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1.  Overview of a roundtable on NHANES monitoring of biomarkers of folate and vitamin B-12 status: measurement procedure issues123456 
A roundtable dialogue to discuss “NHANES Monitoring of Biomarkers of Folate and Vitamin B-12 Status” took place in July 2010. This article provides an overview of the meeting and this supplement issue. Although the focus of the roundtable dialogue was on the measurement of folate and vitamin B-12 status biomarkers in NHANES, this article also describes the relevance and importance of these issues for clinical and research laboratories. The roundtable identified the microbiological assay (MA) as the gold standard for measurement of serum and red blood cell folate concentrations. The roundtable noted that differences in results between the Bio-Rad Quantaphase II procedure (Bio-Rad Laboratories, Hercules, CA) that NHANES 1991–1994 and 1999–2006 used and the MA that NHANES 2007–2010 used will require adjustment equations to evaluate time trends. The roundtable found that the close agreement between the serum results for the MA and liquid chromatography–tandem mass spectrometry (LC-MS/MS) procedures supported the conversion to LC-MS/MS for serum folate in future NHANES. The roundtable recognized the uncertainty about whether subclinical vitamin B-12 deficiency is a public health concern but encouraged reinstatement of at least one circulating vitamin B-12 measure and one functional vitamin B-12 status measure in future NHANES. The use of serum vitamin B-12 and plasma methylmalonic acid would provide continuity with past NHANES. The roundtable supported the continued use of the National Institute of Standards and Technology (NIST) reference materials in NHANES biomarker analyses and the further development of additional reference materials by the NIST.
doi:10.3945/ajcn.111.017392
PMCID: PMC3127514  PMID: 21593504
2.  Folate and vitamin B-12 biomarkers in NHANES: history of their measurement and use12345 
NHANES measured folate and vitamin B-12 status biomarkers, starting with serum folate from NHANES I (1974–1975) through 2010. Subsequent NHANES measured additional biomarkers [eg, red blood cell folate, serum vitamin B-12, total homocysteine (tHcy), methylmalonic acid, serum folic acid, and 5-methyltetrahydrofolic acid]. Examples of the uses of these data are wide ranging and include public policy applications, the derivation of reference intervals, and research. Periodically, the National Center for Health Statistics and its federal partners convene expert panels to review the use of the folate- and vitamin B-12–related biomarkers in NHANES. These panels have evaluated the need for results to be comparable across time and with published data and the use of crossover studies and adjustment equations to ensure comparability. With the recent availability of reference methods and materials for serum folate and tHcy, NHANES has started to use traceability approaches to enhance the accuracy and comparability of its results. A major user concern over the years has been the use of cutoffs to estimate the prevalence of inadequate folate and vitamin B-12 status. Because these cutoffs depend on the measurement procedure, several expert panels suggested approaches for dealing with cutoff challenges. This review summarizes the history and use of folate- and vitamin B-12–related biomarkers beginning with NHANES I (1974–1975) through 2010.
doi:10.3945/ajcn.111.013300
PMCID: PMC3127520  PMID: 21593508
3.  Biomarkers of vitamin B-12 status in NHANES: a roundtable summary123456 
A roundtable to discuss the measurement of vitamin B-12 (cobalamin) status biomarkers in NHANES took place in July 2010. NHANES stopped measuring vitamin B-12–related biomarkers after 2006. The roundtable reviewed 3 biomarkers of vitamin B-12 status used in past NHANES—serum vitamin B-12, methylmalonic acid (MMA), and total homocysteine (tHcy)—and discussed the potential utility of measuring holotranscobalamin (holoTC) for future NHANES. The roundtable focused on public health considerations and the quality of the measurement procedures and reference methods and materials that past NHANES used or that are available for future NHANES. Roundtable members supported reinstating vitamin B-12 status measures in NHANES. They noted evolving concerns and uncertainties regarding whether subclinical (mild, asymptomatic) vitamin B-12 deficiency is a public health concern. They identified the need for evidence from clinical trials to address causal relations between subclinical vitamin B-12 deficiency and adverse health outcomes as well as appropriate cutoffs for interpreting vitamin B-12–related biomarkers. They agreed that problems with sensitivity and specificity of individual biomarkers underscore the need for including at least one biomarker of circulating vitamin B-12 (serum vitamin B-12 or holoTC) and one functional biomarker (MMA or tHcy) in NHANES. The inclusion of both serum vitamin B-12 and plasma MMA, which have been associated with cognitive dysfunction and anemia in NHANES and in other population-based studies, was preferable to provide continuity with past NHANES. Reliable measurement procedures are available, and National Institute of Standards and Technology reference materials are available or in development for serum vitamin B-12 and MMA.
doi:10.3945/ajcn.111.013243
PMCID: PMC3127527  PMID: 21593512
4.  Folate status assessment history: implications for measurement of biomarkers in NHANES12345 
This article presents a historical perspective on the different methods used to measure folate status in populations and clinical settings. I discuss some of the advantages and limitations of these procedures. For >50 y researchers have used microbiological assay methods to assess folate status in clinical settings and in population-based studies, such as NHANES. Serum and red blood cell folate values obtained with the Lactobacillus casei assay have formed the basis for current ranges and cutoffs for the establishment of folate sufficiency and for the current dietary reference intakes for folate. Over the past 30 y competitive folate protein binding assays, which are available in kit form, have supplanted microbiological assays in many clinical laboratories because of their ease of use. Several NHANES cycles have used these assays. Folate concentrations obtained with these kits are lower than those from microbiological assays and show a wide variation between different protein binding assay kits. This variation has complicated the setting of values for normal ranges of folate status and the comparison of status changes between different NHANES cycles. The recent development of mass spectrometry methods for folate opens up the possibility of measurement of individual folate vitamers such as folic acid. Past experience with microbiological and competitive protein binding assays indicates some of the technical problems that research will need to address before this promise becomes reality.
