Biological Variation of Vitamins in Blood of Healthy Individuals

Abstract Background: Components of biological variation can be used to define objective quality specifications (imprecision, bias, and total error), to assess the usefulness of reference values [index of individuality (II)], and to evaluate significance of changes in serial results from an individual [reference change value (RCV)]. However, biological variation data on vitamins in blood are limited. The aims of the present study were to determine the intra- and interindividual biological variation of vitamins A, E, B1, B2, B6, C, and K and carotenoids in plasma, whole blood, or erythrocytes from apparently healthy persons and to define quality specifications for vitamin measurements based on their biology. Methods: Fasting plasma, whole blood, and erythrocytes were collected from 14 healthy volunteers at regular weekly intervals over 22 weeks. Vitamins were measured by HPLC. From the data generated, the intra- (CVI) and interindividual (CVG) biological CVs were estimated for each vitamin. Derived quality specifications, II, and RCV were calculated from CVI and CVG. Results: CVI was 4.8%–38% and CVG was 10%–65% for the vitamins measured. The CVIs for vitamins A, E, B1, and B2 were lower (4.8%–7.6%) than for the other vitamins in blood. For all vitamins, CVG was higher than CVI, with II <1.0 (range, 0.36–0.95). The RCVs for vitamins were high (15.8%–108%). Apart from vitamins A, B1, and erythrocyte B2, the imprecision of our methods for measurement of vitamins in blood was within the desirable goal. Conclusions: For most vitamin measurements in plasma, whole blood, or erythrocytes, the desirable imprecision goals based on biological variation are obtainable by current methodologies. Population reference intervals for vitamins are of limited value in demonstrating deficiency or excess.

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Within-subject and between-subject biological variation of first morning void urine amino acids in 12 healthy subjects

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2020-0249 ◽

2020 ◽

Vol 58 (11) ◽

pp. 1901-1909

Author(s):

Hamit Hakan Alp ◽

Halil İbrahim Akbay ◽

Erdem Çokluk ◽

Zubeyir Huyut ◽

Sıddık Keskin ◽

...

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Amino Acid Analysis ◽

Healthy Subjects ◽

Total Error ◽

Reference Intervals ◽

Biological Variation ◽

Reference Change Value ◽

Index Of Individuality ◽

Variance Homogeneity

AbstractBackgroundUrine amino acid analysis is used for the assessment of various diseases. The aim of this study was to estimate the valid biological variation (BV) components (within- and between-subjects) required for the safe clinical application of free urine amino acids.MethodsFirst morning void urine samples were taken from 12 healthy subjects (five females, seven males) once a week for 10 consecutive weeks, and amino acid analysis was performed using an Agilent 6470 triple quadrupole tandem mass spectrometer instrument. The obtained data were subjected to normality, outlier and variance homogeneity analyses prior to coefficient of variation (CV) analysis. Within- and between-subject BV values (CVI and CVG) of 39 amino acids were determined for all subjects. In addition, the index of individuality (II), reference change value (RCV), imprecision, bias and total error were estimated using BV data obtained from our study.ResultsThe CVI values ranged from 8.9 (histidine) to 36.8% (trans-4-hydroxyprolin), while the CVG values ranged from 25.0 (1-methyl-L-histidine) to 63.3% (phenylalanine). The II value of most amino acids was less than 0.6 and ranged between 0.21 and 0.88. The imprecision, bias and total error ranged between 4.45 and 16.6, between 7.69 and 16.6, and between 18.4 and 43.2, respectively.ConclusionsThis study, designed according to a rigorous protocol, has the feature of being the first to give information about BV data of urine amino acids. We believe that the reference intervals have a limitation in the evaluation of consecutive results from an individual, so the use of RCV would be more appropriate.

