Analytical performance specifications based on biological variation data - considerations, strengths and limitations.

Analytical performance specifications (APS) are typically established through one of three models: (i) outcome studies, (ii) biological variation (BV), or (iii) state-of-the-art. Presently, The APS can, for most measurands that have a stable concentration, be based on BV. BV based APS, defined for imprecision, bias, total allowable error and allowable measurement uncertainty, are applied to many different processes in the laboratory. When calculating APS, it is important to consider the different APS formulae, for what setting they are to be applied and if they are suitable for the intended purpose. In this opinion paper, we elucidate the background, limitations, strengths, and potential intended applications of the different BV based APS formulas. When using BV data to set APS, it is important to consider that all formulae are contingent on accurate and relevant BV estimates. During the last decade, efficient procedures have been established to obtain reliable BV estimates that are presented in the EFLM biological variation database. The database publishes detailed BV data for numerous measurands, global BV estimates derived from meta-analysis of quality-assured studies of similar study design and automatic calculation of BV based APS.

The European biological variation study (EuBIVAS): Biological variation data for testosterone, follicle stimulating hormone, prolactin, luteinizing hormone and dehydroepiandrosterone sulfate in men.

BACKGROUND: Knowledge of biological variation (BV) of hormones is essential for interpretation of laboratory tests and for diagnostics of endocrinological and reproductive diseases. There is a lack of robust BV data for many hormones in men. METHODS: We used serum samples collected weekly over 10 weeks from the European Biological Variation Study (EuBIVAS) to determine BV of testosterone, follicle-stimulating hormone (FSH), prolactin, luteinizing hormone (LH) and dehydroepiandrosterone sulfate (DHEA-S) in 38 men. We derived within-subject (CVI) and between-subject (CVG) BV estimates by CV-ANOVA after trend, outlier, and homogeneity analysis and calculated reference change values, index of individuality (II), and analytical performance specifications. RESULTS: The CVI estimates were 10 % for testosterone, 8 % for FSH, 13 % for prolactin, 22 % for LH, and 9 % for DHEA-S, respectively. The IIs ranged between 0.14 for FSH to 0.66 for LH, indicating high individuality. CONCLUSIONS: In this study, we have used samples from the highly powered EuBIVAS study to derive BV estimates for testosterone, FSH, prolactin, LH and DHEA-S in men. Our data confirm previously published BV estimates of testosterone, FSH and LH. For prolactin and DHEA-S BV data for men are reported for the first time.

Biological variation of inflammatory and iron metabolism markers in high-endurance recreational athletes; are these markers useful for athlete monitoring?

OBJECTIVES: To deliver biological variation (BV) data for serum hepcidin, soluble transferrin receptor (sTfR), erythropoietin (EPO) and interleukin 6 (IL-6) in a population of well-characterized high-endurance athletes, and to evaluate the potential influence of exercise and health-related factors on the BV. METHODS: Thirty triathletes (15 females) were sampled monthly (11 months). All samples were analyzed in duplicate and BV estimates were delivered by Bayesian and ANOVA methods. A linear mixed model was applied to study the effect of factors related to exercise, health, and sampling intervals on the BV estimates. RESULTS: Within-subject BV estimates (CVI) were for hepcidin 51.9 % (95 % credibility interval 46.9-58.1), sTfR 10.3 % (8.8-12) and EPO 27.3 % (24.8-30.3). The mean concentrations were significantly different between sex, but CVI estimates were similar and not influenced by exercise, health-related factors, or sampling intervals. The data were homogeneously distributed for EPO but not for hepcidin or sTfR. IL-6 results were mostly below the limit of detection. Factors related to exercise, health, and sampling intervals did not influence the BV estimates. CONCLUSIONS: This study provides, for the first time, BV data for EPO, derived from a cohort of well-characterized endurance athletes and indicates that EPO is a good candidate for athlete follow-up. The application of the Bayesian method to deliver BV data illustrates that for hepcidin and sTfR, BV data are heterogeneously distributed and using a mean BV estimate may not be appropriate when using BV data for laboratory and clinical applications.