doi:10.3945/ajcn.111.013367
PMCID: PMC3127515  PMID: 21593497
5.  A Practical Approach to Red Blood Cell Folate Analysis 
The measurement of folate in red blood cells (RBCs) is preferred since it reflects long-term folate status in the body compared to plasma/serum folate which may be influenced by recent dietary intake. The commonly accepted technique for RBC folate analysis involves preparation of a hemolysate using a fresh whole blood sample. Hematocrit and plasma folate concentrations are needed to calculate RBC folate values. Because of the need for immediate access to a laboratory where processing can be performed, it may not be practical to assess RBC folate status using this method in field-based epidemiological studies. It is however, feasible to isolate packed RBSs from a blood sample under these conditions. The purpose of this study is to validate RBC folate analysis using packed red cells by comparing the RBC folate values obtained by hemolysate method (routine assay) with those obtained by using packed RBCs (new assay) in the same individuals (n = 50) using the folate microbiological assay. The correlation between plasma folate and the routine RBC folate assay (r = 0.58, p = 0.001) and the correlation between plasma folate and the new RBC folate assay was statistically significant (r = 0.55, p = 0.001). The correlation between RBC folate by the routine assay and new assay was also statistically significant (r = 0.78, p < 0.001). We conclude that measurement of folate in packed RBC is a practical approach in assessing long-term folate status in field-based and or larger scale epidemiological studies where an immediate access to a laboratory is unavailable for necessary sample processing for the routine RBC folate assay.
PMCID: PMC2716806  PMID: 19662184
folate; packed RBC; hemolysate
6.  Intake and blood concentrations of folate and their association with health-related behaviors in Korean college students 
Nutrition Research and Practice  2013;7(3):216-223.
The purpose of this study is to assess folate intake, and serum and red blood cell (RBC) folate concentrations, and investigate the association between folate status and health-related behaviors among Korean college students. A total of 169 students, aged between 18 and 27 years, participated in this study. Dietary intake data were collected by trained interviewers using a 24-hour recall method for three non-consecutive days in 2009. Information on health-related behaviors was obtained by a self-administered questionnaire. Serum and RBC folate concentrations were measured by microbiological assay. The average intakes of folate were 456 µgDFE and 347 µgDFE in male and female students, respectively. While the average serum folate concentration was significantly lower in male students (8.9 ng/mL) compared to female students (12.5 ng/mL), RBC concentrations were not significantly different between male (398.6 ng/mL) and female students (405.3 ng/mL). In male students, low serum folate concentrations were associated with total folate intake less than the Estimated Average Requirement, non-use of folic acid supplements, smoking, alcohol drinking at least once a week and low physical activity. In female students, low serum folate concentrations were associated with smoking and alcohol drinking at least two drinks at a time and BMI ≥ 25. Alcohol drinking and low physical activity were also associated with low RBC folate concentrations in both male and female students. In order to improve folate nutritional status of college students, the practice of desirable health-related behaviors, such as non-smoking, moderate alcohol drinking, regular physical activity, and maintenance of healthy BMI should be encouraged along with consumption of folate-rich foods and supplements.
doi:10.4162/nrp.2013.7.3.216
PMCID: PMC3679331  PMID: 23766883
Folate intake; serum folate; RBC folate; health-related behaviors; college students
7.  Plasma and Red Cell Reference Intervals of 5-Methyltetrahydrofolate of Healthy Adults in Whom Biochemical Functional Deficiencies of Folate and Vitamin B12 Had Been Excluded 
Advances in Hematology  2014;2014:465623.
5-Methyltetrahydrofolate (5-MTHF) is the predominant form of folate and a strong determinant of homocysteine concentrations. There is evidence that suboptimal 5-MTHF availability is a risk factor for cardiovascular disease independent of homocysteine. The analysis of folates remains challenging and is almost exclusively limited to the reporting of “total” folate rather than individual molecular forms. The purpose of this study was to establish the reference intervals of 5-MTHF in plasma and red cells of healthy adults who had been prescreened to exclude biochemical evidence of functional deficiency of folate and/or vitamin B12. Functional folate and vitamin B12 status was assessed by respective plasma measurements of homocysteine and methylmalonic acid in 144 healthy volunteers, aged 19–64 years. After the exclusion of 10 individuals, values for 134 subjects were used to establish the upper reference limits for homocysteine (13 μmol/L females and 15 μmol/L males) and methylmalonic acid (430 nmol/L). Subjects with values below these cutoffs were designated as folate and vitamin B12 replete and their plasma and red cell 5-MTHF reference intervals determined, N = 126: 6.6–39.9 nmol/L and 223–1041 nmol/L, respectively. The application of these intervals will assist in the evaluation of folate status and facilitate studies to evaluate the relationship of 5-MTHF to disease.
doi:10.1155/2014/465623
PMCID: PMC3914575  PMID: 24527038
8.  Folate and Homocysteine Phenotypes: Comparative Findings Using Research and Clinical Laboratory Data 
Clinical biochemistry  2009;42(12):1275-1281.
