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Title:   Author  item
                                            FEDOSOV, SERGEY - Aarhus Universityitem
                                            BRITO, ALEX - University Of Californiaitem
                                            MILLER, JOSHUA - University Of Californiaitem
                                            GREEN, RALPH - University Of Californiaitem
                                            Allen, Lindsay

                                                         - *A*
  Submitted to: Clinical Chemistry and Laboratory Medicine
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 12/7/2014
                                    Publication  Date: 1/16/2015
                                    Citation: Fedosov, S.N., Brito, A., Miller, J., Green, R., Allen, L.H. 2015. Combined indicator of vitamin B 12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points. Clinical Chemistry and Laboratory Medicine.  DOI: 10.1515/cclm-2014-0818.Interpretive Summary: Background: A new approach is described for assessing vitamin B12 status by combining four blood markers: total B12 (B12), holotranscobalamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy). Combined B12 status is calculated as cB12=log10[(holoTC·B12)/(MMA·Hcy)]–(age factor). Here we calculate cB12 in datasets with some of the four biomarkers missing, examine the influence of folate deficiency which can increase tHcy, and revise diagnostic cut-points.
Methods: We prepared a database from studies which had all four markers (n=5211) plus serum folate measurements (n=972). A biomarker Z (assumed missing) was plotted versus X (a combination of other markers) and Y (age) so that a function (Ztheor) could be calculated to predict the potentially absent value(s). Statistical distributions of cB12 were aligned with physiological indicators of deficiency (hemoglobin and cognitive function) to determine cut-points for diagnosing vitamin B12 inadequacy.
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. tHcy increased when serum folate was low (<10 nmol/L) showing that cB12 needs correction for low folate status. Statistical distributions of cB12 revealed the cut-points for different levels of B12 deficiency, i.e., cB12 < -0.5.
Conclusions: We provide equations that combine two, three or four biomarkers of vitamin B12 status into one diagnostic indicator. 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.
                                Technical Abstract: Background: A novel approach to determine vitamin B 12 status is to combine four blood markers: total B 12 (B 12 ), holotranscobalamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy). This combined indicator of B 12 status is expressed as cB 12 = log 10 [(holoTC · B 12 )/ (MMA · Hcy)] – (age factor). Here we calculate cB 12 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 theor , which predicted the potentially absent value(s). Statistical distributions of cB 12 were aligned with physiological indicators of deficiency and used to determine cut-offs.
Results: The predictive functions Z theor allowed assessment of the “ incomplete ” indicators, 3cB 12 (three markers known) and 2cB 12 (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 12 + ' folate ) based on the function of ' folate = log 10 (Hcy real /Hcy theor ) versus folate. Statistical distributions of cB 12 revealed the boundaries of groups with B 12 deficiency, i.e., cB 12 < – 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.


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