Biological variation estimates of Alzheimer's disease plasma biomarkers in healthy individuals.

INTRODUCTION: Blood biomarkers have proven useful in Alzheimer's disease (AD) research. However, little is known about their biological variation (BV), which improves the interpretation of individual-level data. METHODS: We measured plasma amyloid beta (Aß42, Aß40), phosphorylated tau (p-tau181, p-tau217, p-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) in plasma samples collected weekly over 10 weeks from 20 participants aged 40 to 60 years from the European Biological Variation Study. We estimated within- (CVI ) and between-subject (CVG ) BV, analytical variation, and reference change values (RCV). RESULTS: Biomarkers presented considerable variability in CVI and CVG . Aß42/Aß40 had the lowest CVI (≈ 3%) and p-tau181 the highest (≈ 16%), while others ranged from 6% to 10%. Most RCVs ranged from 20% to 30% (decrease) and 25% to 40% (increase). DISCUSSION: BV estimates for AD plasma biomarkers can potentially refine their clinical and research interpretation. RCVs might be useful for detecting significant changes between serial measurements when monitoring early disease progression or interventions. Highlights Plasma amyloid beta (Aß42/Aß40) presents the lowest between- and within-subject biological variation, but also changes the least in Alzheimer's disease (AD) patients versus controls. Plasma phosphorylated tau variants significantly vary in their within-subject biological variation, but their substantial fold-changes in AD likely limits the impact of their variability. Plasma neurofilament light chain and glial fibrillary acidic protein demonstrate high between-subject variation, the impact of which will depend on clinical context. Reference change values can potentially be useful in monitoring early disease progression and the safety/efficacy of interventions on an individual level. Serial sampling revealed that unexpectedly high values in heathy individuals can be observed, which urges caution when interpreting AD plasma biomarkers based on a single test result.

Critical review and meta-analysis of biological variation estimates for tumor markers.

OBJECTIVES: Biological variation data (BV) can be used for different applications, but this depends on the availability of robust and relevant BV data. In this study, we aimed to summarize and appraise BV studies for tumor markers, to examine the influence of study population characteristics and concentrations on BV estimates and to discuss the applicability of BV data for tumor markers in clinical practice. METHODS: Studies reporting BV data for tumor markers related to gastrointestinal, prostate, breast, ovarian, haematological, lung, and dermatological cancers were identified by a systematic literature search. Relevant studies were evaluated by the Biological Variation Data Critical Appraisal Checklist (BIVAC) and meta-analyses were performed for BIVAC compliant studies to deliver global estimates of within-subject (CVI) and between-subject (CVG) BV with 95% CI. RESULTS: The systematic review identified 49 studies delivering results for 22 tumor markers; four papers received BIVAC grade A, 3 B, 27 C and 15 D. Out of these, 29 CVI and 29 CVG estimates met the criteria to be included in the meta-analysis. Robust data are lacking to conclude on the relationship between BV and different disease states and tumor marker concentrations. CONCLUSIONS: This review identifies a lack of high-quality BV studies for many tumor markers and a need for delivery of BIVAC compliant studies, including in different disease states and tumor marker concentrations. As of yet, the state-of-the-art may still be the most appropriate model to establish analytical performance specifications for the majority of tumor markers.

Within- and between-subject biological variation data for tumor markers based on the European Biological Variation Study.

OBJECTIVES: Reliable biological variation (BV) data are required for the clinical use of tumor markers in the diagnosis and monitoring of treatment effects in cancer. The European Biological Variation Study (EuBIVAS) was established by the EFLM Biological Variation Working Group to deliver BV data for clinically important measurands. In this study, EuBIVAS-based BV estimates are provided for cancer antigen (CA) 125, CA 15-3, CA 19-9, carcinoembryonic antigen, cytokeratin-19 fragment, alpha-fetoprotein and human epididymis protein 4. METHODS: Subjects from five European countries were enrolled in the study, and weekly samples were collected from 91 healthy individuals (53 females and 38 males; 21-69 years old) for 10 consecutive weeks. All samples were analyzed in duplicate within a single run. After excluding outliers and homogeneity analysis, the BVs of tumor markers were determined by CV-ANOVA on trend-corrected data, when relevant (Røraas method). RESULTS: Marked individuality was found for all tumor markers. CYFRA 21-1 was the measurand with the highest index of individuality (II) at 0.67, whereas CA 19-9 had the lowest II at 0.07. The CV I s of HE4, CYFRA 21-1, CA 19-9, CA 125 and CA 15-3 of pre- and postmenopausal females were significantly different from each other. CONCLUSIONS: This study provides updated BV estimates for several tumor markers, and the findings indicate that marked individuality is characteristic. The use of reference change values should be considered when monitoring treatment of patients by means of tumor markers.