Objectives
A low folate/high homocysteine phenotype is associated with several pathologies, including spina bifida and cardiovascular disease. Folate and total homocysteine (tHcy) measurements are used clinically to assess risk and the need for folic acid supplementation and in research to investigate the metabolic basis of disease. Red blood cell (RBC) folate, the best indicator of long-term folate status, is usually measured as “total” folate. However, different folate derivatives support distinct biochemical functions, suggesting a need to develop more precise methods. This study was designed to evaluate a method based on stable isotope dilution liquid chromatography–multiple reaction monitoring/mass spectrometry (LC-MRM/MS).
Design and Methods
We used LC-MRM/MS to quantify the RBC folate derivatives 5- methyltetrahydrofolate (5-CH3-THF), tetrahydrofolate (THF), and 5,10-methenyltetrahydrofolate (5,10-methenylTHF) in pre-menopausal women. The concentrations of each folate derivative was assessed for utility in predicting tHcy levels, and compared to folate and tHcy measurements derived by routine clinical laboratory methods.
Results
LC-MRM/MS was qualitatively and quantitatively superior to routine clinical laboratory methods for determining folate and tHcy concentrations. RBC 5-CH3-THF had a reciprocal relationship with tHcy (p=0.0003), whereas RBC THF and RBC 5,10-methenylTHF had direct relationships (p=0.01, 0.04 respectively). In combination, these three variables accounted for 42% of the variation in tHcy.
Conclusions
Robust methods for measuring RBC 5-CH3-THF would improve the utility of folate/homocysteine phenotyping in patient management. The use of LC-MRM/MS would allow studies of hyperhomocysteinemia and diseases associated with a low folate/high homocysteine phenotype to be performed with less measurement error and greater statistical power to generate data with the potential to elucidate the etiologic mechanisms of complex diseases and traits.
doi:10.1016/j.clinbiochem.2009.04.014
PMCID: PMC4051207  PMID: 19427846
folate; homocysteine; hyperhomocysteinemia; disease risk; LC-MRM/MS
9.  Higher Serum Folate Levels are Associated with a Lower Risk of Atopy and Wheeze 
Background
Folic acid is known to be associated with inflammatory diseases, but the relationship between folic acid and allergic diseases is unclear.
Objectives
The purpose of the study was to examine the relationship between serum folate levels and markers of atopy, wheeze, and asthma.
Methods
Data were obtained from the 2005–2006 National Health and Nutrition Examination Survey (NHANES) in which serum folate and total IgE levels were measured in 8,083 subjects 2 years of age and older. A high total IgE level was defined as >100kU/L. Allergen-specific IgE levels were measured for a panel of 5 common aeroallergens. Atopy was defined as at least 1 positive allergen-specific IgE level. Doctor-diagnosed asthma and wheeze in the previous 12 months were assessed by questionnaire.
Results
Serum folate levels were inversely associated with total IgE levels (p<.001). The odds of a high total IgE, atopy, and wheeze decreased across quintiles of serum folate, indicating a dose-response relationship between serum folate levels and these outcomes. Each of these associations remained statistically significant after adjusting for age, sex, race/ethnicity and poverty index ratio. Adjusted odds ratios[95% confidence intervals] associated with the fifth quintile (Q5) of folate relative to the first quintile (Q1) were as follows: High IgE: 0.70[0.53–0.92]; atopy: 0.69[0.57–0.85]; and wheeze: 0.60[0.44–0.82]. Higher folate levels were also associated with a lower risk of doctor-diagnosed asthma, but this finding was not statistically significant (OR[95% CI] for Q5 vs. Q1: 0.84 [0.70–1.02]).
Conclusions
Serum folate levels are inversely associated with high total IgE, atopy, and wheeze.
Clinical Implications
Folic acid status may influence the development and/or progression of atopy and wheeze.
doi:10.1016/j.jaci.2009.03.007
PMCID: PMC2693474  PMID: 19409604
asthma; allergy; atopy; folate; NHANES; Centers for Disease Control
10.  Validity of U.S. Nutritional Surveillance: National Health and Nutrition Examination Survey Caloric Energy Intake Data, 1971–2010 
PLoS ONE  2013;8(10):e76632.
Importance
Methodological limitations compromise the validity of U.S. nutritional surveillance data and the empirical foundation for formulating dietary guidelines and public health policies.
Objectives
Evaluate the validity of the National Health and Nutrition Examination Survey (NHANES) caloric intake data throughout its history, and examine trends in the validity of caloric intake estimates as the NHANES dietary measurement protocols evolved.
Design
Validity of data from 28,993 men and 34,369 women, aged 20 to 74 years from NHANES I (1971–1974) through NHANES 2009–2010 was assessed by: calculating physiologically credible energy intake values as the ratio of reported energy intake (rEI) to estimated basal metabolic rate (BMR), and subtracting estimated total energy expenditure (TEE) from NHANES rEI to create ‘disparity values’.
