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.

Biological Variation of Cardiac Troponins in Health and Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Many studies have assessed the biological variation (BV) of cardiac-specific troponins (cTn), reporting widely varying within-subject BV (CVI) estimates. The aim of this study was to provide meta-analysis-derived BV estimates for troponin I (cTnI) and troponin T (cTnT) for different sampling intervals and states of health. METHODS: Relevant studies were identified by a systematic literature search. Studies were classified according to their methodological quality by the Biological Variation Data Critical Appraisal Checklist (BIVAC). Meta-analyses of BIVAC-compliant studies were performed after stratification by cTn isoform, exclusion of results below the limit of detection, states of health, and sampling interval to deliver reference change values (RCV), index of individuality (II) and analytical performance specifications (APS) for these settings. RESULTS: Sixteen and 15 studies were identified for cTnI and cTnT, respectively, out of which 6 received a BIVAC grade A. Five studies had applied contemporary cTnI assays, but none contemporary cTnT. High-sensitivity (hs-) cTnI and cTnT delivered similar estimates in all settings. Long-term CVI estimates (15.1; 11.3%) derived from healthy individuals were higher than short-term (4.3%; 5.3%) for hs-cTnI and hs-cTnT, respectively, although confidence intervals overlapped. Estimates derived from diseased subjects were similar to estimates in healthy individuals for all settings. CONCLUSIONS: This study provides robust estimates for hs-cTnI and hs-cTnT applicable for different clinical settings and states of health, allowing for the use of RCV both to aid in the diagnosis of myocardial injury and for prognosis. BV-based APS appear too strict for some currently available technologies.

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.

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.

Reaching consensus on communication of critical laboratory results using a collective intelligence method.

BACKGROUND: There is no consensus in the literature about what analytes or values should be informed as critical results and how they should be communicated. The main aim of this project is to establish consensual standards of critical results for the laboratories participating in the study. Among the project's secondary objectives, establishing consensual procedures for communication can be highlighted. METHODS: Consensus was reached among all participating laboratories establishing the basis for the construction of the initial model put forward for consensus in conjunction with the clinicians. A real-time Delphi, methodology "health consensus" (HC), with motivating and participative questions was applied. The physician was expected to choose a numeric value within a scale designed for each analyte. RESULTS: The medians of critical results obtained represent the consensus on critical results for outpatient and inpatient care. Both in primary care and in hospital care a high degree of consensus was observed for critical values proposed in the analysis of creatinine, digoxin, phosphorus, glucose, international normalized ratio (INR), leukocytes, magnesium, neutrophils, chloride, sodium, calcium and lithium. For the rest of critical results the degree of consensus obtained was "medium high". The results obtained showed that in 72% of cases the consensual critical value coincided with the medians initially proposed by the laboratories. CONCLUSIONS: The real-time Delphi has allowed obtaining consensual standards for communication of critical results among the laboratories participating in the study, which can serve as a basis for other organizations.

Biological variation database: structure and criteria used for generation and update.

BACKGROUND: Numerical data on the components of biological variation (BV) have many uses in laboratory medicine, including in the setting of analytical quality specifications, generation of reference change values and assessment of the utility of conventional reference values. METHODS: Generation of a series of up-to-date comprehensive database of components of BV was initiated in 1997, integrating the more relevant information found in publications concerning BV. A scoring system was designed to evaluate the robustness of the data included. The database has been updated every 2 years, made available on the Internet and derived analytical quality specifications for imprecision, bias and total allowable error included in the tabulation of data. RESULTS AND CONCLUSIONS: Our aim here is to document, in detail, the methodology we used to evaluate the reliability of the included data compiled from the published literature. To date, our approach has not been explicitly documented, although the principles have been presented at many symposia, courses and conferences.

Rationale for using data on biological variation.

The aims of this study are: 1) to use the data included in the biological variation (BV) database to address the usability of BV estimates; and 2) to use different examples from the authors' laboratories to illustrate the use and the usefulness of BV data in laboratory medicine. The BV database is an essential tool for laboratory management. Examples of application of data derived from BV are given in this paper, such as analytical performance specifications that have been included in various quality control software designed to optimize operative rules; also they have been incorporated as acceptability limits in external quality assurance reports. BV data from pathological status are of utmost interest for monitoring patients and differences between the intra-individual coefficients of variation (CVI) estimated from healthy and patients are shown. However, for a number of analytes there are limited data available and for many there are no data, consequently new studies should be encouraged at an international level. In addition, developing international criteria to evaluate publications dealing with the estimation of BV components would be of the utmost interest. We are ready and willing to collaborate with such worthy initiatives. The first EFLM strategic conference on analytical performance specifications is an excellent opportunity for debating these ideas.

Harmonization in hemolysis detection and prevention. A working group of the Catalonian Health Institute (ICS) experience.