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.

The European Biological Variation Study (EuBIVAS): a summary report.

Biological variation (BV) data have many important applications in laboratory medicine. Concerns about quality of published BV data led the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) 1st Strategic Conference to indicate need for new studies to generate BV estimates of required quality. In response, the EFLM Working Group on BV delivered the multicenter European Biological Variation Study (EuBIVAS). This review summarises the EuBIVAS and its outcomes. Serum/plasma samples were taken from 91 ostensibly healthy individuals for 10 consecutive weeks at 6 European centres. Analysis was performed by Siemens ADVIA 2400 (clinical chemistry), Cobas Roche 8000, c702 and e801 (proteins and tumor markers/hormones respectively), ACL Top 750 (coagulation parameters), and IDS iSYS or DiaSorin Liaison (bone biomarkers). A strict preanalytical and analytical protocol was applied. To determine BV estimates with 95% CI, CV-ANOVA after analysis of outliers, homogeneity and trend analysis or a Bayesian model was applied. EuBIVAS has so far delivered BV estimates for 80 different measurands. Estimates for 10 measurands (non-HDL cholesterol, S100-ß protein, neuron-specific enolase, soluble transferrin receptor, intact fibroblast growth-factor-23, uncarboxylated-unphosphorylated matrix-Gla protein, human epididymis protein-4, free, conjugated and %free prostate-specific antigen), prior to EuBIVAS, have not been available. BV data for creatinine and troponin I were obtained using two analytical methods in each case. The EuBIVAS has delivered high-quality BV data for a wide range of measurands. The BV estimates are for many measurands lower than those previously reported, having an impact on the derived analytical performance specifications and reference change values.

Biological variation estimates of thyroid related measurands - meta-analysis of BIVAC compliant studies.

OBJECTIVES: Testing for thyroid disease constitutes a high proportion of the workloads of clinical laboratories worldwide. The setting of analytical performance specifications (APS) for testing methods and aiding clinical interpretation of test results requires biological variation (BV) data. A critical review of published BV studies of thyroid disease related measurands has therefore been undertaken and meta-analysis applied to deliver robust BV estimates. METHODS: A systematic literature search was conducted for BV studies of thyroid related analytes. BV data from studies compliant with the Biological Variation Data Critical Appraisal Checklist (BIVAC) were subjected to meta-analysis. Global estimates of within subject variation (CVI) enabled determination of APS (imprecision and bias), indices of individuality, and indicative estimates of reference change values. RESULTS: The systematic review identified 17 relevant BV studies. Only one study (EuBIVAS) achieved a BIVAC grade of A. Methodological and statistical issues were the reason for B and C scores. The meta-analysis derived CVI generally delivered lower APS for imprecision than the mean CVA of the studies included in this systematic review. CONCLUSIONS: Systematic review and meta-analysis of studies of BV of thyroid disease biomarkers have enabled delivery of well characterized estimates of BV for some, but not all measurands. The newly derived APS for imprecision for both free thyroxine and triiodothyronine may be considered challenging. The high degree of individuality identified for thyroid related measurands reinforces the importance of RCVs. Generation of BV data applicable to multiple scenarios may require definition using "big data" instead of the demanding experimental approach.

Long-term within- and between-subject biological variation of 29 routine laboratory measurands in athletes.

