CVI Estimates Research Articles

Systematic review and meta-analysis of biological variation data of urine albumin, albumin to creatinine ratio and other markers in urine

IntroductionSignificant variations in Biological Variation (BV) estimates have been reported for urine markers. This study aimed to systematically review and critically appraise BV studies for albumin, creatinine, albumin-to-creatinine ratio (ACR), and other urine markers to perform a meta-analysis of eligible studies. MethodsPublications were identified through a systematic search and evaluated using the Biological Variation Data Critical Appraisal Checklist (BIVAC). BIVAC-compliant studies (grades A-C; A being fully compliant) conducted in healthy individuals were included in the meta-analysis, providing within-subject (CVI) and between-subject (CVG) BV estimates with 95% confidence intervals for various sample collection types. ResultsOut of 37 studies evaluated, 16 were included (one grade A, three B, twelve C). No eligible publications were identified for meta-analysis of albumin and ACR. Limited data were available for first-morning urine specimens. A CVI between 15% and 30% was found for most measurands in 24-hour urine samples, while CVI estimates for random urine appeared higher. ConclusionPublished BV studies on urine markers utilized different sample collections and reporting units. Most were considered unfit for use or ineligible for meta-analysis. Given the critical role of urine albumin and ACR in chronic kidney disease risk assessment, there is a need for more BIVAC-compliant studies.

Biological Variation Data in Triathletes for Metabolism and Growth-Related Biomarkers Included in the Athlete Biological Passport.

When using biological variation (BV) data, BV estimates need to be robust and representative. High-endurance athletes represent a population under special physiological conditions, which could influence BV estimates. Our study aimed to estimate BV in athletes for metabolism and growth-related biomarkers involved in the Athlete Biological Passport (ABP), by 2 different statistical models. Thirty triathletes were sampled monthly for 11 months. The samples were analyzed for human growth hormone (hGH), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), insulin, and N-terminal propeptide of type III procollagen (P-III-NP) by immunoassay. Bayesian and ANOVA methods were applied to estimate within-subject (CVI) and between-subject BV. CVI estimates ranged from 7.8% for IGFBP-3 to 27.0% for insulin, when derived by the Bayesian method. The 2 models gave similar results, except for P-III-NP. Data were heterogeneously distributed for P-III-NP for the overall population and in females for IGF-1 and IGFBP-3. BV components were not estimated for hGH due to lack of steady state. The index of individuality was below 0.6 for all measurands, except for insulin. In an athlete population, to apply a common CVI for insulin would be appropriate, but for IGF-1 and IGFBP-3 gender-specific estimates should be applied. P-III-NP data were heterogeneously distributed and using a mean CVI may not be representative for the population. The high degree of individuality for IGF-1, IGFBP-3, and P-III-NP makes them good candidates to be interpreted through reference change values and the ABP.

Biological Variation Estimates for Plasma Copeptin and Clinical Implications.

Plasma copeptin measurement is useful for the differential diagnoses of polyuria-polydipsia syndrome. It has also been proposed as a prognostic marker for cardiovascular diseases. However, limited information is available about the within- (CVI) and between-subject (CVG) biological variation (BV). This study presents BV estimates for copeptin in healthy individuals. Samples were collected weekly from 41 healthy subjects over 5 weeks and analyzed using the BRAHMS Copeptin proAVP KRYPTOR assay after at least 8 h of food and fluid abstinence. Outlier detection, variance homogeneity, and trend analysis were performed followed by CV-ANOVA for BV and analytical variation (CVA) estimation with 95% confidence intervals. Reference change values (RCVs), index of individuality (II), and analytical performance specification (APS) were also calculated. The analysis included 178 results from 20 males and 202 values from 21 females. Copeptin concentrations were significantly higher in males than in females (mean 8.5 vs 5.2 pmol/L, P < 0.0001). CVI estimates were 18.0% (95% CI, 15.4%-21.6%) and 19.0% (95% CI, 16.4%-22.6%), for males and females, respectively; RCVs were -35% (decreasing value) and 54% (increasing value). There was marked individuality for copeptin. No result exceeded the diagnostic threshold (>21.4 pmol/L) for arginine vasopressin resistance. The availability of BV data allows for refined APS and associated II, and RCVs applicable as aids in the serial monitoring of patients with specific diseases such as heart failure. The BV estimates are only applicable in subjects who abstained from oral intake due to the rapid and marked effects of fluids on copeptin physiology.