Main Outcome Measures
1) Physiologically credible values expressed as the ratio rEI/BMR and 2) disparity values (rEI–TEE).
Results
The historical rEI/BMR values for men and women were 1.31 and 1.19, (95% CI: 1.30–1.32 and 1.18–1.20), respectively. The historical disparity values for men and women were −281 and −365 kilocalorie-per-day, (95% CI: −299, −264 and −378, −351), respectively. These results are indicative of significant under-reporting. The greatest mean disparity values were −716 kcal/day and −856 kcal/day for obese (i.e., ≥30 kg/m2) men and women, respectively.
Conclusions
Across the 39-year history of the NHANES, EI data on the majority of respondents (67.3% of women and 58.7% of men) were not physiologically plausible. Improvements in measurement protocols after NHANES II led to small decreases in underreporting, artifactual increases in rEI, but only trivial increases in validity in subsequent surveys. The confluence of these results and other methodological limitations suggest that the ability to estimate population trends in caloric intake and generate empirically supported public policy relevant to diet-health relationships from U.S. nutritional surveillance is extremely limited.
doi:10.1371/journal.pone.0076632
PMCID: PMC3793920  PMID: 24130784
11.  Relationship of sex steroid hormones with body size and with body composition measured by dual-energy X-ray absorptiometry in US men 
Cancer causes & control : CCC  2012;23(12):1881-1891.
Purpose
To evaluate the association of body size – captured via whole body dual-energy x-ray absorptiometry (DXA) and physical measurement – with serum sex steroid hormones and sex hormone binding globulin (SHBG) we utilized cross-sectional data and serum samples from the National Health and Nutrition Examination Survey (NHANES; 1999-2004).
Methods
Testosterone, androstanediol glucuronide (3-alpha-diol-G), estradiol and SHBG were measured via immunoassay in serum samples from a total of 898 adult men (ages 20-90) participating in the morning examination. As part of the NHANES data collection DXA scans and measurements of weight, height and waist circumference were performed by trained staff. Linear regression was used to estimate associations between body size and hormone levels adjusted for potential confounders and NHANES sampling procedures.
Results
Total bone area (cm2) was inversely associated with total testosterone (ng/mL) [beta=-0.12; p-value<0.01], while bone mineral density (g/cm2) was inversely associated with SHBG (nmol/L) [beta=-17.16; p-value=0.01]. Increased percent body fat was associated with lower concentrations of total testosterone [beta=-0.16; p-value<0.01] and SHBG [beta=-1.11; p-value<0.01] and higher concentrations of free estradiol (fg/mL) [beta=12.52; p-value<0.01].
Conclusions
Clinical measures of body fat (measured via DXA scan) and anthropometric measures of body fat (BMI and waist circumference) provided similar inferences regarding the association between increased body fat and hormone levels in men. Increased body fat was associated with lower circulating levels of testosterone (total and free) and SHBG and higher circulating levels of free estradiol in men, while decreased bone mineral density was associated with higher circulating levels of SHBG.
doi:10.1007/s10552-012-0024-9
PMCID: PMC3499640  PMID: 23053790
dual-energy X-ray absorptiometry; DXA; estradiol; testosterone; androstanediol glucuronide; sex hormone binding globulin; National Health and Nutrition Examination Survey; NHANES; men
12.  Red cell N5-methyltetrahydrofolate concentrations and C677T methylenetetrahydrofolate reductase genotype in patients with stroke 
Journal of Clinical Pathology  2004;57(1):54-57.
Aims: To investigate the relation between total red cell folate, red cell N5-methyltetrahydrofolate (N5MTHF) concentrations, and N5N10-methylenetetrahydrofolate reductase (MTHFR) genotypes in stroke.
Methods: The study comprised 120 consecutive patients presenting to hospital with acute stroke. Multivitamin supplement use was recorded. Serum and red cell folate were measured by microbiological assays using Lactobacillus casei and Enterococcus faecalis, and by the DPC-BioMediq Immulite™ 2000 analyser. Total plasma homocysteine (tHcy), serum cobalamin, and serum vitamin B6 were measured and the C677T MTHFR genotype determined.
Results: There were no significant differences in blood tHcy or vitamin concentrations according to MTHFR genotype in the overall patient cohort. However, when patients taking vitamins were excluded, total red cell folate and red cell N5MTHF were significantly lower in patients with the TT genotype compared with CT or CC genotypes. In the overall cohort, irrespective of genotype, red cell folate was significantly lower when assayed microbiologically than with the Immulite assay. This discrepancy remained after exclusion of patients taking vitamins.
Conclusion: Total red cell folate and red cell N5MTHF are significantly lower in stroke patients with the TT compared with the CT and TT MTHFR genotypes, particularly those not taking vitamin supplements. Microbiological assays that measure biologically active folates provide substantially lower estimates of folate than the Immulite™ assay. Because folate is a key determinant of blood homocysteine values, these findings may impact on the interpretation of the strength and independence of the association between raised blood concentrations of homocysteine and atherothrombosis risk reported in most epidemiological studies.
PMCID: PMC1770163  PMID: 14693836
stroke; folate; methylenetetrahydrofolate reductase; homocysteine
13.  Determinants of neural tube defect (NTD)-protective circulating concentrations of folate in women of child-bearing age in the US post-folic acid fortification era 
Nutrition Research and Practice  2013;7(4):315-325.
