Surrogate disease markers as substitutes for chronic disease outcomes in studies of diet and chronic disease relations.

Surrogate biomarkers for clinical outcomes afford scientific and economic efficiencies when investigating nutritional interventions in chronic diseases. However, valid scientific results are dependent on the qualification of these disease markers that are intended to be substitutes for a clinical outcome and to accurately predict benefit or harm. In this article, we examine the challenges of evaluating surrogate markers and describe the framework proposed in a 2010 Institute of Medicine report. The components of this framework are presented in the context of nutritional interventions for chronic diseases. We present case studies of 2 well-accepted surrogate markers [blood pressure within sodium intake and cardiovascular disease (CVD) context and low density lipoprotein-cholesterol concentrations within a saturated fat and CVD context]. We also describe additional cases in which the evidence is insufficient to validate their surrogate status. Guidance is offered for future research that evaluates or uses surrogate markers.

Correspondence of folate dietary intake and biomarker data.

Background: Public health concerns with regard to both low and high folate status exist in the United States. Recent publications have questioned the utility of self-reported dietary intake data in research and monitoring.Objectives: The purpose of this analysis was to examine the relation between self-reported folate intakes and folate status biomarkers and to evaluate their usefulness for several types of applications.Design: We examined usual dietary intakes of folate by using the National Cancer Institute method to adjust two 24-h dietary recalls (including dietary supplements) for within-person variation and then compared these intakes with serum and red blood cell (RBC) folate among 4878 men and nonpregnant, nonlactating women aged ≥19 y in NHANES 2011-2012, a nationally representative, cross-sectional survey, with respect to consistency across prevalence estimates and rank order comparisons.Results: There was a very low prevalence (<1%) of folate deficiency when serum (<7 nmol/L) and RBC (<305 nmol/L) folate were considered, whereas a higher proportion of the population reported inadequate total dietary folate intakes (6%). Similar patterns of change occurred between intakes and biomarkers of folate status when distributions were examined (i.e., dose response), particularly when diet was expressed in µg. Intakes greater than the Tolerable Upper Intake Level greatly increased the odds of having high serum folate (OR: 17.6; 95% CI: 5.5, 56.0).Conclusions: When assessing folate status in the United States, where fortification and supplement use are common, similar patterns in the distributions of diet and biomarkers suggest that these 2 types of status indicators reflect the same underlying folate status; however, the higher prevalence estimates for inadequate intakes compared with biomarkers suggest, among other factors, a systematic underestimation bias in intake data. Caution is needed in the use of dietary folate data to estimate the prevalence of inadequacy among population groups. The use of dietary data for rank order comparisons or to estimate the potential for dietary excess is likely more reliable.

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

BACKGROUND: Folate cutoffs for risk of deficiency compared with possible deficiency were originally derived differently (experimental compared with epidemiologic data), and their interpretations are different. The matching of cutoffs derived from one assay with population-based data derived from another assay requires caution. OBJECTIVE: We assessed the extent of folate-status misinterpretation with the use of inappropriate cutoffs. DESIGN: In the cross-sectional NHANES, serum and red blood cell (RBC) folate were first measured with the use of a radioprotein-binding assay (RPBA) (1988-2006) and, afterwards, with the use of a microbiologic assay (2007-2010). We compared prevalence estimates for assay-matched cutoffs (e.g., with the use of an RPBA cutoff with RPBA data) and assay-mismatched cutoffs (e.g., with the use of microbiologic assay cutoff with RPBA data) for risk of deficiency on the basis of megaloblastic anemia as a hematologic indicator in persons ≥4 y of age (e.g., serum folate concentration <7 nmol/L and RBC folate concentration <305 nmol/L derived with the use of a microbiologic assay), possible deficiency on the basis of rising homocysteine as a metabolic indicator in persons ≥4 y of age (e.g., serum folate concentration <10 nmol/L and RBC folate concentration <340 nmol/L derived with the use of an RPBA), and insufficiency on the basis of elevated risk of neural tube defects in women 12-49 y old (e.g., RBC folate concentration <906 nmol/L derived with the use of a microbiologic assay). RESULTS: Pre-folic acid fortification (1988-1994), risks of deficiency for assay-matched compared with assay-mismatched cutoffs were 5.6% compared with 16% (serum folate), respectively, and 7.4% compared with 28% (RBC folate), respectively; risks declined postfortification (1999-2006) to <1% compared with <1% (serum folate), respectively, and to <1% compared with 2.5% (RBC folate), respectively. Prefortification (1988-1994), risks of possible deficiency for assay-matched compared with assay-mismatched cutoffs were 35% compared with 56% (serum folate), respectively, and 37% compared with 84% (RBC folate), respectively; risks declined postfortification (1999-2006) to 1.9% compared with 7.0% (serum folate), respectively, and to 4.8% compared with 53% (RBC folate), respectively. Postfortification (2007-2010), risks of insufficiency were 3% (assay matched) compared with 39% (assay mismatched), respectively. CONCLUSIONS: The application of assay-mismatched cutoffs leads to a misinterpretation of folate status. This confusion likely applies to clinical assays because no comparability data are available, to our knowledge.