The biological variation of serum 1,25-dihydroxyvitamin D and parathyroid hormone, and plasma fibroblast growth factor 23 in healthy individuals

Background and aimsMeasuring 1,25-dihydroxyvitamin D (1,25(OH)2D), parathyroid hormone 1–84 (PTH 1–84) and intact FGF23 (iFGF23) is crucial for diagnosing a variety of diseases affecting bone and mineral homeostasis. Biological variability (BV) data are important for defining analytical quality specifications (APS), the usefulness of reference intervals, and the significance of variations in serial measurements in the same subject. The aim of this study was to pioneer the provision of BV estimates for 1,25(OH)2D and to improve existing BV estimates for iFGF23 and PTH 1–84. Materials and methodsSerum and plasma-EDTA samples of sixteen healthy subjects have been collected for seven weeks and measured in duplicate by chemiluminescent immunoassay on the DiaSorin Liaison platform. After variance verification, within-subject (CVI) and between-subject (CVG) BV estimates were assessed by either standard ANOVA, or CV-ANOVA. The APSs were calculated according to the EFLM-BV-model. ResultsWe found the following CVI estimates with 95% confidence intervals:1,25(OH)2D, 22.2% (18.9–26.4); iFGF23, 16.1% (13.5–19.5); and PTH 1–84, 17.9% (14.8–21.8). The CVG were: 1,25(OH)2D, 21.2% (14.2–35.1); iFGF23, 21.1% (14.5–35.8); and PTH 1–84, 31.1% (22.1–50.8). ConclusionsWe report for the first time BV estimates for 1,25(OH)2D and enhance existing data about iFGF23-BV and PTH 1–84-BV through cutting-edge immunometric methods.

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

BackgroundKnowledge 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. MethodsWe 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. ResultsThe 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. ConclusionsIn 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?

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. Thirty triathletes (15 females) were sampled monthly (11months). 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. 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. 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.

Sex-related differences in within-subject biological variation estimates for 22 essential and non-essential amino acids

BackgroundMeasurement of serum amino acid (AA) concentrations is important in particular for the diagnosis and monitoring of inborn errors of AA metabolism. To ensure optimal clinical interpretation of AAs, reliable biological variation (BV) data are essential. In the present study, we derived BV data for 22 non-essential, conditionally essential, and essential AAs and assessed differences in BV of AAs related to sex. MethodsMorning blood samples were drawn from 66 subjects (31 males and 35 females) once a week for 10 consecutive weeks. All samples were analyzed in duplicate using liquid chromatography-tandem mass-spectrometry. The data were assessed for outliers, trends, normality and variance homogeneity analysis prior to estimating within-subject (CVI) and between-subject (CVG) BV. ResultsCVI estimates ranged from 9.0 % for histidine (male) to 33.0 % for taurine (male). CVI estimates in males and females were significantly different for all AAs except for aspartic acid, citrulline and phenylalanine, in most cases higher in females than in males. Apart from for arginine, CVG estimates in males and females were similar. ConclusionsIn this highly powered BV study, we provide updated BV estimates for 22 AAs and demonstrate that for most AAs, CVI estimates differ between males and females, with implications for interpretation and use of AAs in clinical practice.

Personalized and Population-Based Reference Intervals for 48 Common Clinical Chemistry and Hematology Measurands: A Comparative Study.

Personalized reference intervals (prRIs) have the potential to improve individual patient follow-up as compared to population-based reference intervals (popRI). In this study, we estimated popRI and prRIs for 48 clinical chemistry and hematology measurands using samples from the same reference individuals and explored the effect of using group-based and individually based biological variation (BV) estimates to derive prRIs. 143 individuals (median age 28 years) were included in the study and had fasting blood samples collected once. From this population, 41 randomly selected subjects had samples collected weekly for 5 weeks. PopRIs were estimated according to Clinical Laboratory Standards Institute EP28 and within-subject BV (CVI) were estimated by CV-ANOVA. Data were assessed for trends and outliers prior to calculation of individual prRIs, based on estimates of (a) within-person BV (CVP), (b) CVI derived in this study, and (c) publically available CVI estimates. For most measurands, the individual prRI ranges were smaller than the popRI range, but overall about half the study participants had a prRI wider than the popRI for 5 or more out of 48 measurands. The dispersion of prRIs based on CVP was wider than that of prRIs based on CVI. The prRIs derived in our study varied significantly between different individuals, especially if based on CVP. Our results highlight the limitations of popRIs in interpreting test results of individual patients. If sufficient data from a steady-state situation are available, using prRI based on CVP estimates will provide a RI most specific for an individual patient.

