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Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points

  • Sergey N. Fedosov EMAIL logo , Alex Brito , Joshua W. Miller , Ralph Green and Lindsay H. Allen
Published/Copyright: January 14, 2015
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 53 Issue 8

Abstract

Background: A novel approach to determine vitamin B12 status is to combine four blood markers: total B12 (B12), holotranscobalamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy). This combined indicator of B12 status is expressed as cB12=log10[(holoTC·B12)/(MMA·Hcy)]–(age factor). Here we calculate cB12 in datasets with missing biomarkers, examine the influence of folate status, and revise diagnostic cut-points.

Methods: We used a database with all four markers (n=5211) plus folate measurements (n=972). A biomarker Z (assumed missing) was plotted versus X (a combination of other markers) and Y (age). Each chart was approximated by a function Ztheor, which predicted the potentially absent value(s). Statistical distributions of cB12 were aligned with physiological indicators of deficiency and used to determine cut-offs.

Results: The predictive functions Ztheor allowed assessment of the “incomplete” indicators, 3cB12 (three markers known) and 2cB12 (two markers known). Predictions contained a systematic deviation associated with dispersion along two axes Z and X (and unaccounted by the least squares fit). Increase in tHcy at low serum folate was corrected (cB12+Δfolate) based on the function of Δfolate=log10(Hcyreal/Hcytheor) versus folate. Statistical distributions of cB12 revealed the boundaries of groups with B12 deficiency, i.e., cB12<–0.5.

Conclusions: We provide equations that combine two, three or four biomarkers into one diagnostic indicator, thereby rescaling unmatched data into the same coordinate system. Adjustment of this indicator is required if serum folate is <10 nmol/L and tHcy is measured. Revised cut-points and guidelines for using this approach are provided.

Keywords: cobalamin; deficiency; diagnostics; folate; markers; vitamin B12
Corresponding author: Sergey N. Fedosov, Department of Clinical Chemistry, Aarhus University, Science Park, Gustav Wieds Vej 10C, 8000, Aarhus C, Denmark, E-mail: ;

Acknowledgments

The work of L.H. Allen and A. Brito was supported in part by USDA, ARS Project #5306-51000-003-00D.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Financial support: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Supplemental Material

The online version of this article (DOI: 10.1515/cclm-2014-0818) offers supplementary material, available to authorized users.

Received: 2014-8-14
Accepted: 2014-12-7
Published Online: 2015-1-14
Published in Print: 2015-7-1

©2015 by De Gruyter

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https://doi.org/10.1515/cclm-2014-0818
Keywords for this article
cobalamin; deficiency; diagnostics; folate; markers; vitamin B12

Articles in the same Issue

  1. Frontmatter
  2. Editorials
  3. Once upon a time: a tale of ISO 15189 accreditation
  4. A new integrated tool for assessing and monitoring test comparability and stability
  5. Liver-FibroSTARD checklist and glossary: tools for standardized design and reporting of diagnostic accuracy studies of liver fibrosis tests
  6. Reviews
  7. Thromboembolic risk in hematological malignancies
  8. A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population
  9. Opinion Paper
  10. Permissible limits for uncertainty of measurement in laboratory medicine
  11. EFLM Position Paper
  12. Flexible scope for ISO 15189 accreditation: a guidance prepared by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group Accreditation and ISO/CEN standards (WG-A/ISO)
  13. Genetics and Molecular Diagnostics
  14. Evaluation of a low-cost procedure for sampling, long-term storage, and extraction of RNA from blood for qPCR analyses
  15. Application of real-time PCR of sex-independent insertion-deletion polymorphisms to determine fetal sex using cell-free fetal DNA from maternal plasma
  16. General Clinical Chemistry and Laboratory Medicine
  17. The Empower project – a new way of assessing and monitoring test comparability and stability
  18. Comparison of four automated serum vitamin B12 assays
  19. Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points
  20. INR vs. thrombin generation assays for guiding VKA reversal: a retrospective comparison
  21. Determination of dabigatran in plasma, serum, and urine samples: comparison of six methods
  22. Simple high-throughput analytical method using ultra-performance liquid chromatography coupled with tandem mass spectrometry to quantify total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in urine
  23. Revival of physostigmine – a novel HPLC assay for simultaneous determination of physostigmine and its metabolite eseroline designed for a pharmacokinetic study of septic patients
  24. Relationship between antiphosphatidylserine/prothrombin and conventional antiphospholipid antibodies in primary antiphospholipid syndrome
  25. Reference Values and Biological Variations
  26. Relevance of EDTA carryover during blood collection
  27. Reference intervals for renal injury biomarkers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in young infants
  28. Cardiovascular Diseases
  29. NT-proBNP levels and their relationship with systemic ventricular impairment in adult patients with transposition of the great arteries long after Mustard or Senning procedure
  30. Letters to the Editors
  31. Troponin T measured with highly sensitive assay (hsTnT) on admission does not reflect infarct size in ST-elevation myocardial infarction patients receiving primary percutaneous coronary intervention
  32. Analytical challenges related to the use of biomarker ratios for the biological diagnosis of Alzheimer’s disease
  33. Serum brain injury biomarkers as predictors of mortality after severe aneurysmal subarachnoid hemorrhage: preliminary results
  34. Tumor markers assay by the Lumipulse G
  35. Real-world costs of laboratory tests for non-small cell lung cancer
  36. Impact of stopping vitamin K antagonist therapy on concentrations of dephospho-uncarboxylated Matrix Gla protein
  37. Practicability of fetal scalp blood sampling during labor using microtubes and a point-of-care (POC) lactate testing device: difficulty assessment, sampling time and failure rates
  38. Establishing objective analytical quality requirements in the IgE specific assay: a message in a bottle
  39. Bacteria on a peripheral blood smear as presenting sign of overwhelming post-splenectomy infection in a patient with secondary acute myeloid leukemia
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