OBJECTIVES: Within- and between-subject biological variation (BV) estimates have many applications in laboratory medicine. However, robust high-quality BV estimates are lacking for many populations, such as athletes. This study aimed to deliver BV estimates of 29 routine laboratory measurands derived from a Biological Variation Data Critical Appraisal Checklist compliant design in a population of high-endurance athletes. METHODS: Eleven samples per subject were drawn from 30 triathletes monthly, during a whole sport season. Serum samples were measured in duplicate for proteins, liver enzymes, lipids and kidney-related measurands on an Advia2400 (Siemens Healthineers). After outlier and homogeneity analysis, within-subject (CVI) and between-subject (CVG) biological variation estimates were delivered (CV-ANOVA and log-ANOVA, respectively) and a linear mixed model was applied to analyze the effect of exercise and health related variables. RESULTS: Most CVI estimates were similar or only slightly higher in athletes compared to those reported for the general population, whereas two- to three-fold increases were observed for amylase, ALT, AST and ALP. No effect of exercise and health related variables were observed on the CVI estimates. For seven measurands, data were not homogeneously distributed and BV estimates were therefore not reported. CONCLUSIONS: The observation of higher CVI estimates in athletes than what has been reported for the general population may be related to physiological stress over time caused by the continuous practice of exercise. The BV estimates derived from this study could be applied to athlete populations from disciplines in which they exercise under similar conditions of intensity and duration.

A New Electrochemiluminescence-Based Multiplex Assay for the Assessment of Human Antibody Responses to Bordetella pertussis Vaccines.

INTRODUCTION: Commercially available enzyme-linked immunosorbent assay (ELISA) kits designed for pertussis diagnostic purposes are frequently used to assess antibody responses to pertussis vaccines in clinical trials, but have limited accuracy and are not calibrated against international standards. We developed a new electrochemiluminescence (ECL)-based multiplexed assay and compared its performance to two commercial Bordetella pertussis ELISA kits and to historical in-house ELISAs. METHODS: The ECL assay quantifies serum concentrations of antibodies against four B. pertussis antigens: pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbrial agglutinogen (FIM). The assay was validated for precision, accuracy, dilutability, lower limit of quantification, and specificity. Sera from a clinical trial (CTRI/2016/11/007434) were used to compare the ECL assay to two commercial ELISA kits available from GenWay BioTech and Demeditec Diagnostics for accuracy, linearity, specificity, and concordance to both internal (WWO-2-043) and international (NIBSC 06/140) references. Sera from four clinical trials (NCT02587520, NCT00255047, NCT00347958, NCT01346293) were used to compare the concordance to clinical ELISAs. Informed consent was ensured prior to using any sera. RESULTS: Precision, accuracy, dilutability, lower limit of quantification, and specificity were demonstrated for the ECL assay. Concordance between the ECL assay and established clinical ELISAs was met for antibody responses to PT, FIM, and PRN, but not for FHA. The ECL assay demonstrated higher accuracy and linearity than the ELISA kits. While concordance between the ECL and commercial kits was low, the ECL assay better distinguished between pre- and post-vaccination clinical samples. CONCLUSION: The new ECL assay was validated for the quantitative evaluation of anti-PT, anti-FHA, anti-FIM, and anti-PRN IgG antibodies in samples from clinical trials, and demonstrated equivalent or better performance than two commercially available ELISA kits.

Personalising laboratory medicine in the 'real world': Assessing clinical utility, by clinical indication, of serum total B12 and Active-B12® (holotranscobalamin) in the diagnosis of vitamin B12 deficiency.

