Managing biological variation data: modern approaches for study design and clinical application

Author(s):  
Paul R. Johnson ◽  
Shahram Shahangian ◽  
J. Rex Astles
Author(s):  
Carmen Ricós ◽  
Pilar Fernández-Calle ◽  
Elisabet Gonzalez-Lao ◽  
Margarida Simón ◽  
Jorge Díaz-Garzón ◽  
...  

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


2012 ◽  
Vol 58 (12) ◽  
pp. 1703-1710 ◽  
Author(s):  
Yeo-Min Yun ◽  
Julianne Cook Botelho ◽  
Donald W Chandler ◽  
Alex Katayev ◽  
William L Roberts ◽  
...  

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.


Author(s):  
Judith M. Hilderink ◽  
Lieke J.J. Klinkenberg ◽  
Kristin M. Aakre ◽  
Norbert C.J. de Wit ◽  
Yvonne M.C. Henskens ◽  
...  

AbstractBackground:Middle- and long-term biological variation data for hematological parameters have been reported in the literature. Within-day 24-h variability profiles for hematological parameters are currently lacking. However, comprehensive hour-to-hour variability data are critical to detect diurnal cyclical rhythms, and to take into account the ‘time of sample collection’ as a possible determinant of natural fluctuation. In this study, we assessed 24-h variation profiles for 20 hematological parameters.Methods:Blood samples were collected under standardized conditions from 24 subjects every hour for 24 h. At each measurement, 20 hematological parameters were determined in duplicate. Analytical variation (CVResults:All parameters showed higher CVConclusions:We present complete 24-h variability profiles for 20 hematological parameters. Hour-to-hour reference changes values may help to better discriminate between random fluctuations and true changes in parameters with rhythmic diurnal oscillations.


2017 ◽  
Vol 63 (9) ◽  
pp. 1527-1536 ◽  
Author(s):  
Anna Carobene ◽  
Irene Marino ◽  
Abdurrahman Coşkun ◽  
Mustafa Serteser ◽  
Ibrahim Unsal ◽  
...  

Abstract BACKGROUND The European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) European Biological Variation Study (EuBIVAS) has been established to deliver rigorously determined biological variation (BV) indices. EuBIVAS determined BV for serum creatinine using the enzymatic and alkaline picrate measurement methods. METHOD In total, 91 healthy individuals (38 males, 53 females; age range, 21–69 years) were bled for 10 consecutive weeks at 6 European laboratories. An equivalent protocol was followed at each center. Sera were stored at −80 °C before analysis. Analyses for each patient were performed in duplicate within a single run on an ADVIA 2400 system (San Raffaele Hospital, Milan). The data were subjected to outlier and homogeneity analysis before performing CV-ANOVA to determine BV and analytical variation (CVA) estimates with confidence intervals (CI). RESULTS The within-subject BV estimates [CVI (95% CI)] were similar for enzymatic [4.4% (4.2–4.7)] and alkaline picrate [4.7% (4.4–4.9)] methods and lower than the estimate presently available online (CVI = 5.9%). No significant male/female BV differences were found. Significant differences were observed in mean creatinine values between men and women and between Turkish individuals and those of other nationalities. Between-subject BV (CVG) estimates, stratified accordingly, produced CVG values similar to historical BV data. CVA was 1.1% for the enzymatic and 4.4% for alkaline picrate methods, indicating that alkaline picrate methods fail to fulfill analytical performance specifications for imprecision (CVAPS). CONCLUSIONS The serum creatinine CVI obtained by EuBIVAS specifies a more stringent CVAPS than previously identified. The alkaline picrate method failed to meet this CVAPS, raising questions regarding its future use.


Author(s):  
Fatma Ucar ◽  
Gonul Erden ◽  
Seyda Ozdemir ◽  
Nurgul Ozcan ◽  
Erdem Bulut ◽  
...  

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.


2016 ◽  
Vol 40 (2) ◽  
Author(s):  
Rainer Haeckel ◽  
Werner Wosniok ◽  
Eberhard Gurr ◽  
Burkhard Peil

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.


Author(s):  
Anil Baysoy ◽  
Inanc Karakoyun ◽  
Fatma Demet Arslan ◽  
Banu Isbilen Basok ◽  
Ayfer Colak ◽  
...  

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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