We evaluated folate status of child-bearing age women diagnosed with abnormal pap smear in the US post-folic acid (FA) fortification era and assessed the determinants of NTD-protective and supra-physiologic (SP) concentrations of folate. The distribution of 843 women according to NTD-protective concentrations of RBC folate, plasma folate and SP concentrations of plasma folate were tested in relation to demographic and life-style factors. Logistic regression models specified NTD-protective concentrations of RBC and plasma folate or SP concentrations of plasma folate as dependent variables and demographic and life-style factors as independent predictors of interest. More than 82% reached NTD-protective concentrations of RBC and plasma folate and ~30% reached SP concentrations of plasma folate. FA supplement use was associated with having SP concentrations of plasma folate rather than NTD-protective concentrations of folate. African American (AA) women and smokers were significantly less likely to achieve NTD-protective concentrations of RBC and plasma folate. A large majority of women reached NTD-protective concentrations of folate with the current level of FA fortification without using supplementary FA. Therefore, the remaining disparities in AA women and in smokers should be addressed by targeted individual improvements in folate intake.
doi:10.4162/nrp.2013.7.4.315
PMCID: PMC3746167  PMID: 23964320
Folate; neural tube defect; child-bearing age
14.  Serum 25-hydroxyvitamin D status of the US population: 1988–1994 versus 2000–20041 
Background
Changes in serum 25-hydroxyvitamin D (25OHD) concentrations in the US population have not been described.
Objective
Use data from the National Health and Nutrition Examination Surveys (NHANES) to compare serum 25OHD concentrations in the US population in 2000–2004 versus 1988–1994, and to identify contributing factors.
Design
Serum 25OHD was measured with a radioimmunoassay kit in 20,289 participants in NHANES 2000–2004 and 18,158 participants in NHANES III (1988–1994). Body mass index (BMI) was calculated from measured height and weight. Milk intake and sun protection were assessed by questionnaire. Assay differences were assessed by re-analyzing 150 stored sera specimens from NHANES III with the current assay.
Results
Age-adjusted mean serum 25OHD concentrations were significantly lower by 5–20 nmol/L in NHANES 2000–2004 than in NHANES III. After accounting for assay shifts, age-adjusted means in NHANES 2000–2004 remained significantly lower (by 5–9 nmol/L) in most males, but not in most females. In a study subsample, accounting for the confounding effects of assay differences changed mean serum 25OHD by ~10 nmol/L, while accounting for changes in the factors likely related to real changes in vitamin D status (BMI, milk intake, and sun protection) changed means by 1–1.6 nmol/L.
Conclusions
Overall, mean serum 25OHD was lower in 2000–2004 than 1988–1994. Assay changes unrelated to changes in vitamin D status accounted for much of the difference in most population groups. In an adult subgroup, combined changes in BMI, milk intake and sun protection appeared to contribute to a real decline in vitamin D status.
doi:10.3945/ajcn.2008.26182
PMCID: PMC2745830  PMID: 19064511
Serum 25-hydroxyvitamin D; Vitamin D status; NHANES
15.  Folate Status of Reproductive Age Women and Neural Tube Defect Risk: The Effect of Long-Term Folic Acid Supplementation at Doses of 140 µg and 400 µg per Day 
Nutrients  2011;3(1):49-62.
Primary prevention of most folate-responsive neural tube defects (NTDs) may not require 400 μg folic acid/day but may be achieved by attaining a high maternal folate status. Using RBC folate ≥906 nmol/L as a marker for NTD risk reduction, the study aimed to determine the change in blood folate concentrations in reproductive age women in response to long-term folic acid supplementation at 400 µg/day and 140 µg/day (dose designed to mimic the average daily folic acid intake received from New Zealand’s proposed mandatory bread fortification program). Participants were randomly assigned to a daily folic acid supplement of 140 µg (n = 49), 400 µg (n = 48) or placebo (n = 47) for 40 weeks. RBC folate concentrations were measured at baseline, and after 6, 12, 29 and 40 weeks. At 40 weeks, the overall prevalence of having a RBC folate <906 nmol/L decreased to 18% and 35% in the 400 µg and 140 µg groups, respectively, while remaining relatively unchanged at 58% in the placebo group. After 40 weeks, there was no evidence of a difference in RBC folate between the two treatment groups (P = 0.340), nor was there evidence of a difference in the odds of a RBC folate <906 nmol/L (P = 0.078). In conclusion, the average daily intake of folic acid received from the proposed fortification program would increase RBC folate concentrations in reproductive age women to levels associated with a low risk of NTDs.
