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Title:   Author  item
                                            FEDOSOV, SERGEY - Aarhus Universityitem
                                            BRITIO, ALEX - University Of Californiaitem
                                            MILLER, JOSHUA - Rutgers Universityitem
                                            GREEN, RALPH - University Of Californiaitem
                                            Allen, Lindsay

                                                         - *A*
  Submitted to: Clinical Chemistry
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 7/1/2015
                                    Publication  Date: 7/1/2015
                                    Citation: Fedosov, S.N., Britio, A., Miller, J.W., Green, R., Allen, L.H. 2015. Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status, and recommendations for revised cut-points. Clinical Chemistry. 53(8):1215-1225.Interpretive Summary: There are four commonly used blood markers for diagnosing vitamin B12 status: total serum B12 (B12), holotranscobalamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy). The individual biomarkers often give contradictory diagnosis of B12 status and prevalence of deficiency. For this reason we developed a new approach that combines all four biomarkers into a single indicator of combined B12 status (cB12), with correction for age. In this article we used a database (n=5211) from studies that measured all four biomarkers and an overlapping data set that contained 972 subjects with serum folate measures. We increased the applicability of the approach by developing equations that combine two, three or four biomarkers into one diagnostic parameter and comparative data showing the reliability of different biomarker combinations. Because folate status affects tHcy, we also investigated the effect of folate status and revealed that adjustment of cB12 is required if serum folate is <10 nmol/L. Revised cut points for using cB12 to diagnose B12 status, and guidelines for using this approach are provided.
                                Technical Abstract: Background: We propose a novel approach to diagnose B12 status by combining four blood markers: total B12 (B12), holo-transcobalamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy). Combined B12 status is expressed as cB12=log10[(holoTC•B12)/(MMA•Hcy)]–(reference, age function). 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 (hemoglobin, cognitive function) to determine cut-offs.
	
Results: The predictive functions Ztheor allowed assessment of the “incomplete” indicators, 3cB12 (three markers known) and 2cB12 (two markers known). The charts of 3cB12 (or 2cB12) versus the true indicator 4cB12 were linear but had dispersion along both axes. The associated systematic deviation of prognosis was, therefore, compensated. Increase in tHcy at low serum folate was corrected (cB12+'folate) based on the function of 'folate=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 parameter and comparative data showing the reliability of biomarker combinations. Adjustment of this indicator is required if serum folate is <10 nmol/L. Revised cut points and guidelines for using this approach are provided.


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