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

Fernando Marques-Garcia (Lead / Corresponding author), Beatriz Boned, Elisabet González-Lao, Federica Braga, Anna Carobene, Abdurrahman Coskun, Jorge Díaz-Garzón, Pilar Fernández-Calle, Maria Carmen Perich, Margarida Simon, Niels Jonker, Berna Aslan, William Alexander Bartlett, Sverre Sandberg, Aasne K. Aarsand, , Task Group for the Biological Variation Database

Research output: Contribution to journalReview articlepeer-review

15 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)494-504
Number of pages11
JournalClinical Chemistry and Laboratory Medicine (CCLM)
Issue number4
Early online date10 Feb 2022
Publication statusPublished - 4 Mar 2022


  • biological variation
  • critical review
  • meta-analysis
  • tumor marker

ASJC Scopus subject areas

  • Biochemistry, medical
  • Clinical Biochemistry


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