Systematic review of the biological variation data for diabetes related analytes.

BACKGROUND: Objective interpretation of laboratory test results used to diagnose and monitor diabetes mellitus in part requires the application of biological variation data (BVD). The quality of published BVD has been questioned. The aim of this study was to quality assess publications reporting BVD for diabetes-related analytes using the Biological Variation Data Critical Appraisal Checklist (BIVAC); to assess whether published BVD are fit for purpose and whether the study design and population attributes influence BVD estimates and to undertake a meta-analysis of the BVD from BIVAC-assessed publications. METHODS: Publications reporting data for glucose, HbA1c, adiponectin, C-peptide, fructosamine, insulin like growth factor 1 (IGF-1), insulin like growth factor binding protein 3 (IGFBP-3), insulin, lactate and pyruvate were identified using a systematic literature search. These publications were assessed using the BIVAC, receiving grades A, B, C or D, where A is of highest quality. A meta-analysis of the BVD from the assessed studies utilised weightings based upon BIVAC grades and the width of the data confidence intervals to generate global BVD estimates. RESULTS: BIVAC assessment of 47 publications delivered 1 A, 3 B, 39C and 4 D gradings. Publications relating to adiponectin, C-peptide, IGF-1, IGFBP-3, lactate and pyruvate were all assessed as grade C. Meta-analysis enabled global BV estimates for all analytes except pyruvate, lactate and fructosamine. CONCLUSIONS: This study delivers updated and evidence-based BV estimates for diabetes-related analytes. There remains a need for delivery of new high-quality BV studies for several clinically important analytes.

Components of biological variation of biochemical markers of bone turnover in Paget's bone disease.

The aims of this study were to evaluate the components of biological variation of the new markers of bone turnover in patients with Paget's bone disease and to compare the results with data obtained in healthy subjects. Fifteen patients with Paget's disease in a stable period of the disease and 12 healthy premenopausal women were included for a 1 year follow-up study. Within- and between-subject biological variation, indices of individuality, and critical differences were evaluated for the following biochemical markers: in serum, total (tAP), and bone (bAP) alkaline phosphatases, procollagen type I N-terminal propeptide (PINP) and beta-carboxyterminal telopeptide of type I collagen (sCTx); in urine, hydroxyproline (Hyp), and amino (NTx) and beta-carboxyterminal (CTx) telopeptides of collagen type I. Serum markers of bone turnover showed lower biological variability than urinary markers. Within-subject biological variation was higher in pagetic patients than in healthy subjects for all serum markers. In both groups, bAP presented the lowest within-subject biological variation. In pagetic patients, all markers presented indices of individuality of <0.6, indicating their usefulness for patient monitoring. Critical differences were lower for serum markers than for urinary markers. Among pagetic patients, serum bAP and PINP showed the lowest critical differences with values close to 30%, whereas urinary CTx presented the highest critical differences (near 70%). Conversely, in healthy subjects, tAP was the marker with the lowest critical differences, being two-fold higher in pagetic patients. This study confirms the lower sensitivity of urinary markers to detect significant changes and indicates that data obtained on biological variations from healthy populations cannot always be extrapolated to pathological conditions. In addition, serum bAP and PINP seem to be the markers that best reflect a significant change in activity of Paget's disease.

Are equally spaced specimen collections necessary to assess biological variation? Evidence from renal transplant recipients.

The established method for determining the components of biological variation (BV) requires equispaced time intervals between samplings. In a previous study, we determined BV in renal post transplantation patients, taking advantage of the samples obtained within their clinical treatment protocol (not necessarily equispaced). To confirm the validity of this practice, we sought to determine if the use of varying sampling intervals has an effect on the results obtained in such biological variation studies. The study included two phases: comparison of the results found with identical and non-identical sampling intervals and correlation between the within-subject BV and the length of the sampling interval. There were no differences in within-subject BV between the groups or correlations with sampling intervals for any of the constituents studied. We conclude that samples acquired within established clinical protocols for kidney transplant recipients can be used for estimating BV.

Commutability between stabilized materials and fresh human serum to improve laboratory performance.