Safe use of high intakes of folic acid: research challenges and paths forward.

Adequate folic acid intake is an effective dietary-based prevention tool for reducing the risk of neural tube defects. Achieving adequate intake for the prevention of neural tube defects frequently requires the consumption of foods fortified with folic acid and/or the use of folic acid-containing dietary supplements. To date, research on the potential for adverse effects of high intakes of folic acid has been limited. Without such research, it is difficult to define a value for high intake. In May 2015, an expert panel was tasked with examining the available scientific literature and making research recommendations within 4 general categories of potential folate-related adverse health effects: cancer, cognition in conjunction with vitamin B12 deficiency, hypersensitivity-related outcomes, and thyroid and diabetes-related disorders. This article summarizes the expert panel's conclusions, outlines the challenges faced when reviewing the literature, and examines some of the panel's recommendations for research.

Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011-2.

Serum and erythrocyte (RBC) total folate are indicators of folate status. No nationally representative population data exist for folate forms. We measured the serum folate forms (5-methyltetrahydrofolate (5-methylTHF), unmetabolised folic acid (UMFA), non-methyl folate (sum of tetrahydrofolate (THF), 5-formyltetrahydrofolate (5-formylTHF), 5,10-methenyltetrahydrofolate (5,10-methenylTHF)) and MeFox (5-methylTHF oxidation product)) by HPLC-MS/MS and RBC total folate by microbiologic assay in US population ≥ 1 year (n approximately 7500) participating in the National Health and Nutrition Examination Survey 2011-2. Data analysis for serum total folate was conducted including and excluding MeFox. Concentrations (geometric mean; detection rate) of 5-methylTHF (37·5 nmol/l; 100 %), UMFA (1·21 nmol/l; 99·9 %), MeFox (1·53 nmol/l; 98·8 %), and THF (1·01 nmol/l; 85·2 %) were mostly detectable. 5-FormylTHF (3·6 %) and 5,10-methenylTHF (4·4 %) were rarely detected. The biggest contributor to serum total folate was 5-methylTHF (86·7 %); UMFA (4·0 %), non-methyl folate (4·7 %) and MeFox (4·5 %) contributed smaller amounts. Age was positively related to MeFox, but showed a U-shaped pattern for other folates. We generally noted sex and race/ethnic biomarker differences and weak (Spearman's r< 0·4) but significant (P< 0·05) correlations with physiological and lifestyle variables. Fasting, kidney function, smoking and alcohol intake showed negative associations. BMI and body surface area showed positive associations with MeFox but negative associations with other folates. All biomarkers showed significantly higher concentrations with recent folic acid-containing dietary supplement use. These first-time population data for serum folate forms generally show similar associations with demographic, physiological and lifestyle variables as serum total folate. Patterns observed for MeFox may suggest altered folate metabolism dependent on biological characteristics.

Unmetabolized serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative sample of adults aged > or =60 y in the United States.