doi:10.3390/nu3010049
PMCID: PMC3257734  PMID: 22254076
neural tube defects; blood folate status; folic acid fortification; supplementation
16.  Folate Intake and Markers of Folate Status in Women of Reproductive Age, Pregnant and Lactating Women: A Meta-Analysis 
Background. Pregnant and breastfeeding women are at risk for folate deficiency. Folate supplementation has been shown to be associated with enhanced markers of folate status. However, dose-response analyses for adult women are still lacking. Objective. To assess the dose-response relationship between total folate intake (folic acid plus dietary folate) and markers of folate status (plasma/serum folate, red blood cell folate, and plasma homocysteine); to evaluate potential differences between women in childbearing age, pregnant and lactating women. Methods. Electronic literature searches were carried out on three databases until February 2010. The overall pooled regression coefficient (β) and SE(β) were calculated using meta-analysis on a double-log scale. Results. The majority of data was based on nonpregnant, nonlactating women in childbearingage. The pooled estimate of the relationship between folate intake and serum/plasma folate was 0.56 (95% CI = 0.40–0.72, P < 0.00001); that is, the doubling of folate intake increases the folate level in serum/plasma by 47%. For red blood cell folate, the pooled-effect estimate was 0.30 (95% CI = 0.22–0.38, P < 0.00001), that is, +23% for doubling intake. For plasma-homocysteine it was –0.10 (95% = –0.17 to –0.04, P = 0.001), that is, –7% for doubling the intake. Associations tended to be weaker in pregnant and lactating women. Conclusion. Significant relationships between folate intake and serum/plasma folate, red blood cell folate, and plasma homocysteine were quantified. This dose-response methodology may be applied for setting requirements for women in childbearing age, as well as for pregnant and lactating women.
doi:10.1155/2012/470656
PMCID: PMC3449134  PMID: 23024859
17.  Changes in Inflammatory Biomarkers Across Weight Classes in a Representative US Population: A Link Between Obesity and Inflammation 
Journal of Gastrointestinal Surgery  2009;13(7):1205-1212.
Background
Obesity has been linked with a chronic state of inflammation which may be involved in the development of metabolic syndrome, cardiovascular disease, non-alcoholic steatohepatitis, and even cancer. The objective of this study was to examine the association between obesity class and levels of inflammatory biomarkers from men and women who participated in the 1999–2004 National Health and Nutrition Examination Survey (NHANES).
Methods
Serum concentrations of C-reactive protein (CRP) and fibrinogen were measured among US participants of the 1999–2004 NHANES. We examined biomarker levels across different weight classes with normal weight, overweight, and obesity classes 1, 2, and 3 were defined as BMI of <25.0, 25.0–29.9, 30.0–34.9, 35.0–39.9, and ≥40.0, respectively.
Results
With CRP levels for normal weight individuals as a reference, CRP levels nearly doubled with each increase in weight class: +0.11 mg/dl (95% CI, 0.06–0.16) for overweight, +0.21 mg/dl (95% CI, 0.16–0.27) for obesity class 1, +0.43 mg/dl (95% CI, 0.26–0.61) for obesity class 2, and +0.73 mg/dl (95% CI, 0.55–0.90) for obesity class 3. With normal weight individuals as a reference, fibrinogen levels increase with increasing weight class and were highest for obesity class 3 individuals, +93.5 mg/dl (95% CI, 72.9–114.1). Individuals with hypertension or diabetes have higher levels of CRP and fibrinogen levels compared to individuals without hypertension or diabetes, even when stratified according to BMI.
Conclusions
There is a direct association between increasing obesity class and the presence of obesity-related comorbidities such as diabetes and hypertension with high levels of inflammatory biomarkers.
doi:10.1007/s11605-009-0904-9
PMCID: PMC2693771  PMID: 19415399
Inflammation; C-reactive protein; Fibrinogen; Obesity; Biomarker; Hypertension; Diabetes; NHANES
18.  Determination of unmetabolized folic acid in human plasma using affinity HPLC12345 
Background: Folic acid (FA) fortification of food created the need to determine whether fortification elevated concentrations of unmetabolized FA in plasma and whether this form of the vitamin in blood is associated with adverse health outcomes.
Objective: The objective of this research was to devise a simple, rapid method for the measurement of unmetabolized plasma FA in epidemiologic studies.
Design: We previously used the affinity/HPLC with electrochemical detection method to measure folate distribution in human plasma and red blood cells (RBCs). We modified this method with the inclusion of synthetic ethyltetrahydrofolate as an internal standard and with the use of 2 affinity columns connected in parallel to the analytic column through a switching valve to allow one column to be loaded while the other column was eluted into the analytic column.
Results: We identified FA and 5-methyltetrahydrofolate (5-mTHF) by retention time and characteristic response across the channels of the electrochemical detector. Limits of detection were 0.034 pmol for 5-mTHF and 0.027 pmol for FA per injection, and the recovery was 92.2% (5-mTHF) and 98.9% (FA). CVs for samples were 8.1% (within day) and 6.8% (between day) for 5-mTHF and 3.2% (within day) and 5.9% (between day) for FA. Total folate with the use of this method correlated highly (r2 = 0.98, P < 0.001) with values from the microbial assay. The run time for the method was 30 min per sample. Researchers can use this method with longer run times to measure the distribution of folate forms in RBCs.
Conclusion: This updated method allows efficient analysis of folate forms in human plasma and tissues without the loss of sensitivity or precision.
doi:10.3945/ajcn.111.013433
PMCID: PMC3127506  PMID: 21593489
19.  Association between Serum Perfluorooctanoic Acid (PFOA) and Thyroid Disease in the U.S. National Health and Nutrition Examination Survey 
Environmental Health Perspectives  2010;118(5):686-692.
Background
Perfluorooctanoic acid (PFOA, also known as C8) and perfluorooctane sulfonate (PFOS) are stable compounds with many industrial and consumer uses. Their persistence in the environment plus toxicity in animal models has raised concern over low-level chronic exposure effects on human health.
