A standard to report biological variation data studies - based on an expert opinion.

There is a need for standards for generation and reporting of Biological Variation (BV) reference data. The absence of standards affects the quality and transportability of BV data, compromising important clinical applications. To address this issue, international expert groups under the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) have developed an online resource (https://tinyurl.com/bvmindmap) in the form of an interactive mind map that serves as a guideline for researchers planning, performing and reporting BV studies. The mind map addresses study design, data analysis, and reporting criteria, providing embedded links to relevant references and resources. It also incorporates a checklist approach, identifying a Minimum Data Set (MDS) to enable the transportability of BV data and incorporates the Biological Variation Data Critical Appraisal Checklist (BIVAC) to assess study quality. The mind map is open to access and is disseminated through the EFLM BV Database website, promoting accessibility and compliance to a reporting standard, thereby providing a tool to be used to ensure data quality, consistency, and comparability of BV data. Thus, comparable to the STARD initiative for diagnostic accuracy studies, the mind map introduces a Standard for Reporting Biological Variation Data Studies (STARBIV), which can enhance the reporting quality of BV studies, foster user confidence, provide better decision support, and be used as a tool for critical appraisal. Ongoing refinement is expected to adapt to emerging methodologies, ensuring a positive trajectory toward improving the validity and applicability of BV data in clinical practice.

Critical appraisal and meta-analysis of biological variation estimates for kidney related analytes.

OBJECTIVES: Kidney markers are some of the most frequently used laboratory tests in patient care, and correct clinical decision making depends upon knowledge and correct application of biological variation (BV) data. The aim of this study was to review available BV data and to provide updated BV estimates for the following kidney markers in serum and plasma; albumin, creatinine, cystatin C, chloride, potassium, sodium and urea. CONTENT: Relevant studies were identified from a historical BV database as well as by systematic literature searches. Retrieved publications were appraised by the Biological Variation Data Critical Appraisal Checklist (BIVAC). Meta-analyses of BIVAC compliant studies with similar design were performed to deliver global estimates of within-subject (CVI) and between-subject (CVG) BV estimates. Out of the 61 identified papers, three received a BIVAC grade A, four grade B, 48 grade C, five grade D grade and one was not appraised as it did not report numerical BV estimates. Most studies were identified for creatinine (n=48). BV estimates derived from the meta-analysis were in general lower than previously reported estimates for all analytes except urea. For some measurands, BV estimates may be influenced by age or states of health, but further data are required. SUMMARY: This review provides updated global BV estimates for kidney related measurands. For all measurands except for urea, these estimates were lower than previously reported. OUTLOOK: For the measurands analyzed in this review, there are sufficient well-designed studies available to publish a trustworthy estimate of BV. However, for a number of newly appearing kidney markers no suitable data is available and additional studies are required.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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 OS1 strategies, an overestimation of the CVI value was obtained. CONCLUSIONS: 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.

Critical review and meta-analysis of biological variation estimates for tumor markers.

OBJECTIVES: Biological variation data (BV) can be used for different applications, but this depends on the availability of robust and relevant BV data. In this study, we aimed to summarize and appraise BV studies for tumor markers, to examine the influence of study population characteristics and concentrations on BV estimates and to discuss the applicability of BV data for tumor markers in clinical practice. METHODS: Studies reporting BV data for tumor markers related to gastrointestinal, prostate, breast, ovarian, haematological, lung, and dermatological cancers were identified by a systematic literature search. Relevant studies were evaluated by the Biological Variation Data Critical Appraisal Checklist (BIVAC) and meta-analyses were performed for BIVAC compliant studies to deliver global estimates of within-subject (CVI) and between-subject (CVG) BV with 95% CI. RESULTS: The systematic review identified 49 studies delivering results for 22 tumor markers; four papers received BIVAC grade A, 3 B, 27 C and 15 D. Out of these, 29 CVI and 29 CVG estimates met the criteria to be included in the meta-analysis. Robust data are lacking to conclude on the relationship between BV and different disease states and tumor marker concentrations. CONCLUSIONS: This review identifies a lack of high-quality BV studies for many tumor markers and a need for delivery of BIVAC compliant studies, including in different disease states and tumor marker concentrations. As of yet, the state-of-the-art may still be the most appropriate model to establish analytical performance specifications for the majority of tumor markers.