With the recent advances in laboratory technology, many quality-related problems have been improved. However, the issue of commutability, a factor that greatly affects daily decisions concerning patient status, still remains to be solved. This paper determines the commutability between 27 stabilized materials (controls and calibrators) and clinical specimens for five serum quantities, using carrier-bound reagent chemistry and conventional wet methods. Our aim was to pinpoint the specific problems related to non-commutable calibrators and controls in our setting, and minimize their effect in daily practice. We found major difficulties in selecting appropriate accuracy controls in carrier-bound reagent techniques, and in finding materials commutable for several analytes simultaneously. Several suggestions for reducing problems related to non-commutability, such as procedures for assigning values to multicalibrators, are proposed. We explain the apparent incongruencies observed in daily quality surveillance, when data from different control materials (internal quality control and external quality assessment) are evaluated. The conclusions emphasize the need for a combined effort (manufacturers, organizers of external quality assessment schemes and individual laboratories) to find the cause of, and eliminate, the negative repercussions on laboratory performance produced by non-commutability.

Commutability and traceability: their repercussions on analytical bias and inaccuracy.

The commutability of calibrators and accuracy control materials affects the traceable link between patient sample results and standards. We sought to identify the repercussions of commutability on various aspects of laboratory practice (calibration, control of bias and accuracy assessment) and to discover the solutions that can reduce the problems produced by non-commutability with presently available resources. Ten serum constituents, ten comparison procedures and 37 analytical procedures were studied. The information concerning accuracy and bias provided from materials found to be commutable in previous works was challenged with native serum results for each routine and reference method compared, using Passing-Bablok regression and decision limits derived from biological variation. We found that: (1) Use of commutable control materials did not assure reliable information on the bias (systematic component of analytical error) of analytical procedures, and (2) Results from native serum and commutable controls were very highly concordant, indicating that these materials provide a good indication of the inaccuracy (total analytical error) of results. We suggest that the performance of individual laboratories would be better evaluated by occasional use of native sera with values assigned by reference methods in EQAS schemes. Moreover, our findings support the idea that manufacturers should assign values to calibrators using reference methods and native sera to reduce matrix effects and promote traceability.

Procedure for studying commutability validated by biological variation.

In the field of laboratory medicine, the two quantitative approaches designed to identify the stabilized materials that produce results that are commutable with results from patients' samples were found to differ. In commutability evaluations, the responses of each material and each method studied are specific, thus, it is vital to standardise the procedure used for determining this characteristic. We incorporated statistical components from the two described methods that seemed to be consistent, and added a new element based on biological variation, to validate the criterion of acceptability that determines whether or not a material is commutable. The three methods for studying commutability (using the confidence interval [alpha = 0.05], the +/- 2s(yx) formula, and the limit based on biological variation as acceptability criteria) were applied to creatinine results from 31 stabilised materials and serum samples analysed with seven instruments, when compared against a reference method for creatinine analysis. Over the wide range of concentrations studied, the confidence interval limit and the biological variation limit coincided in the identification of commutable materials, whereas the +/- 2s(yx) was excessively permissive at normal and low concentration levels. We therefore recommend the use of Passing-Bablok regression with its confidence interval (alpha = 0.05) in studies concerning commutability. Using this method, commutability is simple to calculate with available software and, as validated by biological variation, results are reliable.

Quality goals for hormone testing.

Estimates of intra-individual biological variation in normal subjects have been made for 17 hormones commonly measured for diagnostic purposes and the results have been compared with state-of-the-art analytical imprecision data. The implications of using these results for setting goals for analytical performance are discussed.

Approaches for providing target values to improve usefulness of external quality assessment scheme. The Spanish experience.

The aim of this communication is to highlight the specific aspects of external quality assessment schemes that need to be discussed in a European context: target values, transferability of results and accredit of laboratories. The Spanish situation is presented here. The most reliable way to provide target values is to analyse the control samples by reference methods. However, it is not possible for the majority of national schemes and other approaches are presently used: the verification of consensus means is a practicable solution adopted in Spain. An initial network involving selected routine laboratories has been developed, to attain transferability of results. The traceability of routine calibrators from certified reference materials should be demonstrated. To accredit laboratories for licensing is a complex activity that should consider many aspects, results from the national quality assessment scheme bring one. A scoring system is being used in Spain for guidance, and the complete guidelines are under preparation.

External quality assurance programs as a tool for verifying standardization of measurement procedures: Pilot collaboration in Europe.