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Study of total error specifications of lymphocyte subsets enumeration using China National EQAS data and Biological Variation Data Critical Appraisal Checklist (BIVAC)-compliant publications

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2020-0741 ◽

2021 ◽

Vol 59 (1) ◽

pp. 179-186

Author(s):

Chenbin Li ◽

Yu Wang ◽

Hong Lu ◽

Zhongli Du ◽

Chengshan Xu ◽

...

Keyword(s):

Quality Control ◽

Critical Appraisal ◽

Total Error ◽

Reference Intervals ◽

Biological Variation ◽

Lymphocyte Subset ◽

High Concentration ◽

Variation Data ◽

Quality Specifications ◽

Minimum Criteria

AbstractObjectivesIt is important to select proper quality specifications for laboratories and external quality assessment (EQA) providers for their quality control and assessment. The aim of this study is to produce new total error (TE) specifications for lymphocyte subset enumeration by analyzing the allowable TE using EQAS data and comparing them with that based on reliable biological variation (BV).MethodsA total of 54,400 results from 1,716 laboratories were collected from China National EQAS for lymphocyte subset enumeration during the period 2017–2019. The EQA data were grouped according to lower limits of reference intervals for establishing concentration-dependent specifications. The TE value that 80% of laboratories can achieve were considered as TE specifications based on state of the art. The BV studies compliant with Biological Variation Data Critical Appraisal Checklist (BIVAC) were used to calculate the three levels of TE specifications. Then these TE specifications were compared for determining the recommended TE specifications.ResultsFour parameters whose quality specifications could achieve the optimum criteria were as follows: the percentages of CD3+, CD3+CD4+ (high concentration) and CD3–CD16/56+ cells, and the absolute count of CD3–CD16/56+ cells. Only the TE specifications of CD3–CD19+ cells could achieve the minimum criteria. The TE specifications of remaining parameters should reach the desirable criteria.ConclusionsNew TE specifications were established by combining the EQA data and reliable BV data, which could help laboratories to apply proper criteria for continuous improvement of quality control, and EQA providers to use robust acceptance limits for better evaluation of EQAS results.

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Biological variation and reference change value data for serum copper, zinc and selenium in Turkish adult population

Turkish Journal of Biochemistry ◽

10.1515/tjb-2020-0298 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Ceylan Bal ◽

Serpil Erdogan ◽

Gamze Gök ◽

Cemil Nural ◽

Betül Özbek ◽

...

Keyword(s):

Adult Population ◽

Reference Intervals ◽

Serum Copper ◽

Biological Variation ◽

Serum Samples ◽

Reference Change Value ◽

Index Of Individuality ◽

Copper Zinc ◽

Clinically Significant ◽

Analytical Variation

Abstract Objectives Calculation of biological variation (BV) components is very important in evaluating whether a test result is clinically significant. The aim of this study is to analyze BV components for copper, zinc and selenium in a cohort of healthy Turkish participants. Methods A total of 10 serum samples were collected from each of the 15 healthy individuals (nine female, six male), once a week, during 10 weeks. Copper, zinc and selenium levels were analyzed by atomic absorption spectrometer. BV parameters were calculated with the approach suggested by Fraser. Results Analytical variation (CVA), within-subject BV (CVI), between-subject BV (CVG) values were 8.4, 7.1 and 4.3 for copper; 4.2, 9.1 and 13.7 for zinc; 7.6, 2.5 and 6.9 for selenium, respectively. Reference change values (RCV) were 30.46, 27.56 and 22.16% for copper, zinc and selenium, respectively. The index of individuality (II) values were 1.65, 0.66 and 0.36 for copper, zinc and selenium, respectively. Conclusions According to the results of this study, traditional reference intervals can be used for copper but we do not recommend using it for zinc and selenium. We think that it would be more accurate to use RCV value for zinc and selenium in terms of following significant changes in recurrent results of a patient.

