Systematic Review of Observational Studies with Dose-Response Meta-Analysis between Folate Intake and Status Biomarkers in Adults and the Elderly.

BACKGROUND: Dietary reference values for folate intake vary widely across Europe. METHODS: MEDLINE and Embase through November 2016 were searched for data on the association between folate intake and biomarkers (serum/plasma folate, red blood cell [RBC] folate, plasma homocysteine) from observational studies in healthy adults and elderly. The regression coefficient of biomarkers on intake (ß) was extracted from each study, and the overall and stratified pooled ß and SE (ß) were obtained by random effects meta-analysis on a double log scale. These dose-response estimates may be used to derive folate intake reference values. RESULTS: For every doubling in folate intake, the changes in serum/plasma folate, RBC folate and plasma homocysteine were +22, +21, and -16% respectively. The overall pooled regression coefficients were ß = 0.29 (95% CI 0.21-0.37) for serum/plasma folate (26 estimates from 17 studies), ß = 0.28 (95% CI 0.21-0.36) for RBC (13 estimates from 11 studies), and ß = -0.21 (95% CI -0.31 to -0.11) for plasma homocysteine (10 estimates from 6 studies). CONCLUSION: These estimates along with those from randomized controlled trials can be used for underpinning dietary recommendations for folate in adults and elderly.

Prediction of fruit and vegetable intake from biomarkers using individual participant data of diet-controlled intervention studies.

Fruit and vegetable consumption produces changes in several biomarkers in blood. The present study aimed to examine the dose-response curve between fruit and vegetable consumption and carotenoid (α-carotene, ß-carotene, ß-cryptoxanthin, lycopene, lutein and zeaxanthin), folate and vitamin C concentrations. Furthermore, a prediction model of fruit and vegetable intake based on these biomarkers and subject characteristics (i.e. age, sex, BMI and smoking status) was established. Data from twelve diet-controlled intervention studies were obtained to develop a prediction model for fruit and vegetable intake (including and excluding fruit and vegetable juices). The study population in the present individual participant data meta-analysis consisted of 526 men and women. Carotenoid, folate and vitamin C concentrations showed a positive relationship with fruit and vegetable intake. Measures of performance for the prediction model were calculated using cross-validation. For the prediction model of fruit, vegetable and juice intake, the root mean squared error (RMSE) was 258.0 g, the correlation between observed and predicted intake was 0.78 and the mean difference between observed and predicted intake was - 1.7 g (limits of agreement: - 466.3, 462.8 g). For the prediction of fruit and vegetable intake (excluding juices), the RMSE was 201.1 g, the correlation was 0.65 and the mean bias was 2.4 g (limits of agreement: -368.2, 373.0 g). The prediction models which include the biomarkers and subject characteristics may be used to estimate average intake at the group level and to investigate the ranking of individuals with regard to their intake of fruit and vegetables when validating questionnaires that measure intake.

Optimising the selection of food items for FFQs using Mixed Integer Linear Programming.

OBJECTIVE: To support the selection of food items for FFQs in such a way that the amount of information on all relevant nutrients is maximised while the food list is as short as possible. DESIGN: Selection of the most informative food items to be included in FFQs was modelled as a Mixed Integer Linear Programming (MILP) model. The methodology was demonstrated for an FFQ with interest in energy, total protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, total carbohydrates, mono- and disaccharides, dietary fibre and potassium. RESULTS: The food lists generated by the MILP model have good performance in terms of length, coverage and R 2 (explained variance) of all nutrients. MILP-generated food lists were 32-40 % shorter than a benchmark food list, whereas their quality in terms of R 2 was similar to that of the benchmark. CONCLUSIONS: The results suggest that the MILP model makes the selection process faster, more standardised and transparent, and is especially helpful in coping with multiple nutrients. The complexity of the method does not increase with increasing number of nutrients. The generated food lists appear either shorter or provide more information than a food list generated without the MILP model.

Comparison of approaches to correct intake­health associations for FFQ measurement error using a duplicate recovery biomarker and a duplicate 24 h dietary recall as reference method.