INTRODUCTION: Current external quality assurance schemes have been classified into six categories, according to their ability to verify the degree of standardization of the participating measurement procedures. SKML (Netherlands) is a Category 1 EQA scheme (commutable EQA materials with values assigned by reference methods), whereas SEQC (Spain) is a Category 5 scheme (replicate analyses of non-commutable materials with no values assigned by reference methods). AIM: The results obtained by a group of Spanish laboratories participating in a pilot study organized by SKML are examined, with the aim of pointing out the improvements over our current scheme that a Category 1 program could provide. METHOD: Imprecision and bias are calculated for each analyte and laboratory, and compared with quality specifications derived from biological variation. RESULTS: Of the 26 analytes studied, 9 had results comparable with those from reference methods, and 10 analytes did not have comparable results. The remaining 7 analytes measured did not have available reference method values, and in these cases, comparison with the peer group showed comparable results. The reasons for disagreement in the second group can be summarized as: use of non-standard methods (IFCC without exogenous pyridoxal phosphate for AST and ALT, Jaffé kinetic at low-normal creatinine concentrations and with eGFR); non-commutability of the reference material used to assign values to the routine calibrator (calcium, magnesium and sodium); use of reference materials without established commutability instead of reference methods for AST and GGT, and lack of a systematic effort by manufacturers to harmonize results. CONCLUSIONS: Results obtained in this work demonstrate the important role of external quality assurance programs using commutable materials with values assigned by reference methods to correctly monitor the standardization of laboratory tests with consequent minimization of risk to patients.

Proposed quality specifications for the imprecision and inaccuracy of analytical systems for clinical chemistry.

A Working Group of the European Group for the Evaluation of Reagents and Analytical Systems in Laboratory Medicine proposes, after detailed study of the advantages and disadvantages of available strategies, the following quality specifications for analytical systems for clinical chemistry. Total imprecision should be: (a) less than one-half of the average within-subject biological variation, or (b) less than the state of the art achieved by the best 0.20 fractile of laboratories, whichever is the less stringent. The second approach may be used when data on biological variation do not exist. Inaccuracy should be: (a) less than one-quarter of the group (within- plus between-subject) biological variation, or (b) less than one-sixteenth of the reference interval, when data on group biological variation do not exist, or (c) less than twice the ideal imprecision, if the above specifications are too demanding.

Current stage of standardization of measurements of specific polypeptides and proteins discussed in light of steps needed towards a comprehensive measurement system.

We present a standardization model for the measurement of specific polypeptides and proteins, which is based on an integrated development of all important elements of a reference measurement system. Generally, the model is in line with other current recommendations. However, it puts special emphasis on the definition of the analyte and on the role of reference methods for verification of the standardization process by measurement of patient specimens. Further, we discuss the needs for its implementation in the routine laboratory. In the light of this model, we investigate the current stage of standardization of routine methods for enzymes, peptide hormones, proteins, apolipoproteins, glycohaemoglobin, and tumour markers.

Analytical quality specifications for reference methods and operating specifications for networks of reference laboratories. discussion paper from the members of the external quality assessment (EQA) Working Group B1) on target values in EQAS.

The aim of the Working Group was to describe guidelines for the establishment of networks of reference laboratories. The need for such networks to achieve an accuracy-based uniform measurement system with traceability of results of analytical systems/test-kits to the true value is outlined. Criteria for analytical quality specifications, which are related to the ultimate purpose of the reference method and thereby to the objectives of the networks, are emphasized. The group recommends the use of two models: one based on specifications for routine methods, which are dictated by the biological variations of the respective analytes, the second respecting the analytical state-of-the-art of reference methodology. Further, the group presents operating specifications for networks that guarantee the continuous performance of reference method measurements whilst maintaining a uniform and stable level of quality.

Biological variation in urine samples used for analyte measurements.

To determine the influence of biological variation on the reliability of data from different types of urine specimens, we measured nine analytes in first-morning, randomly collected, and 24-h samples of urine from 53 healthy individuals (14 men and 39 women). The urines were collected once a week for 10 weeks. The data obtained were used as a basis for specimen collection and to gain insight into the influence of urine quantities in the diagnosis, screening, and monitoring of patients. We found that 24-h urine expressed in output rather than concentration units is the most reliable specimen for diagnosis and monitoring for most of the analytes studied. On the basis of the ratio between estimated within- and between-subject variation, the tests with greatest medical usefulness for diagnosis and screening of specific pathologies are those measuring protein and sodium. Moreover, the results indicate that urine creatinine may be a poor test for diagnosis, monitoring, and screening.