Combined indicator of vitamin B<inf>12</inf> status: Modification for missing biomarkers and folate status and recommendations for revised cut-points

Sergey N. Fedosov, Alex Brito, Joshua W. Miller, Ralph Green, Lindsay H. Allen

Research output: Contribution to journalArticlepeer-review

91 Scopus citations


Background: A novel approach to determine vitamin B<inf>12</inf> status is to combine four blood markers: total B<inf>12</inf> (B<inf>12</inf>), holotranscobalamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy). This combined indicator of B<inf>12</inf> status is expressed as cB<inf>12</inf>=log<inf>10</inf>[(holoTC·B<inf>12</inf>)/(MMA·Hcy)]-(age factor). Here we calculate cB<inf>12</inf> 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 Z<inf>theor</inf>, which predicted the potentially absent value(s). Statistical distributions of cB<inf>12</inf> were aligned with physiological indicators of deficiency and used to determine cut-offs. Results: The predictive functions Z<inf>theor</inf> allowed assessment of the "incomplete" indicators, 3cB<inf>12</inf> (three markers known) and 2cB<inf>12</inf> (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 (cB<inf>12</inf>+Δ<inf>folate</inf>) based on the function of Δ<inf>folate</inf>=log<inf>10</inf>(Hcy<inf>real</inf>/Hcy<inf>theor</inf>) versus folate. Statistical distributions of cB<inf>12</inf> revealed the boundaries of groups with B<inf>12</inf> deficiency, i.e., cB<inf>12</inf><-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.

Original languageEnglish (US)
Pages (from-to)1215-1225
Number of pages11
JournalClinical Chemistry and Laboratory Medicine
Issue number8
StatePublished - Jul 1 2015


  • cobalamin
  • deficiency
  • diagnostics
  • folate
  • markers
  • vitamin B<inf>12</inf>

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Biochemistry, medical


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