OBJECTIVE: To illustrate the impact of intake-related bias in FFQ and 24 h recall (24hR), and correlated errors between these methods, on intake-health associations. DESIGN: Dietary intake was assessed by a 180-item semi-quantitative FFQ and two 24hR. Urinary N and urinary K were estimated from two 24 h urine samples. We compared four scenarios to correct associations for errors in an FFQ estimating protein and K intakes. SETTING: Wageningen, The Netherlands. SUBJECTS: Fifty-nine men and fifty-eight women aged 45­65 years. RESULTS: For this FFQ, measurement error weakened a true relative risk of 2·0 to 1·4 for protein and 1·5 for K. As compared with calibration to duplicate recovery biomarkers (i.e. the preferred scenario 1), estimating a validity coefficient using this duplicate biomarker resulted in overcorrected associations, caused by intake-related bias in the FFQ (scenario 2). The correction factor based on a triad using biomarkers and 24hR was hampered by this intake-related bias and by correlated errors between FFQ and 24hR, and in this population resulted in a nearly perfect correction for protein but an overcorrection for K (scenario 3). When the 24hR was used for calibration, only a small correction was done, due to correlated errors between the methods and intake-related bias in the 24hR (scenario 4). CONCLUSIONS: Calibration to a gold standard reference method is the preferred approach to correct intake-health associations for FFQ measurement error. If it is not possible to do so, using the 24hR as reference method only partly removes the errors, but may result in improved intake-health associations.

Vitamin B12 intake and status and cognitive function in elderly people.

Current recommendations on vitamin B12 intake vary from 1.4 to 3.0 µg per day and are based on the amount needed for maintenance of hematologic status or on the amount needed to compensate obligatory losses. This systematic review evaluates whether the relation between vitamin B12 intake and cognitive function should be considered for underpinning vitamin B12 recommendations in the future. The authors summarized dose-response evidence from randomized controlled trials and prospective cohort studies on the relation of vitamin B12 intake and status with cognitive function in adults and elderly people. Two randomized controlled trials and 6 cohort studies showed no association or inconsistent associations between vitamin B12 intake and cognitive function. Random-effects meta-analysis showed that serum/plasma vitamin B12 (50 pmol/L) was not associated with risk of dementia (4 cohort studies), global cognition z scores (4 cohort studies), or memory z scores (4 cohort studies). Although dose-response evidence on sensitive markers of vitamin B12 status (methylmalonic acid and holotranscobalamin) was scarce, 4 of 5 cohort studies reported significant associations with risk of dementia, Alzheimer's disease, or global cognition. Current evidence on the relation between vitamin B12 intake or status and cognitive function is not sufficient for consideration in the development of vitamin B12 recommendations. Further studies should consider the selection of sensitive markers of vitamin B12 status.

EURRECA-Evidence-based methodology for deriving micronutrient recommendations.

The EURopean micronutrient RECommendations Aligned (EURRECA) Network of Excellence explored the process of setting micronutrient recommendations to address the variance in recommendations across Europe. Work centered upon the transparent assessment of nutritional requirements via a series of systematic literature reviews and meta-analyses. In addition, the necessity of assessing nutritional requirements and the policy context of setting micronutrient recommendations was investigated. Findings have been presented in a framework that covers nine activities clustered into four stages: stage one "Defining the problem" describes Activities 1 and 2: "Identifying the nutrition-related health problem" and "Defining the process"; stage two "Monitoring and evaluating" describes Activities 3 and 7: "Establishing appropriate methods," and "Nutrient intake and status of population groups"; stage three "Deriving dietary reference values" describes Activities 4, 5, and 6: "Collating sources of evidence," "Appraisal of the evidence," and "Integrating the evidence"; stage four "Using dietary reference values in policy making" describes Activities 8 and 9: "Identifying policy options," and "Evaluating policy implementation." These activities provide guidance on how to resolve various issues when deriving micronutrient requirements and address the methodological and policy decisions, which may explain the current variation in recommendations across Europe. [Supplementary materials are available for this article. Go to the publisher's online edition of Critical Reviews in Food Science and Nutrition for the following free supplemental files: Additional text, tables, and figures.].

EURRECA-Estimating zinc requirements for deriving dietary reference values.

Zinc was selected as a priority micronutrient for EURRECA, because there is significant heterogeneity in the Dietary Reference Values (DRVs) across Europe. In addition, the prevalence of inadequate zinc intakes was thought to be high among all population groups worldwide, and the public health concern is considerable. In accordance with the EURRECA consortium principles and protocols, a series of literature reviews were undertaken in order to develop best practice guidelines for assessing dietary zinc intake and zinc status. These were incorporated into subsequent literature search strategies and protocols for studies investigating the relationships between zinc intake, status and health, as well as studies relating to the factorial approach (including bioavailability) for setting dietary recommendations. EMBASE (Ovid), Cochrane Library CENTRAL, and MEDLINE (Ovid) databases were searched for studies published up to February 2010 and collated into a series of Endnote databases that are available for the use of future DRV panels. Meta-analyses of data extracted from these publications were performed where possible in order to address specific questions relating to factors affecting dietary recommendations. This review has highlighted the need for more high quality studies to address gaps in current knowledge, in particular the continued search for a reliable biomarker of zinc status and the influence of genetic polymorphisms on individual dietary requirements. In addition, there is a need to further develop models of the effect of dietary inhibitors of zinc absorption and their impact on population dietary zinc requirements.