Biological variation estimates for spot urine analytes and analyte/creatinine ratios in 33 healthy subjects.

Urine samples are frequently used in the clinical practice. In our study, we aimed to calculate the biological variations (BV) of analytes and analyte/creatinine ratios measured in spot urine. Second-morning spot urine samples were collected from 33 (16 female, 17 male) healthy volunteers once weekly for 10weeks and analyzed in the Roche Cobas 6,000 instrument. Statistical analyzes were performed using BioVar, an online BV calculation software. The data were evaluated in terms of normality, outliers, steady state, homogeneity of the data, and BV values were obtained by analysis of variance (ANOVA). A strict protocol was established for within-subject (CVI) and between-subject (CVG) estimates for both genders. There was a significant difference between female/male CVI estimates of all analytes except potassium, calcium and magnesium. No difference was found in CVG estimates. When the analytes that had a significant difference in CVI estimates in spot urine analytes were compared to creatinine, it was observed that the significant difference between the genders disappeared. There was no significant difference between female/male CVI and CVG estimates in all spot urine analyte/creatinine ratios. Since the CVI estimates of analyte/creatinine ratios are lower, it would be more reasonable to use them inresult reporting. Reference ranges should be used with caution, since II values of almost all parameters are between 0.6 and 1.4. The CVI detection power of our study is 1, which is the highest value.

Long-Term Within- and Between-Subject Biological Variation Data of Hematological Parameters in Recreational Endurance Athletes.

Hematological parameters have many applications in athletes, from monitoring health to uncovering blood doping. This study aimed to deliver biological variation (BV) estimates for 9 hematological parameters by a Biological Variation Data Critical Appraisal Checklist (BIVAC) design in a population of recreational endurance athletes and to assess the effect of self-reported exercise and health-related variables on BV. Samples were drawn from 30 triathletes monthly for 11 months and measured in duplicate for hematological measurands on an Advia 2120 analyzer (Siemens Healthineers). After outlier and homogeneity analysis, within-subject (CVI) and between-subject (CVG) BV estimates were delivered (CV-ANOVA and log-ANOVA, respectively) and a linear mixed model was applied to analyze the effect of exercise and other related variables on the BV estimates. CVI estimates ranged from 1.3% (95%CI, 1.2-1.4) for mean corpuscular volume to 23.8% (95%CI, 21.6-26.3) for reticulocytes. Sex differences were observed for platelets and OFF-score. The CVI estimates were higher than those reported for the general population based on meta-analysis of eligible studies in the European Biological Variation Database, but 95%CI overlapped, except for reticulocytes, 23.9% (95%CI, 21.6-26.5) and 9.7% (95%CI, 6.4-11.0), respectively. Factors related to exercise and athletes' state of health did not appear to influence the BV estimates. This is the first BIVAC-compliant study delivering BV estimates that can be applied to athlete populations performing high-level aerobic exercise. CVI estimates of most parameters were similar to the general population and were not influenced by exercise or athletes' state of health.

Within-subject biological variation estimates using an indirect data mining strategy. Spanish multicenter pilot study (BiVaBiDa).

The estimates of biological variation (BV) have traditionally been determined using direct methods, which present limitations. In response to this issue, two papers have been published addressing these limitations by employing indirect methods. Here, we present a new procedure, based on indirect methods that analyses data collected within a multicenter pilot study. Using this method, we obtain CVI estimates and calculate confidence intervals (CI), using the EFLM-BVD CVI estimates as gold standard for comparison. Data were collected over a 18-month period for 7 measurands, from 3 Spanish hospitals; inclusion criteria: patients 18-75 years with more than two determinations. For each measurand, four different strategies were carried out based on the coefficient of variation ratio (rCoeV) and based on the use of the bootstrap method (OS1, RS2 and RS3). RS2 and RS3 use symmetry reference change value (RCV) to clean database. RS2 and RS3 had the best correlation for the CVI estimates with respect to EFLM-BVD. RS2 used the symmetric RCV value without eliminating outliers, while RS3 combined RCV and outliers. When using the rCoeV and OS1strategies, an overestimation of the CVI value was obtained. Our study presents a new strategy for obtaining robust CVI estimates using an indirect method together with the value of symmetric RCV to select the target population. The CVI estimates obtained show a good correlation with those published in the EFLM-BVD database. Furthermore, our strategy can resolve some of the limitations encountered when using direct methods such as calculating confidence intervals.

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

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. 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. 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. 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.

Annual biological variation and personalized reference intervals of clinical chemistry and hematology analytes.