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

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2021-0479 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Shuo Wang ◽

Min Zhao ◽

Zihan Su ◽

Runqing Mu

Keyword(s):

Clinical Chemistry ◽

Population Based ◽

Reference Intervals ◽

Biological Variation ◽

Annual Data ◽

Healthy Individuals ◽

Reference Change Value ◽

Index Of Individuality ◽

Personalized Diagnosis

Abstract Objectives 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. Methods 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). Results 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. Conclusions 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.

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Biological variation data for kidney function related parameter: serum beta trace protein, creatinine and cystatin C from 22 apparently healthy Turkish subjects

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2021-0543 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Anil Baysoy ◽

Inanc Karakoyun ◽

Fatma Demet Arslan ◽

Banu Isbilen Basok ◽

Ayfer Colak ◽

...

Keyword(s):

Serum Creatinine ◽

Cystatin C ◽

Biological Variation ◽

Reference Ranges ◽

Disease Dynamics ◽

Single Session ◽

Nephelometric Method ◽

Reference Change Value ◽

Variation Data ◽

Apparently Healthy

Abstract Objectives Biological variation is defined as the variation in analytical concentration between and within individuals, and being aware of this biological variation is important for understanding disease dynamics. The aim of our study is to calculate the within-subject (CVI) and between-subject (CVG) biological variations of serum creatinine, cystatin C and Beta trace protein (BTP), as well as the reference change value (RCV) and individuality indexes (II), which are used to calculate the glomerular filtration rate while evaluating kidney damage. Methods Blood samples were collected from 22 healthy volunteers for 10 consecutive weeks and stored at −80 °C until the day of analysis. While the analysis for serum creatinine was performed colorimetrically with the kinetic jaffe method, the nephelometric method was employed for cystatin C and BTP measurements. All analyses were carried out in a single session for each test. Results Analytical coefficient of variation (CVA) for serum creatinine, cystatin C and beta trace protein was 5.56, 3.48 and 5.37%, respectively. CVI and CVG: for serum creatinine: 3.31, 14.50%, respectively, for cystatin C: 3.15, 12.24%, respectively, for BTP: 9.91, 14.36%, respectively. RCV and II were calculated as 17.94%, 0.23 for serum creatinine, 13.01%, 0.26 for cystatin C, 31.24%, 0.69 for BTP, respectively. Conclusions According to the data obtained in our study, serum creatinine and cystatin C show high individuality, therefore we think that the use of RCV instead of reference ranges would be appropriate. Although II is found to be low for BTP, more studies are needed to support this finding.

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Performance Criteria for Testosterone Measurements Based on Biological Variation in Adult Males: Recommendations from the Partnership for the Accurate Testing of Hormones

Clinical Chemistry ◽

10.1373/clinchem.2012.186569 ◽

2012 ◽

Vol 58 (12) ◽

pp. 1703-1710 ◽

Cited By ~ 22

Author(s):

Yeo-Min Yun ◽

Julianne Cook Botelho ◽

Donald W Chandler ◽

Alex Katayev ◽

William L Roberts ◽

...

Keyword(s):

Total Error ◽

Full Range ◽

Biological Variation ◽

Analytical Performance ◽

Performance Criteria ◽

Performance Goals ◽

Adult Males ◽

Large Variability ◽

Wide Range ◽

Variation Data

BACKGROUND Testosterone measurements that are accurate, reliable, and comparable across methodologies are crucial to improving public health. Current US Food and Drug Administration–cleared testosterone assays have important limitations. We sought to develop assay performance requirements on the basis of biological variation that allow physiologic changes to be distinguished from assay analytical errors. METHODS From literature review, the technical advisory subcommittee of the Partnership for the Accurate Testing of Hormones compiled a database of articles regarding analytical and biological variability of testosterone. These data, mostly from direct immunoassay-based methodologies, were used to specify analytical performance goals derived from within- and between-person variability of testosterone. RESULTS The allowable limits of desirable imprecision and bias on the basis of currently available biological variation data were 5.3% and 6.4%, respectively. The total error goal was 16.7%. From recent College of American Pathologists proficiency survey data, most currently available testosterone assays missed these analytical performance goals by wide margins. Data from the recently established CDC Hormone Standardization program showed that although the overall mean bias of selected certified assays was within 6.4%, individual sample measurements could show large variability in terms of precision, bias, and total error. CONCLUSIONS Because accurate measurement of testosterone across a wide range of concentrations [approximately 2–2000 ng/dL (0.069–69.4 nmol/L)] is important, we recommend using available data on biological variation to calculate performance criteria across the full range of expected values. Additional studies should be conducted to obtain biological variation data on testosterone from women and children, and revisions should be made to the analytical goals for these patient populations.

