Applying inappropriate cutoffs leads to misinterpretation of folate status in the US population

Abstract

Background Folate cutpoints for risk of deficiency vs. possible deficiency were originally derived differently (experimental vs. epidemiologic data) and their interpretation is different. Matching cutpoints derived from one assay with population-based data derived from another assay requires caution. Objective We assessed the extent of folate status misinterpretation using inappropriate cutpoints. Methods In the cross-sectional NHANES, serum and red blood cell (RBC) folate were first measured using a radioproteinbindingassay (RPBA, 1988–2006), then using a microbiologic assay (MBA, 2007–2010). We compared prevalence estimates for assay-matched (e.g., using RPBA cutpoint with RPBA data) and assay-mismatched (e.g., using MBA cutpoint with RPBA data) cutpoints for risk of deficiency based on megaloblastic anemia as a hematologic indicator in persons ≥4 y [e.g., <7 nmol/L serum folate, <305 nmol/L RBC folate, derived by MBA], possible deficiency based on rising homocysteine as a metabolic indicator in persons ≥4 y (e.g., <10 nmol/L serum folate, <340 nmol/L RBC folate, derived by RPBA), and insufficiency based on elevated risk of neural tube defects in women 12–49 y (e.g., <906 nmol/L RBC folate, derived by MBA). Results Pre-folic acid fortification (1988–1994), risk of deficiency for assay-matched vs. assay-mismatched cutpoints was 5.6% vs. 16% (serum folate) and 7.4% vs. 28% (RBC folate); it declined post-fortification (1999–2006) to <1% vs. <1% (serum folate) and <1% vs. 2.5% (RBC folate). Pre-fortification (1988–1994), risk of possible deficiency for assay-matched vs. assay-mismatched cutpoints was 35% vs. 56% (serum folate) and 37% vs. 84% (RBC folate); it declined post-fortification (1999–2006) to 1.9% vs. 7.0% (serum folate) and 4.8% vs. 53% (RBC folate). Post-fortification (2007–2010), risk of insufficiency was 23% (assay-matched) vs. 39% (assay-mismatched). Conclusions Applying assay-mismatched cutpoints leads to misinterpretation of folate status. This likely applies to clinical assays as no comparability data are available.

Correspondence of folate dietary intake and biomarker data

“…The methods used in our report were assaymatched to the cutoffs applied in the National Academy of Medicine report, which strengthens the interpretability of their use (26). As with deriving cutoffs for intake data, the cutoffs for determining biomarker-based status of sufficiency derive from a distribution that reflects variability in requirements among individuals (27).…”

Folate Deficiency Is Prevalent in Women of Childbearing Age in Belize and Is Negatively Affected by Coexisting Vitamin B-12 Deficiency: Belize National Micronutrient Survey 2011

“…In contrast to the WHO cutoffs, the Institute of Medicine (41) previously reported cutoffs from controlled folate-depletion feeding studies in which folate was measured by MBA and cutoffs were defined based on hematological changes indicative of deficient erythropoiesis with the final stage being megaloblastic anemia. In our study, a substantially higher prevalence of folate deficiency based on serum (6.9% absolute difference) and RBC folate (28.9% absolute difference) concentrations was observed by using the assay-matched cutoffs from Pfeiffer et al (26) compared with the WHO cutoffs (25). Thus, the prevalence of folate deficiency in Belize appears to be substantially higher than what the WHO cutoffs would suggest.…”

“…The national prevalence estimates for serum folate deficiency and RBC folate deficiency by using the WHO-recommended cutoffs for deficiency were 4.1% (95% CI: 2.7%, 6.3%) and 6.8% (95% CI: 4.9%, 9.4%), respectively, and by using the cutoffs from Pfeiffer et al (26) were 11.0% (95% CI: 8.6%, 14.0%) and 35.1% (95% CI: 31.3%, 39.2%), respectively (Table 2). In addition, the prevalence for RBC folate insufficiency was 48.9% (95% CI: 44.8%, 53.1%).…”

“…In our study, 2 different sets of cutoffs, those published by the WHO (25) and the assay-matched cutoffs of Pfeiffer et al (26), were used to determine folate status. The WHO cutoffs are based on cross-sectional data from NHANES 1988–1994 that associated rising plasma homocysteine as a metabolic indicator of insufficient serum and RBC folate concentrations measured by using a commercial RPBA.…”

“…For the purposes of this survey, the prevalence of folate deficiency was assessed by using both the WHO–radioproteinbinding assay (RPBA) cutoffs of <10 nmol/L for serum folate and <340 nmol/L for RBC folate (25) and the assay-matched cutoffs for the MBA of ≤14 nmol/L for serum folate and <624 nmol/L for RBC folate from Pfeiffer et al (26). In addition, RBC folate insufficiency was defined based on the recent WHO guideline establishing a threshold for the optimal RBC folate concentration for NTD risk reductions (<906 nmol/L) (15).…”