whereas platelet (except MPV and PDW) and leukocyte related parameters ranged from 5% to 15%. Conclusions A systematic review of CBC parameters has provided updated, global estimates of CVI and CVG that will be included in the newly published European Federation of Clinical Chemistry and Laboratory Medicine BV Database.

Biological variation data for lipid cardiovascular risk assessment biomarkers. A systematic review applying the biological variation data critical appraisal checklist (BIVAC).

BACKGROUND: Biological variation (BV) data can be used to set analytical performance specifications (APS) for lipid assays. Poor performance will impact upon the efficacy of international guidelines for cardiovascular risk assessment (CVR) and relevant clinical decision limits. This systematic review applies the Biological Variation Data Critical Appraisal Checklist (BIVAC) to published studies of BV of CVR biomarkers enabling metanalysis of the data. METHODS: Studies of BV of total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and apolipoproteins A1 and B, retrieved using a systematic literature search, were evaluated and graded using the BIVAC. Meta-analysis of CVI and CVG estimates were performed utilizing weightings based upon BIVAC grades and the width of the data confidence intervals. RESULTS: Applying the BIVAC, ten publications were graded as D, 43 as C, 5 as B and 1 as A (fully compliant). A total of 196 CVI and 87 CVG estimates were available for the different lipid measurands. The meta-analysis-derived BV data estimates were generally concordant with those in the online 2014 BV database. CONCLUSIONS: Application of BIVAC identifies BV data suitable for many important applications including setting APS. Additionally, this review identifies a need for new BIVAC compliant studies to deliver BV reference data in different subpopulations.

Standardization in laboratory medicine: Two years' experience from category 1 EQA programs in Spain.

INTRODUCTION: Standardization is the ability to obtain interchangeable results leading to same medical interpretation. External quality assessment (EQA) is the main support of the on-going harmonization initiatives. Aim of study was to evaluate results obtained from two years category 1 EQA program experience in Spain and determine the impact of applying this type of EQA program on the analytical standardization. MATERIALS AND METHODS: According to the analytical method, traceability and instrument different groups were established which results were evaluated by calculating mean, coefficient of variation and percent of deviation to the reference value. Analytical performance specifications used to the results' evaluation were derived from biological variation for bias and from the inter-laboratory coefficients of variation found in a previous pilot study. RESULTS: Only creatinine measured by enzymatic methods gave excellent results, although few laboratories used this method. Creatine kinase and GGT gave good precision and bias in all, but one instrument studied. For the remaining analytes (ALT, ALP, AST, bilirubin, calcium, chloride, glucose, magnesium, potassium, sodium, total protein and urate) some improvement is still necessary to achieve satisfactory standardization in our setting. CONCLUSIONS: The two years of category 1 EQA program experience in Spain have manifested a lack of standardization of 17 most frequent biochemistry tests used in our laboratories. The impact of the information obtained on the lack of standardization is to recommend abandoning methods such as ALT, AST without exogenous pyridoxal phosphate, Jaffe method for creatinine, and do not use non-commutable calibrators, such as aqueous solutions for calcium and sodium.

The Biological Variation Data Critical Appraisal Checklist: A Standard for Evaluating Studies on Biological Variation.

BACKGROUND: Concern has been raised about the quality of available biological variation (BV) estimates and the effect of their application in clinical practice. A European Federation of Clinical Chemistry and Laboratory Medicine Task and Finish Group has addressed this issue. The aim of this report is to (a) describe the Biological Variation Data Critical Appraisal Checklist (BIVAC), which verifies whether publications have included all essential elements that may impact the veracity of associated BV estimates, (b) use the BIVAC to critically appraise existing BV publications on enzymes, lipids, kidney, and diabetes-related measurands, and (c) apply metaanalysis to deliver a global within-subject BV (CVI) estimate for alanine aminotransferase (ALT). METHODS: In the BIVAC, publications were rated as A, B, C, or D, indicating descending compliance for 14 BIVAC quality items, focusing on study design, methodology, and statistical handling. A D grade indicated that associated BV estimates should not be applied in clinical practice. Systematic searches were applied to identify BV studies for 28 different measurands. RESULTS: In total, 128 publications were identified, providing 935 different BV estimates. Nine percent achieved D scores. Outlier analysis and variance homogeneity testing were scored as C in >60% of 847 cases. Metaanalysis delivered a CVI estimate for ALT of 15.4%. CONCLUSIONS: Application of BIVAC to BV publications identified deficiencies in required study detail and delivery, especially for statistical analysis. Those deficiencies impact the veracity of BV estimates. BV data from BIVAC-compliant studies can be combined to deliver robust global estimates for safe clinical application.

Category 1 external quality assessment program for serum creatinine.

BACKGROUND: The Commission of Analytical Quality and the Committee of External Quality Programs of Spanish Society of Laboratory Medicine (SEQC) in collaboration with the Dutch Foundation for the Quality organized the first national category 1 External Quality Assessment Programs (EQAP) pilot study. The aim is to evaluate the standardization of serum creatinine measurements in the Spanish laboratories through a category 1 external quality assurance program with commutable material and reference method assigned values. METHODS: A total of 87 Spanish laboratories were involved in this program in 2015. Each day a sample control was measured by duplicate during 6 consecutive days. Percentage deviations and coefficients of variation obtained were compared with quality specifications derived from biological variation. RESULTS: A total of 1044 creatinine results were obtained. Laboratories were coded in 11 different method-traceability combinations. Only enzymatic methods get all results within the acceptability limits. DISCUSSION: To participate in a category 1 EQAP is a valuable tool to assess the standardization degree in our country; a big effort should be made to promote laboratories to change their procedures and to use enzymatic creatinine methods, in order to achieve a satisfactory standardization degree for this important analyte.

Biologic Variation Approach to Daily Laboratory.

Biological variation gives valuable information about how the living organism regulates its constituents within and between subjects; this information on the behavior of body components allows us to derive consequences concerning reference populations and intervals. With a more pragmatic approach biological variation has three uses: setting the appropriate analytical performance specification for each analyte to limit the amount of error that laboratory could introduce in its measurements, to help distinguish health from disease, and to implement internal quality control with the automatic verification of results.

State-of-the-art Approach to Goal Setting.

Four external quality assurance programs combined their data to calculate the minimum acceptable quality specifications for laboratory testing. Other sources of quality specifications may be too stringent for the current market, or too lenient given the clinical demands on the test result, but these state-of-the-art goals may be practical and useful. Two main approaches were used: (1) defining the 95% percentile and comparing with other quality specifications, and (2) using an iterative approach to increase the quality specification until 90% of laboratories could achieve 75% of their results within the specification. 72 out of 82 analytes followed procedure 2.

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.

Respuesta de los autores «Ventajas del control de calidad interno de gestión externa» / Reply for author «Advantages of externally managed internal quality control»

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