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Reference intervals and biological variation for kallikrein 6: influence of age and renal failure

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2012-0075 ◽

2012 ◽

Vol 50 (5) ◽

Author(s):

Eduardo Martínez-Morillo ◽

Anastasia Diamandis ◽

Eleftherios P. Diamandis

Keyword(s):

Renal Failure ◽

Significant Positive Correlation ◽

Reference Interval ◽

Serum Marker ◽

Reference Intervals ◽

Biological Variation ◽

Serum Samples ◽

Positive Correlation ◽

Reference Change Value ◽

Kallikrein 6

AbstractKallikrein 6 (KLK6) is a serine protease involved in numerous cellular processes, up-regulated in many cancers and associated with some neurodegenerative disorders. The aim of this study was to establish a reference interval and estimate the biological variation of KLK6 in serum samples of adults. Furthermore, levels of this protein in patients with renal failure were also studied.Serum samples from healthy volunteers (n=136) were collected. Between 15 and 18 additional samples from four of these subjects were obtained over a period of 2 months. Samples from individuals (n=1043) who visited the University Health Network for a routine check-up were collected to study the association between KLK6 with age and gender. Samples from patients with renal failure (n=106) were also obtained and KLK6 and creatinine concentrations were analyzed by ELISA and an automated enzymatic method, respectively.The reference interval was established to be 1.04–3.93 ng/mL. The index of individuality was 0.43 and the reference change value was 35%. Only two serum samples would be required to estimate the homeostatic setting point of an individual. There is a weak but highly significant positive correlation between KLK6 and age (p<0.0001). Furthermore, there is a significant positive correlation between serum concentrations of KLK6 and creatinine (p<0.0001), in patients with renal failure.The established reference interval for KLK6 and the estimation of its biological variation will further aid in the clinical use of this protein as a serum marker of malignancy and other diseases.

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Biological variation of intact fibroblast growth factor 23 measured on a fully automated chemiluminescent platform

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/0004563219826161 ◽

2019 ◽

Vol 56 (3) ◽

pp. 381-386 ◽

Cited By ~ 1

Author(s):

Antonín Jabor ◽

Zdenek Kubíček ◽

Jitka Komrsková ◽

Tereza Vacková ◽

Jiří Vymětalík ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Biological Variation ◽

