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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.

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.

To the Editor: To obtain reliable estimates of biological variation (BV)1, studies must conform to a standardized approach and be adequately powered and properly documented. The recently published Biological Variation Data Critical Appraisal Checklist (BIVAC) aims to assess whether BV studies contain all elements necessary for the associated BV estimates to be reliable and fit for purpose (1). We here present European Biological Variation Study (EuBIVAS) results for S100-β (S100B) and neuron-specific enolase (NSE) proteins to illustrate the importance of study designs following the BIVAC checklist to ensure the validity of results. NSE and S100B are used in the diagnosis and follow-up of NSE-secreting tumors and melanoma, respectively, and may aid in the diagnosis of brain damage such as concussion and neurological disease. The EuBIVAS results are compared with a recently published study performed in amateur mixed martial arts athletes (2). Briefly, EuBIVAS samples were collected weekly from 91 healthy volunteers (53 females and 38 males; age range, 21–69 years) for 10 weeks. Samples, stored at −80 °C, were measured with a Roche Cobas e801 electrochemiluminescence immunoassay using Roche reagents, calibrators, and control materials, with simultaneous analysis of the hemolysis index because hemoglobin falsely increases NSE concentrations. All samples from the same participant were analyzed in duplicate within a single run. Trend analysis was performed to ensure steady state. The protocol was approved by the …

Data on biological variation are used for many purposes in laboratory medicine but concern exists over the validity of the data reported in some studies. A critical appraisal checklist has been produced by a working group established by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) to enable standardised assessment of existing and future publications of biological variation data. The checklist identifies key elements to be reported in studies to enable safe accurate and effective transport of biological variation data sets across healthcare systems. The checklist is mapped to the domains of a minimum data set required to enable this process.