Objectives
We estimated associations between serum PFOA and PFOS concentrations and thyroid disease prevalence in representative samples of the U.S. general population.
Methods
Analyses of PFOA/PFOS versus disease status in the National Health and Nutrition Examination Survey (NHANES) for 1999–2000, 2003–2004, and 2005–2006 included 3,974 adults with measured concentrations for perfluorinated chemicals. Regression models were adjusted for age, sex, race/ethnicity, education, smoking status, body mass index, and alcohol intake.
Results
The NHANES-weighted prevalence of reporting any thyroid disease was 16.18% (n = 292) in women and 3.06% (n = 69) in men; prevalence of current thyroid disease with related medication was 9.89% (n = 163) in women and 1.88% (n = 46) in men. In fully adjusted logistic models, women with PFOA ≥ 5.7 ng/mL [fourth (highest) population quartile] were more likely to report current treated thyroid disease [odds ratio (OR) = 2.24; 95% confidence interval (CI), 1.38–3.65; p = 0.002] compared with PFOA ≤ 4.0 ng/mL (quartiles 1 and 2); we found a near significant similar trend in men (OR = 2.12; 95% CI, 0.93–4.82; p = 0.073). For PFOS, in men we found a similar association for those with PFOS ≥ 36.8 ng/mL (quartile 4) versus ≤ 25.5 ng/mL (quartiles 1 and 2: OR for treated disease = 2.68; 95% CI, 1.03–6.98; p = 0.043); in women this association was not significant.
Conclusions
Higher concentrations of serum PFOA and PFOS are associated with current thyroid disease in the U.S. general adult population. More work is needed to establish the mechanisms involved and to exclude confounding and pharmacokinetic explanations.
doi:10.1289/ehp.0901584
PMCID: PMC2866686  PMID: 20089479
C8; human population; PFOA; PFOS; thyroid disease
20.  Ordering folate assays is no longer justified for investigation of anemias, in folic acid fortified countries 
BMC Research Notes  2010;3:22.
Background
Since 1998, in the countries where there is mandatory fortification of grain products with folic acid, folate deficiency has become very rare. Consequently, we decided to find out whether there is any justification for ordering folate assays for investigation of anemias.
Methods
We reviewed serum folate (SF) and red cell folate (RF) data at two teaching hospitals in Canada. At the Health Sciences Centre (HSC) the folate data for the year 2001 were analyzed and the medical records of those with low SF or low RF were reviewed. At St. Boniface General Hospital(SBGH)all folate data between January 1996 and Dec 31,2004 were analyzed and the medical records of all who had low RF between January 1,1999 and December 31,2004 were reviewed.
Results
In 2001, at HSC, 11 out of 2154(0.5%)SF were low(<7.0 nmol/L) and 4 out of 560 (0.7%) RF were low (<417 nmol/L). In no subject with low SF or RF could the anemia be attributed to folate deficiency. At SBGH during the 3-year-period of 1999-2001, 19 out of 991(1.9%) had low RF (<225 nmol/L) but in only 2 patients (0.2%) the low RF was in folate deficiency anemia range; but neither of them had anemia.
Conclusion
In countries where there is mandatory fortification of grain products with folic acid, folate deficiency to the degree that could cause anemia is extremely rare. Ordering folate assays for investigation of anemias, in these countries, is waste of time and money. The result of these tests is more likely to mislead the physicians than to provide any useful information.
doi:10.1186/1756-0500-3-22
PMCID: PMC2843732  PMID: 20181007
21.  Smoothed Urinary Iodine Percentiles for the US Population and Pregnant Women: National Health and Nutrition Examination Survey, 2001-2010 
European Thyroid Journal  2013;2(2):127-134.
Background
Iodine intake is essential for normal growth, development and metabolism throughout life, especially for women during gestation and lactation. The present study applies a novel statistical approach, providing smoothed urinary iodine (UI) percentile curves for the total US population as well as the categories of sex, race/ethnicity, women of childbearing age and pregnant women who were participants in the National Health and Nutrition Examination Survey (NHANES) 2001-2010. To our knowledge, this is the first application of this technique to NHANES nutritional biomarker data.
Methods
We used UI and urinary creatinine that were measured in participants aged 6 and older in the NHANES survey periods 2001-2002, 2003-2004, 2005-2006, 2007-2008 and 2009-2010. A nonparametric double-kernel method was applied to smooth percentile curves for UI and creatinine-corrected results.
Results
The UI population estimates showed a U-shaped distribution by age for the total US population. Overall, females had lower UI concentrations and median values compared to males (median UI for females, 141.8 µg/l; median UI for males, 176.1 µg/l; p < 0.0001). Non-Hispanic blacks had the lowest median UI concentrations compared to other racial/ethnic groups (p < 0.0001). Among women of childbearing age (15-44 years), UI concentrations mostly declined with increasing age. Pregnant women aged 35 years and older tended to have higher UI concentrations than younger pregnant women at similar percentiles.