A large number of people undergo annual health checkup but accurate laboratory criterion for evaluating their health status is limited. The present study determined annual biological variation (BV) and derived parameters of common laboratory analytes in order to accurately evaluate the test results of the annual healthcare population. A total of 43 healthy individuals who had regular healthcare once a year for six consecutive years, were enrolled using physical, electrocardiogram, ultrasonography and laboratory. The annual BV data and derived parameters, such as reference change value (RCV) and index of individuality (II) were calculated and compared with weekly data. We used annual BV and homeostatic set point to calculate personalized reference intervals (RIper) which were compared with population-based reference intervals (RIpop). We have established the annual within-subject BV (CVI), RCV, II, RIper of 24 commonly used clinical chemistry and hematology analytes for healthy individuals. Among the 18 comparable measurands, CVI estimates of annual data for 11 measurands were significantly higher than the weekly data. Approximately 50% measurands of II were <0.6, the utility of their RIpop were limited. The distribution range of RIper for most measurands only copied small part of RIpop with reference range index for 8 measurands <0.5. Compared with weekly BV, for annual healthcare individuals, annual BV and related parameters can provide more accurate evaluation of laboratory results. RIper based on long-term BV data is very valuable for "personalized" diagnosis on annual health assessments.

Biological variation of venous acid-base status measurands in athletes

BackgroundAnalysis of acid-base status (ABS) is requested in a wide range of clinical scenarios, including in the assessment of athletes’ performance and follow up, but there is a lack of high-quality biological variation (BV) data. The aims of this study were to estimate the BV of ABS related parameters in athletes and to evaluate if variables related to exercise may influence the estimates. Material and methodsEleven samples from 30 triathletes were drawn, on a monthly basis. The samples were measured for pH, pCO2, bicarbonate, base excess, TCO2, Ca2+ and lactate. A CV-ANOVA was performed to calculate within-subject (CVI) estimates and a linear mixed model was applied to analyze the effect of the folowing variables on the BV; health status, sampling interval, intensity and duration of the exercise. ResultsFor all ABS parameters except for lactate, higher CVI estimates were found in athletes than what have been reported for the general population. No significant effect of the exercise and sampling related variables were observed, except for Ca2+. ConclusionThis difference founds in ABS parameters between athletes and the general population could be explained by the physiological stress during exercise. Laboratories attending this population could use these BV estimates to establish quality goals.

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

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. 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. 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. 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.

The European Biological Variation Study (EuBIVAS): weekly biological variation of cardiac troponin I estimated by the use of two different high-sensitivity cardiac troponin I assays.

Background Cardiac troponins (cTn) are specific markers for cardiac damage and acute coronary syndromes. The availability of new high-sensitivity assays allows cTn detection in healthy people, thus permitting the estimation of biological variation (BV) of cTn. The knowledge of BV is important to define analytical performance specifications (APS) and reference change values (RCVs). The aim of this study was to estimate the within- and between-subject weekly BV (CVI, CVG) of cTnI applying two high-sensitivity cTnI assays, using European Biological Variation Study (EuBIVAS) specimens. Methods Thirty-eight men and 53 women underwent weekly fasting blood drawings for 10 consecutive weeks. Duplicate measurements were performed with Singulex Clarity (Singulex, USA) and Siemens Atellica (Siemens Healthineers, Germany). Results cTnI was measurable in 99.4% and 74.3% of the samples with Singulex and Atellica assays, respectively. Concentrations were significantly higher in men than in women with both methods. The CVI estimates with 95% confidence interval (CI) were for Singulex 16.6% (15.6-17.7) and for Atellica 13.8% (12.7-15.0), with the observed difference likely being caused by the different number of measurable samples. No significant CVI differences were observed between men and women. The CVG estimates for women were 40.3% and 36.3%, and for men 65.3% and 36.5% for Singulex and Atellica, respectively. The resulting APS and RCVs were similar for the two methods. Conclusions This is the first study able to estimate cTnI BV for such a large cohort of well-characterized healthy individuals deriving objective APS and RCV values for detecting significant variations in cTnI serial measurements, even within the 99th percentile.

European Biological Variation Study (EuBIVAS): within- and between-subject biological variation estimates of β-isomerized C-terminal telopeptide of type I collagen (β-CTX), N-terminal propeptide of type I collagen (PINP), osteocalcin, intact fibroblast growth factor 23 and uncarboxylated-unphosphorylated matrix-Gla protein-a cooperation between the EFLM Working Group on Biological Variation and the International Osteoporosis Foundation-International Federation of Clinical Chemistry Committee on Bone Metabolism.