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.

Structural hemoglobinopathies: Analysis of 128 cases and their relevance in the diabetic control.

BACKGROUND AND OBJECTIVES: Hemoglobinopathies are monogenic disorders with autosomal recessive inheritance. In Europe, with increased migration flows these conditions are appearing more frequently in non-endemic regions. HbA1c testing is useful for evaluating long-term glycaemic status in diabetes mellitus patients. During HbA1c evaluation, other hemoglobin fractions are detected, such as structural hemoglobinopathies. The principal objective of this work is to study the incidence of structural hemoglobinopathies in our area and their management. MATERIAL AND METHODS: Total population of 65,000 patients for glycaemic monitoring was evaluated with HPLC equipment (HPLC-ARKRAY® ADAMS, Menarini Diagnostics, Italy). This equipment quantifies different hemoglobin fractions. RESULTS: We identified a total of 128 variants, representing an incidence with respect to the study population of 0.19% (1.97‰). Most (69) were identified in the foreign population, and the most frequent variant identified was heterozygous S hemoglobinopathy. In six families, structural hemoglobinopathy was identified. Three patients with HbS/HbS were detected. Primary Health Centers were the origin of an important part of these variants (82). CONCLUSIONS: Our study describes a low incidence for structural variants compared with the estimated incidence in Spain. These variants can interfere with HbA1c testing. In these cases, glycated protein study is an appropriate alternative to monitor diabetic therapy.

Impact of Individualized Hemolysis Management Based on Biological Variation Cut-offs in a Clinical Laboratory.

BACKGROUND: Hemolysis is the most common type of preanalytical interference. Cut-offs based on the hemolysis index level can be established using different approaches. The Working Group for Preanalytical Phase of the European Federation of Laboratory Medicine has developed a protocol for hemolysis management based on cut-offs estimated from biological variation (BV) and the use of interpretative comments. We developed and assessed the implementation of the protocol in our laboratory. METHODS: Hemolysates from whole blood were prepared following the Meites method, and pooled serum samples with known Hb concentrations were prepared. For each analyte (42 ), interferograms were generated and used to establish cut-offs: desirable analytical quality specification and reference change value. This protocol was assessed, both pre- and post-implementation, according to expert rules in the Laboratory Information System. RESULTS: Among the analytes evaluated, we selected those that showed the highest degree of hemolysis interference: lactate dehydrogenase (LDH), aspartate aminotransferase, direct bilirubin, potassium, and folic acid. The cut-offs for LDH and direct bilirubin were the lowest. Only 28.16% of all LDH values were adequately reported in the pre-implantation retrospective study, but this percentage improved in the post-implementation stage. CONCLUSIONS: The development and implementation of a harmonized protocol for hemolysis management based on BV cut-offs and result reporting significantly improve hemolysis detection and lead to a decrease in the number of hemolyzed samples over time.

Big data and reference intervals: rationale, current practices, harmonization and standardization prerequisites and future perspectives of indirect determination of reference intervals using routine data.

Reference intervals are commonly used as a decision-making tool. In this review, we provide an overview on "big data" and reference intervals, describing the rationale, current practices including statistical methods, essential prerequisites concerning data quality, including harmonization and standardization, and future perspectives of the indirect determination of reference intervals using routine laboratory data.

Management of postanalytical processes in the clinical laboratory according to ISO 15189:2012 Standard requirements: considerations on the review, reporting and release of results.

The objective of this paper is to share some considerations about the management of postanalytical processes in relation to the review, reporting and release of test results in accordance with UNE-EN ISO 15189:2013 Standard requirements. The scope of this paper includes postanalytical activities and the personnel involved (laboratory management and staff). We describe the criteria and information required to review and validate analytical results and ensure that clear reports are sent to requesters. These criteria also guarantee that results are transcribed in a reliable way and that all necessary information is provided for the correct interpretation of results. Likewise, the requirements for the correct release of laboratory results are described, with special emphasis on the release of alarming or critical results. In some European countries, clinical laboratories are required to hold partial or full ISO 15189 accreditation, which is a global trend. Therefore, understanding ISO 15189 requirements is imperative for a progressive and more effective implementation of the Standard.