Biological variability of the most common biochemical parameters

The results of laboratory tests are analyzed against reference values that are determined in a population of healthy people prepared for the test in accordance with the relevant guidelines. Such a reference system works perfectly when analyzing the results of tests of patients from whom the material for determinations was collected in similar conditions. To better match the reference values ranges are stratified, most often by gender, age, or race of the patient – the most common and the most significant biological variability. The values of the measured parameter are also influenced by within-subject biological variability to e.g. the time of the day, food consumption, or physical exercise. This variability influences the results of random testing, often performed in patients with emergencies. The measure of both of these variations is the index of individuality, i.e. the ratio of within-subject biological variability to between-subject biological variability. In the present work, the factors influencing the circadian, seasonal, and between-subject biological variations of the selected clinical chemistry parameters are presented. Knowledge about these variations is important for the physician and the supporting laboratory diagnostician, particularly helpful in the analysis of pathological or inconsistent with the clinicians' expectations results to distinguish results related to the disease from results related to biological variability.

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

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.

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.

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

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.

Biological variation of glycated albumin, glucose and albumin in healthy Turkish subjects

ObjectivesBiological variation (BV) in laboratory tests can be defined as the variation in analyte concentration over time within and between individuals. Glycated albumin (GA) is a ketoamine which is used in the short-term monitoring of diabetes. The aim of this research was to determine BV of GA, glucose, and albumin under a well-designed and standardized protocol.MethodsBlood samples were collected weekly from 21 healthy subjects (10 males, 11 females) for four consecutive weeks. Samples were analyzed using enzymatic methods in duplicate. After subjected to outlier and normality tests, variables as the within-subject biologic coefficient of variation (CVI) and between-subject biologic coefficient of variation (CVG), the index of individuality (II), and reference change value (RCV) were calculated.ResultsAnalytical coefficient of variation (CVA) was 3.5, 1.78, and 2.9%, for GA, glucose and albumin, respectively. The estimates for CVI and CVG: GA: 4.1%, 6.3%; glucose: 3.8%, 4.8%; albumin: 3.5%, 4%. RCVs and IIs were: 15%, 0.60; 12%, 0.79; 13%, 0.9 for GA, glucose and albumin, respectively.ConclusionsThe BV data of GA derived from this study might be applied to understand routine test results better and establish the quality standards for the analyte.

Biological variation of total thyroxine (T4), free T4 and thyroid-stimulating hormone in 11 clinically healthy cats

Objectives The aim of this study was to investigate the biological variation of total thyroxine (T4), free T4 (fT4) and thyroid-stimulating hormone (TSH) in 11 clinically healthy cats aged between 3 and 15 years old, in Sydney, Australia. Methods Blood was collected weekly for up to 6 weeks and serum T4, fT4 and TSH concentrations were analysed using canine-specific reagents. Restricted maximum likelihood was used to estimate within-subject, between-subject and analytical variance components, which were recorded in terms of the related coefficients of variation. The index of individuality and reference change values were then calculated for each analyte. Results T4 and TSH had intermediate individuality, indicating both subject-based and population-based reference intervals (RIs) could be used, with the knowledge that population-based RIs are suboptimally sensitive. fT4 had high individuality, indicating subject-based RIs are more appropriate than population-based RIs. Conclusions and relevance This study has demonstrated that subject-based RIs could be more sensitive than population-based RIs for the diagnosis of thyroid dysfunction in cats.

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

BackgroundUrine 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.

Biological variation in serum bone turnover markers

Background Serum total N-terminal propeptide of type I collagen (P1NP) and serum C-terminal telopeptide of type I collagen (CTX) are used as reference analytes of bone turnover in clinical application. Biological variation is important for clinical application of these biomarkers. However, the biological variation data of these biomarkers are not consistent. The present study determined biological variations of total P1NP and CTX and their confidence intervals in China using electrochemiluminescence. Methods We collected samples from 25 healthy individuals (17 women and 8 men, ranging from 22 to 49 years of age) at weekly intervals for six weeks. Samples were analysed in a single run in duplicate. Biological variations and their related parameters, such as reference change value and index of individuality (II) were calculated. The results were compared with individual studies in the EFLM database. Results Within-subject and between-subject biological variations were 8.0% and 32.5% for total P1NP and 11.4% and 38.7% for CTX, respectively. The index of individuality for total P1NP and CTX was 0.25 and 0.30, while the reference change value for P1NP values and CTX was 22.4% and 31.9%, respectively. Conclusions No difference was found in weekly biological variation of bone turnover markers between men and premenopausal women. Compared with daily and monthly variation, the present study based on weekly variation provided additional support for clinical application.