BACKGROUND: Assessing the pre- and post-test probability of disease in the context of routine health care is challenging. We wished to study how test performance parameters relating to clinical utility vary by clinical indication in a 'real-world' setting. METHODS: The diagnostic accuracy of serum total B12 and Active-B12® (holotranscobalamin) was evaluated in a primary care population, using serum methylmalonic acid as the reference standard. We used electronic requesting to establish the clinical indication for each request. Routine requests from primary care for serum total B12 were included if creatinine was also measured and estimated glomerular filtration rate was at least 60 mL/min/1.73 m2. RESULTS: Clinical indications included peripheral neuropathy (n = 168), anaemia (n = 168), cognitive decline (n = 125), suspected dietary deficiency (n = 76), other (n = 362). For peripheral neuropathy, the area under the receiver operator curve ± 95% confidence interval (AUC ± CI) was 0.63 (0.54-0.71) (P = 0.002) for total B12 and 0.68 (0.60-0.77) (P < 0.0001) for Active-B12®. For anaemia, AUC ± CI was 0.56 (0.47-0.66) (P = 0.10) for total B12 and 0.69 (0.59-0.78) (P < 0.0001) for Active-B12®. For cognitive decline, AUC ± CI was 0.54 (0.43-0.65) (P = 0.26) for total B12 and 0.69 (0.58-0.80) (P = 0.0002) for Active-B12®. The pre-post-test change in probability of disease varied by clinical indication. CONCLUSION: Combining diagnostic accuracy studies and electronic testing in a 'real-world' setting allows clinical utility to be assessed by clinical indication. Wider application of this would permit more personalised laboratory medicine. In this study, diagnostic performance of total B12 and Active-B12® varied across all indications. Active-B12® provided better discrimination, but this may have reflected the cut-offs used.

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.

Estimation of Instantaneous Oxygen Uptake During Exercise and Daily Activities Using a Wearable Cardio-Electromechanical and Environmental Sensor.

OBJECTIVE: To estimate instantaneous oxygen uptake VO2 with a small, low-cost wearable sensor during exercise and daily activities in order to enable monitoring of energy expenditure (EE) in uncontrolled settings. We aim to do so using a combination of seismocardiogram (SCG), electrocardiogram (ECG) and atmospheric pressure (AP) signals obtained from a minimally obtrusive wearable device. METHODS: In this study, subjects performed a treadmill protocol in a controlled environment and an outside walking protocol in an uncontrolled environment. During testing, the COSMED K5 metabolic system collected gold standard breath-by-breath (BxB) data and a custom-built wearable patch placed on the mid-sternum collected SCG, ECG and AP signals. We extracted features from these signals to estimate the BxB VO2 data obtained from the COSMED system. RESULTS: In estimating instantaneous VO2, we achieved our best results on the treadmill protocol using a combination of SCG (frequency) and AP features (RMSE of 3.68 ± 0.98 ml/kg/min and R2 of 0.77). For the outside protocol, we achieved our best results using a combination of SCG (frequency), ECG and AP features (RMSE of 4.3 ± 1.47 ml/kg/min and R2 of 0.64). In estimating VO2 consumed over one minute intervals during the protocols, our median percentage error was 15.8[Formula: see text] for the treadmill protocol and 20.5[Formula: see text] for the outside protocol. CONCLUSION: SCG, ECG and AP signals from a small wearable patch can enable accurate estimation of instantaneous VO2 in both controlled and uncontrolled settings. SCG signals capturing variation in cardio-mechanical processes, AP signals, and state of the art machine learning models contribute significantly to the accurate estimation of instantaneous VO2. SIGNIFICANCE: Accurate estimation of VO2 with a low cost, minimally obtrusive wearable patch can enable the monitoring of VO2 and EE in everyday settings and make the many applications of these measurements more accessible to the general public.

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.

European Biological Variation Study (EuBIVAS): Within- and Between-Subject Biological Variation Data for 15 Frequently Measured Proteins.

BACKGROUND: The European Biological Variation Study (EuBIVAS) was established to deliver rigorously determined data for biological variation (BV). Here, EuBIVAS-based BV estimates are provided for α1-acid glycoprotein, α1-antitrypsin, albumin, ß2-microglobulin, ceruloplasmin, complement component 3, complement component 4, C-reactive protein (CRP), cystatin C, haptoglobin, IgA, IgG, IgM, soluble transferrin receptor (sTfR), and transferrin (Trf), together with their associated analytical performance specifications (APSs) and reference change values (RCVs). METHOD: Serum samples from weekly blood samplings of 91 healthy study participants (38 males and 53 females, ages 21-69 years old) over 10 consecutive weeks in 6 European laboratories were stored at -80 °C before duplicate analysis on a Roche Cobas c702. Outlier and variance homogeneity analyses were performed followed by CV-ANOVA on trend-corrected data if relevant, to determine BV and analytical variation estimates with CI and the associated RCV. RESULTS: For the acute phase proteins, several participants experienced mild inflammatory episodes during the study, requiring exclusion of 7% of the 25290 results. Within-subject BV (CVI) estimates for specific proteins obtained in our study were lower than those available in the online 2014 BV database, except for Trf, whereas between-subject BV (CVG) estimates were similar. CVI and CVG estimates for sTfR, which have not previously been published, were 6.0% and 19.1%, respectively. CONCLUSIONS: In addition to new BV estimates for sTfR, this EuBIVAS substudy generated more demanding APS for frequently requested plasma specific proteins. APS for CRP should not be calculated from BV data except when CRP is used as a risk factor for cardiovascular disease.