Fibroblast Growth ◽

Vitamin D Metabolism ◽

Automated Assay ◽

Reference Change Value ◽

Index Of Individuality ◽

Non Gaussian

Background Fibroblast growth factor 23 (FGF23), a potent regulator of phosphate and vitamin D metabolism, is a new biomarker of kidney, bone and cardiovascular disorders. The aim of this study was to assess the biological variation of intact fibroblast growth factor 23 (iFGF23). Methods The within-subject (CVI) and between-subject (CVG) biological variations were assessed in 14 healthy volunteers in a six-week protocol (seven samples). Imprecision (CVA) was assessed by duplicate measurements and the EP15-A2 protocol. Intact FGF23 was measured using a fully automated chemiluminescent assay (Liaison XL, DiaSorin S.p.A., Saluggia, Italy). Two methods with different sensitivities to non-Gaussian distribution were used to estimate the CVI, SD ANOVA and CV ANOVA methods. We calculated the index of individuality (II) and reference change values. Results Depending on the statistical method used, the CVI and CVA were 14.2 and 3.7% (SD ANOVA) or 12.5 and 3.9% (CV ANOVA), respectively. The corresponding reference change values were 40.5 and 36.4%, respectively. The CVG was 13.4% (SD ANOVA was the only option), and the total imprecision (EP15-A2) was less than 7%. Conclusions The measurement of iFGF23 demonstrated a CVA less than 4% during the experimental estimation of biological variation. The total imprecision was less than 7% in the EP15-A2 experiment. The CVI values of iFGF23 in healthy persons were 14.2 (SD ANOVA) and 12.5% (CV ANOVA), respectively. The CVG was 13.4%, and the resulting index of individuality was 1.06. The reference change value was less than 41%. The availability of this automated assay for iFGF23 with well-characterized biological variation data delivers opportunities for improved availability and application of this assay clinically.

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First data on the biological variation and quality specifications for plasma ammonia concentrations in healthy subjects

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2015-0591 ◽

2016 ◽

Vol 54 (5) ◽

Cited By ~ 2

Author(s):

Fatma Ucar ◽

Gonul Erden ◽

Seyda Ozdemir ◽

Nurgul Ozcan ◽

Erdem Bulut ◽

...

Keyword(s):

Healthy Subjects ◽

Plasma Sample ◽

Biological Variation ◽

Test Results ◽

Healthy Individuals ◽

Variation Data ◽

Quality Specifications ◽

Collection Period ◽

First Time ◽

Analytical Variation

AbstractBackground:Most of the factors causing preanalytical and analytical variation in ammonia measurement have been identified. Biological variation data for ammonia is still lacking. We therefore estimated the components of biological variation (within-subject=CVMethods:Blood samples from 20 healthy subjects were collected in K2EDTA tubes daily over a period of 4 consecutive days from each subject. Each plasma sample was split into two aliquots; one was immediately analyzed as the samples were collected and the other was stored –80 °C until testing at the end of the collection period and analyzed at once in one analytical run. All samples were analyzed in duplicate. Estimations were calculated according to Fraser and Harris methods.Results:CVConclusions:The present study for the first time described the components of biological variation for ammonia in healthy individuals. These data regarding biological variation of ammonia could be useful for a better evaluation of ammonia test results in clinical interpretation and for determining quality specifications based on biological variation.

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Supplements to a recent proposal for permissible uncertainty of measurements in laboratory medicine

LaboratoriumsMedizin ◽

10.1515/labmed-2015-0112 ◽

2016 ◽

Vol 40 (2) ◽

Author(s):

Rainer Haeckel ◽

Werner Wosniok ◽

Eberhard Gurr ◽

Burkhard Peil

Keyword(s):

Working Group ◽

Laboratory Medicine ◽

Reference Intervals ◽

Standard Uncertainty ◽

Biological Variation ◽

Recent Proposal ◽

New Approach ◽

Permissible Limits ◽

Uncertainty Of Measurements ◽

Variation Data

Abstract:The DGKL Working Group Guide Limits (Arbeitsgruppe Richtwerte) has published a proposal for deriving permissible analytical uncertainty limits related to biological variation data. Reference intervals were used to estimate biological variation. Biological variation data as basis for permissible uncertainty limits are generally accepted. These concepts usually apply a fixed factor leading to unrealistic stringent limits for quantities with a relatively small biological variation and to very permissive limits for quantities with relatively large biological variation. The working group has suggested a non-linear relation between biological variation and permissible uncertainty limits. The new approach has been exemplified with 84 quantities listed in the RiliBÄK (official German guidelines). The algorithms published allowed to derive permissible limits for all quantitative measurands in laboratory medicine. After its publication, three supplements appear necessary: 1. additional specifications of standard uncertainty, 2. a discussion on permissible limits for diagnosis and monitoring purposes, and 3. a discussion on circular reasoning in our approach.

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