BACKGROUND: Unmetabolized serum folic acid (UMFA) has been detected in adults. Previous research indicates that high folic acid intakes may be associated with risk of cancer. OBJECTIVE: The objective was to examine UMFA concentrations in relation to dietary and supplemental folate and status biomarkers in the US population aged > or =60 y. DESIGN: Surplus sera were analyzed with the use of data from the National Health and Nutrition Examination Survey (NHANES) 2001-2002, a cross-sectional, nationally representative survey (n = 1121). RESULTS: UMFA was detected in 38% of the population, with a mean concentration of 4.4 +/- 0.6 nmol/L (median: 1.2+/- 0.2 nmol/L). The group with UMFA (UMFA+) had a significantly higher proportion of folic acid supplement users than did the group without UMFA (60% compared with 41%). UMFA+ men and women also had higher supplemental and total (food + supplements) folic acid intakes than did their counterparts without UMFA. Forty percent of the UMFA+ group was in the highest quartile of total folic acid intake, but total folic acid intake was only moderately related to UMFA concentrations (r(2) = 0.07). Serum folate concentrations were significantly higher in the UMFA+ group and were predictive of UMFA concentrations (r(2) = 0.15). Serum 5-methyltetrahydrofolate and vitamin B-12 concentrations were higher in the UMFA+ group, whereas there was no difference between the 2 UMFA groups in red blood cell folate, serum homocysteine, or methylmalonic acid concentrations. CONCLUSIONS: Approximately 40% of older adults in the United States have UMFA that persists after a fast, and the presence of UMFA is not easily explained in NHANES by folic acid intakes alone. Given the possibility that excessive folic acid exposure may relate to cancer risk, monitoring of UMFA may be warranted.

Total folate and folic acid intake from foods and dietary supplements in the United States: 2003-2006.

BACKGROUND: The term total folate intake is used to represent folate that occurs naturally in food as well as folic acid from fortified foods and dietary supplements. Folic acid has been referred to as a double-edged sword because of its beneficial role in the prevention of neural tube defects and yet possible deleterious effects on certain cancers and cognitive function. Previous monitoring efforts did not include folic acid from dietary supplements and are therefore not complete. OBJECTIVE: Our objective was to combine data on dietary folate (as measured by two 24-h recalls) and folic acid from dietary supplements (collected with a 30-d frequency questionnaire) with the use of the bias-corrected best power method to adjust for within-person variability. DESIGN: The National Health and Nutrition Examination Survey (NHANES) is a nationally representative, cross-sectional survey. Linear contrasts were constructed to determine differences in dietary and total folate intake for age and racial-ethnic groups by sex; prevalence of inadequate and excessive intakes is presented. RESULTS: In 2003-2006, 53% of the US population used dietary supplements; 34.5% used dietary supplements that contained folic acid. Total folate intake (in dietary folate equivalents) was higher for men (813 +/- 14) than for women (724 +/- 16) and higher for non-Hispanic whites (827 +/- 19) than for Mexican Americans (615 +/- 11) and non-Hispanic blacks (597 +/- 12); 29% of non-Hispanic black women had inadequate intakes. Total folate and folic acid intakes are highest for those aged > or =50 y, and 5% exceed the Tolerable Upper Intake Level. CONCLUSIONS: Improved total folate intake is warranted in targeted subgroups, which include women of childbearing age and non-Hispanic black women, whereas other population groups are at risk of excessive intake.

Modeling the level of fortification and post-fortification assessments: U.S. experience.

Mandatory fortification of enriched cereal-grain products became effective in the United States on January 1, 1998. This fortification was undertaken to assist women of child-bearing age in increasing their intake of folic acid to reduce their risk of having a pregnancy affected by a neural tube birth defect. The process by which the Food and Drug Administration modeled the level of fortification with folic acid illustrates the complex issues and general principles that emerge when fortification of a nation's food supply is evaluated as a means of addressing a public health concern. The effectiveness of fortification for a target population and safety for the much larger general population impose conflicting challenges that must be considered concurrently when making decisions regarding fortification. Recent data show improved folate status and apparent decreases in risk of neural tube birth defects in the U.S. Much about the long-term effects of the fortification program remains unknown and careful monitoring over time will be necessary to ensure that the program functions as intended.