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.

Development and validation of diagnostic triage criteria for liver disease from a minimum data set enabling the 'intelligent LFT' pathway for the automated assessment of deranged liver enzymes.

BACKGROUND: Liver function tests (LFTs) are commonly abnormal; most patients with 'incidental' abnormal LFTs are not investigated appropriately and for those who are, current care pathways are geared to find an explanation for the abnormality by a lengthy process of investigation and exclusion, with costs to the patient and to the health service. OBJECTIVE: To validate an intelligent automatable analysis tool (iLFT) for abnormal liver enzymes, which diagnoses common liver conditions, provides fibrosis stage and recommends management. DESIGN: A retrospective case note review from three tertiary referral liver centres, with application of the iLFT algorithm and comparison with the clinician's final opinion as gold standard. RESULTS: The iLFT algorithm in 91.3% of cases would have correctly recommended referral or management in primary care. In the majority of the rest of the cases, iLFT failed safe and recommended referral even when the final clinical diagnosis could have been managed in primary care. Diagnostic accuracy was achieved in 82.4% of cases, consistent with the fail-safe design of the algorithm. Two cases would have remained in primary care as per the algorithm outcome, however on clinical review had features of advanced fibrosis. CONCLUSION: iLFT analysis of abnormal liver enzymes offers a safe and robust method of risk stratifying patients to the most appropriate care pathway as well as providing reliable diagnostic information based on a single blood draw, without repeated contacts with health services. Offers the possibility of high quality investigation and diagnosis to all patients rather than a tiny minority.

The EuBIVAS: Within- and Between-Subject Biological Variation Data for Electrolytes, Lipids, Urea, Uric Acid, Total Protein, Total Bilirubin, Direct Bilirubin, and Glucose.

BACKGROUND: The European Federation of Clinical Chemistry and Laboratory Medicine European Biological Variation Study (EuBIVAS) has been established to deliver rigorously determined data describing biological variation (BV) of clinically important measurands. Here, EuBIVAS-based BV estimates of serum electrolytes, lipids, urea, uric acid, total protein, total bilirubin, direct bilirubin, and glucose, as well as their associated analytical performance specifications (APSs), are presented. METHOD: Samples were drawn from 91 healthy individuals (38 male, 53 female; age range, 21-69 years) for 10 consecutive weeks at 6 European laboratories. Samples were stored at -80 °C before duplicate analysis of all samples on an ADVIA 2400 (Siemens Healthineers). Outlier and homogeneity analyses were performed, followed by CV-ANOVA on trend-corrected data, when relevant, to determine BV estimates with CIs. RESULTS: The within-subject BV (CVI) estimates of all measurands, except for urea and LDL cholesterol, were lower than estimates available in an online BV database, with differences being most pronounced for HDL cholesterol, glucose, and direct bilirubin. Significant differences in CVI for men and women/women <50 years of age were evident for uric acid, triglycerides, and urea. The CVA obtained for sodium and magnesium exceeded the EuBIVAS-based APS for imprecision. CONCLUSIONS: The EuBIVAS, which is fully compliant with the recently published Biological Variation Data Critical Appraisal Checklist, has produced well-characterized, high-quality BV estimates utilizing a stringent experimental protocol. These new reference data deliver revised and more exacting APS and reference change values for commonly used clinically important measurands, thus having direct relevance to diagnostics manufacturers, service providers, clinical users, and ultimately patients.