Within-subject (CVI) and between-subject (CVG) biological variation (BV) estimates are essential in determining both analytical performance specifications (APS) and reference change values (RCV). Previously published estimates of BV for bone metabolism biomarkers are generally not compliant with the most up-to-date quality criteria for BV studies. We calculated the BV and RCV for different bone metabolism markers, namely β-isomerized C-terminal telopeptide of type I collagen (β-CTX), N-terminal propeptide of type I collagen (PINP), osteocalcin (OC), intact fibroblast growth factor 23 (iFGF-23), and uncarboxylated-unphosphorylated Matrix-Gla Protein (uCuP-MGP) using samples from the European Biological Variation Study (EuBIVAS). In the EuBIVAS, 91 subjects were recruited from six European laboratories. Fasting blood samples were obtained weekly for ten consecutive weeks. The samples were run in duplicate on IDS iSYS or DiaSorin Liaison instruments. The results were subjected to outlier and variance homogeneity analysis before CV-ANOVA was used to obtain the BV estimates. We found no effect of gender upon the CVI estimates. The following CVI estimates with 95% confidence intervals (95% CI) were obtained: β-CTX 15.1% (14.4-16.0%), PINP 8.8% (8.4-9.3%), OC 8.9% (8.5-9.4%), iFGF23 13.9% (13.2-14.7%), and uCuP-MGP 6.9% (6.1-7.3%). The EuBIVAS has provided updated BV estimates for bone markers, including iFGF23, which have not been previously published, facilitating the improved follow-up of patients being treated for metabolic bone disease.

Long-term biological variation estimates of 13 hematological parameters in healthy Chinese subjects.

Background The complete blood count (CBC) is a basic test routinely ordered by physicians as a part of initial diagnostic work-up on their patients. To ensure safe clinical application of the CBC, reliable biological variation (BV) data are needed to establish analytical performance specifications. Our aim was to define the BV of CBC parameters using a rigorous protocol that is compliant with the Biological Variation Data Critical Appraisal Checklist (BIVAC) provided by the European Federation of Clinical Chemistry and Laboratory Medicine. Methods Blood samples drawn from 41 healthy Chinese subjects (22 females and 19 males; 23-59 years of age) once monthly for 6 consecutive months were analyzed using an ABX Pentra 80 instrument. The instrument was precisely calibrated. All samples were analyzed in duplicate for 13 CBC parameters. The data were assessed for outliers, normality, and variance homogeneity prior to nested ANOVA. Gender-stratified within-subject (CVI) and between-subject (CVG) BV estimates were calculated. Results The number of remaining data for each subject was 442-484 after removing outliers. No significant differences existed between female/male CVI estimates. Except for leukocytes, neutrophils, and lymphocytes, the mean values of 10 parameters differed significantly between genders, rendering partitioning of CVG data between genders. No significant differences were detected between most BV estimates and recently published estimates representing a Europid population. Conclusions Most BV estimates in BIVAC-compliant studies are similar. The turnover time of blood cells and age distribution of participants should be considered in a CBC BV study. Our study will contribute to global BV estimates and future studies.

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.

Within-subject and between-subject biological variation estimates of 21 hematological parameters in 30 healthy subjects.

The complete blood count (CBC) is used to evaluate health status in the contexts of various clinical situations such as anemia, infection, inflammation, trauma, malignancies, etc. To ensure safe clinical application of the CBC, reliable biological variation (BV) data are required. The study aim was to define the BVs of CBC parameters employing a strict protocol. Blood samples, drawn from 30 healthy subjects (17 females, 13 males) once weekly for 10 weeks, were analyzed using a Sysmex XN 3000 instrument. The data were assessed for normality, trends, outliers and variance homogeneity prior to coefficient of variation (CV)-analysis of variance (ANOVA). Sex-stratified within-subject (CVI) and between-subjects (CVG) BV estimates were determined for 21 CBC parameters. For leukocyte parameters, with the exception of lymphocytes and basophils, significant differences were found between female/male CVI estimates. The mean values of all erythrocyte-, reticulocyte- and platelet parameters differed significantly between the sexes, except for mean corpuscular hemoglobin concentration, mean corpuscular volume and platelet numbers. Most CVI and CVG estimates appear to be lower than those previously published. Our study, based on a rigorous protocol, provides updated and more stringent BV estimates for CBC parameters. Sex stratification of data is necessary when exploring the significance of changes in consecutive results and when setting analytical performance specifications.