BACKGROUND: Hemolysis is the main cause of non-quality samples in clinical laboratories, producing the highest percentage of rejections in the external assurance programs of preanalytical quality. The objective was to: 1) study the agreement between the detection methods and quantification of hemolysis; 2) establish comparable hemolysis interference limits for a series of tests and analytical methods; and 3) study the preanalytical variables which most influence hemolysis production. METHODS: Different hemoglobin concentration standards were prepared using the reference method. Agreement was studied between automated methods [hemolytic indexes (HI)] and reference method, as well as the interference according to hemolysis degree in various biochemical tests was measured. Preanalytical variables which could influence hemolysis production were studied: type of extraction, type of tubes, transport time, temperature and centrifugation conditions. RESULTS: Good agreement was obtained between hemoglobin concentrations measured using the reference method and HI, for the most of studied analyzers, particularly those giving quantitative HI. The hemolysis interference cut-off points obtained for the majority of tests studied (except LDH, K) are dependent on the method/analyzer utilized. Furthermore, discrepancies have been observed between interference limits recommended by the manufacturer. The preanalytical variables which produce a lower percentage of hemolysis rejections were: centrifugation at the extraction site, the use of lower volume tubes and a transport time under 15 min at room temperature. CONCLUSIONS: The setting of interference limits (cut-off) for each used test/method, and the study of preanalytical variability will assist to the results harmonization for this quality indicator.

Indicators and quality specifications for strategic and support processes related to the clinical laboratory: four years' experience.

BACKGROUND: Quality specifications for indicators of the key analytic processes have been defined by international consensus. However, only preliminary specifications for laboratory-related strategic and support processes have been developed. The present study attempts to increase the robustness of the preliminary proposed specifications. METHODS: Recovering records and incidences occurred over a 4-year follow-up period, for 12 indicators, used in all laboratories from this group regarding strategic and support processes. RESULTS AND CONCLUSIONS: The results obtained indicate that it is better to establish an interval rather than a fixed value for the majority of indicators. Longer studies are needed to properly assess some quality specifications, and data recording system must be standardized in others. Additional, multicenter studies are needed to establish more robust specifications and determine the state of the art of laboratories in other settings.

European Biological Variation Study (EuBIVAS): within- and between-subject biological variation estimates for serum biointact parathyroid hormone based on weekly samplings from 91 healthy participants.

BACKGROUND: The European Biological Variation Study (EuBIVAS) was created by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group on Biological Variation to establish high-quality biological variation (BV) estimates for clinically important measurands. In this study, the aim was to deliver reliable BV estimates for the biointact parathyroid hormone (PTH 1-84). METHODS: Serum samples were obtained from a population of 91 healthy individuals (38 men, 43 pre-menopausal women, and 10 post-menopausal women; 21-69 years) from 5 European countries, with all samples stored at -80 °C prior to analysis. PTH 1-84 analysis was performed at the San Raffaele Hospital (Milan, Italy) on the Roche Cobas e801. All samples from each individual were analysed in duplicate within a single run. CV-ANOVA was applied, after analysis of variance homogeneity and outliers, to obtain BV estimates for PTH 1-84 with 95% CIs. RESULTS: The within-subject BV [CVI (95% CI)] estimates were significantly different between men and women [13.0% (12.1-14.2%) and 15.2% (14.3-16.3%), respectively], while the between-subject estimates [CVG (95% CI)] were similar (men: 26.8% (21.4-35.1%), pre-menopausal women: 27.8% (22.7-36.1%)], allowing for delivery of updated analytical performance specifications and reference change values. CONCLUSIONS: Updated BV estimates for serum PTH 1-84 based on the large-scale EuBIVAS may be beneficial for the diagnosis and management of parathyroid glands and bone turnover pathologies.

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.

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.

Within-subject biological variation in disease: collated data and clinical consequences.

Quantitative data on the components of biological variation (BV) are used for several purposes, including calculating the reference change value (RCV) required for the assessment of the significance of changes in serial results in an individual. Pathology may modify the set point in diseased patients and, more importantly, the variation around that set-point. Our aim was to collate all published BV data in situations other than health. We report the within-subject coefficient of variation (CV(I)) for 66 quantities in 34 disease states. We compared the results with the CV(I) determined in healthy individuals and examined whether the data derived in specific diseases could be useful for clinical applications. For the majority of quantities studied, CV(I) values are of the same order in disease and health: thus the use of RCV derived from healthy subjects for monitoring patients would be reasonable. However, for a small number of quantities considered to be disease specific markers, the CV(I) differed from those in health. This could mean that RCV derived from healthy CV(I) may be inappropriate for monitoring patients in certain diseases. Hence, disease-specific RCVs may be clinically useful.

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.

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.

Integration of data derived from biological variation into the quality management system.

BACKGROUND: [corrected] Data on within- and between-subject biological variation are available for around 250 analytes commonly used in medical laboratories. METHODS: Integration of this data into the quality system occurs at all three levels of laboratory activity: (a) Preanalytic process: biological variation provides the basis for selecting the most appropriate specimen for analysis, for defining sample stability and for deciding suitable timing between samplings; (b) analytic process: biological variation-derived goals are fundamental for designing internal quality control procedures, and for evaluating laboratory performance; and (c) postanalytic process: delta checks based on within-subject biological variation values are used for validating results and for interpreting serial results from a patient. CONCLUSION: The biological variation is a pillar for managing quality in laboratory medicine.