Conclusions
The smoothed reference distribution of UI concentrations provides an improved and visual display of the entire distribution of values for the US population and specific demographic categories.
doi:10.1159/000348247
PMCID: PMC3821505  PMID: 24783051
Urinary iodine; Smoothed percentile; Pregnant women; National Health and Nutrition Examination Survey

22.  CKD Surveillance Using Laboratory Data from the Population-Based National Health and Nutrition Examination Survey (NHANES)[EF1] 
Surveillance for chronic kidney disease (CKD) using nationally representative samples of the US population is central in providing information on the magnitude and trends in CKD burden that will guide disease management and prevention planning for clinicians and public health authorities. We used a cross-sectional study design to estimate the change in prevalence of CKD over time using National Health and Nutrition Examination Survey (NHANES) data. NHANES III (1988-1994) included 15,488 participants and NHANES rounds 1999-2004 included 13,233 participants over the age of 20 years with serum creatinine measurements who were examined in a mobile examination center. Early stages of CKD were defined by glomerular filtration rate (GFR) as estimated by the Modification of Diet in Renal Disease (MDRD) Study equation and urinary albumin-to-creatinine ratio (ACR) following the classification system established by the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative. Moderately reduced GFR increased in prevalence from 5.4% to 7.7% (P<0.001) and severely reduced GFR increased from 0.21% to 0.35% (P=0.02) from 1988-1994 to 1999-2004. Within CKD stage 3, 18.6 % (SE 1.6%) of individuals should be referred to a nephrologist following a proposed set of criteria for referral; referral rates were highest for individuals with diabetes and lower among whites compared to other race-ethnicity groups. These survey data suggest that the prevalence of CKD has increased between the years of 1988-1994 and 1999-2004. Surveillance for early stages of CKD (CKD stages 1-4) should monitor these and other trends.
doi:10.1053/j.ajkd.2008.07.054
PMCID: PMC2677815  PMID: 19231761
Surveillance; kidney; NHANES; national surveys; GFR
23.  Advances in standardization of laboratory measurement procedures: implications for measuring biomarkers of folate and vitamin B-12 status in NHANES1234 
Population studies such as NHANES analyze large numbers of laboratory measurements and are often performed in different laboratories using different measurement procedures and over an extended period of time. Correct clinical and epidemiologic interpretations of the results depend on the accuracy of those measurements. Unfortunately, considerable variability has been observed among assays for folate, vitamin B-12, and related biomarkers. In the past few decades, the science of metrology has advanced considerably, with the development of improved primary reference measurement procedures and high-level reference materials, which can serve as the basis for accurate measurement. A rigorous approach has been established for making field methods traceable to the highest-level reference measurement procedures and reference materials. This article reviews some basic principles of metrology and describes their recent application to measurements of folate and vitamin B-12.
doi:10.3945/ajcn.111.013359
PMCID: PMC3127510  PMID: 21562088
24.  Red cell or serum folate? Results from the National Pathology Alliance benchmarking review 
Journal of Clinical Pathology  2003;56(12):924-926.
Aims: The National Pathology Alliance benchmarking review has completed five years of data collection and analysis of the workload and organisation of haematology laboratories in the UK. This study analyses variation in practice in how laboratories respond to a request to determine whether or not a patient has folate deficiency.
Methods: A three year analysis of workload data on the number of serum/plasma folate and red cell folate assays performed on an annual basis for the period 1 April 1999 to 31 March 2002.
Results: Three diagnostic testing strategies were found, namely: serum/plasma folate only, red cell folate only, and both serum/plasma folate and red cell folate.
Conclusion: Evidence from the literature indicates that serum folate measurements provide equivalent information to red cell folate measurements when attempting to determine whether folate deficiency is present. There seems to be no basis for the routine testing of all samples for serum/plasma folate and a red cell folate.
PMCID: PMC1770141  PMID: 14645351
red cell folate; serum folate
25.  Red blood cell folate levels in pregnant women with a history of mood disorders: a case series 
Objective
Maternal folate supplementation reduces offspring risk for neural tube defects (NTDs) and other congenital abnormalities. Maternal red blood cell (RBC) folate concentrations of >906nmol/L have been associated with the lowest risk of having an NTD affected pregnancy. Mood disorders (e.g. depression, bipolar disorder) are common among women and can be associated with folate deficiency. Thus, pregnant women with histories of mood disorders may be prone to RBC folate levels insufficient to provide optimal protection against NTDs. While previous studies have assessed RBC folate concentrations in pregnant women from the general population, none have looked specifically at a group of pregnant women who have a history of a mood disorder.
Methods
We collected data about RBC folate concentrations and folic acid supplement intake during early pregnancy (<161days gestation) from n=24 women with histories of mood disorders. We also collected information about offspring congenital abnormalities and birthweight.
Results
Among women with histories of mood disorders, the mean RBC folate concentration was 674 nmol/L (range: 362 –1105nmol/L). Only 12.5% (n=3) of the women had an RBC folate concentrations >906nmol/L, despite all participants reporting current daily use of folic acid supplements. Data regarding offspring were available for 22 women: birthweights ranged from 2296g to 4819g, and congenital abnormalities were identified in two (hypoplastic left heart, annular pancreas).
Conclusion
Data from this exploratory case series suggest a need for future larger scale controlled studies investigating RBC folate concentrations in early pregnancy and offspring outcomes among women with and without histories of mood disorders.
doi:10.1002/bdra.23144
PMCID: PMC3951991  PMID: 23760977 CAMSID: cams3096
folic acid; folate; pregnancy; mood disorders; depression; birth defects; congenital abnormalities

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