The relationship between zinc intake and serum/plasma zinc concentration in adults: a systematic review and dose-response meta-analysis by the EURRECA Network.

Dietary Zn recommendations vary widely across Europe due to the heterogeneity of approaches used by expert panels. Under the EURopean micronutrient RECommendations Aligned (EURRECA) consortium a protocol was designed to systematically review and undertake meta-analyses of research data to create a database that includes 'best practice' guidelines which can be used as a resource by future panels when setting micronutrient recommendations. As part of this process, the objective of the present study was to undertake a systematic review and meta-analysis of previously published data describing the relationship between Zn intake and status in adults. Searches were performed of literature published up to February 2010 using MEDLINE, Embase and the Cochrane Library. Data extracted included population characteristics, dose of Zn, duration of study, dietary intake of Zn, and mean concentration of Zn in plasma or serum at the end of the intervention period. An intake-status regression coefficient (ß ) was estimated for each individual study, and pooled meta-analysis undertaken. The overall pooled ß for Zn supplementation on serum/plasma Zn concentrations from randomised controlled trials and observational studies was 0·08 (95 % CI 0·05, 0·11; P < 0·0001; I² 84·5 %). An overall ß of 0·08 means that for every doubling in Zn intake, the difference in Zn serum or plasma concentration is ß (2(0·08) = 1·06), which is 6 %. Whether the dose-response relationship, as provided in the present paper, could be used as either qualitative or quantitative evidence to substantiate the daily Zn intake dose necessary to achieve normal or optimal levels of biomarkers for Zn status remains a matter of discussion.

Transformations of summary statistics as input in meta-analysis for linear dose-response models on a logarithmic scale: a methodology developed within EURRECA.

BACKGROUND: To derive micronutrient recommendations in a scientifically sound way, it is important to obtain and analyse all published information on the association between micronutrient intake and biochemical proxies for micronutrient status using a systematic approach. Therefore, it is important to incorporate information from randomized controlled trials as well as observational studies as both of these provide information on the association. However, original research papers present their data in various ways. METHODS: This paper presents a methodology to obtain an estimate of the dose-response curve, assuming a bivariate normal linear model on the logarithmic scale, incorporating a range of transformations of the original reported data. RESULTS: The simulation study, conducted to validate the methodology, shows that there is no bias in the transformations. Furthermore, it is shown that when the original studies report the mean and standard deviation or the geometric mean and confidence interval the results are less variable compared to when the median with IQR or range is reported in the original study. CONCLUSIONS: The presented methodology with transformations for various reported data provides a valid way to estimate the dose-response curve for micronutrient intake and status using both randomized controlled trials and observational studies.

Bias in protein and potassium intake collected with 24-h recalls (EPIC-Soft) is rather comparable across European populations.

PURPOSE: We investigated whether group-level bias of a 24-h recall estimate of protein and potassium intake, as compared to biomarkers, varied across European centers and whether this was influenced by characteristics of individuals or centers. METHODS: The combined data from EFCOVAL and EPIC studies included 14 centers from 9 countries (n = 1,841). Dietary data were collected using a computerized 24-h recall (EPIC-Soft). Nitrogen and potassium in 24-h urine collections were used as reference method. Multilevel linear regression analysis was performed, including individual-level (e.g., BMI) and center-level (e.g., food pattern index) variables. RESULTS: For protein intake, no between-center variation in bias was observed in men while it was 5.7% in women. For potassium intake, the between-center variation in bias was 8.9% in men and null in women. BMI was an important factor influencing the biases across centers (p < 0.01 in all analyses). In addition, mode of administration (p = 0.06 in women) and day of the week (p = 0.03 in men and p = 0.06 in women) may have influenced the bias in protein intake across centers. After inclusion of these individual variables, between-center variation in bias in protein intake disappeared for women, whereas for potassium, it increased slightly in men (to 9.5%). Center-level variables did not influence the results. CONCLUSION: The results suggest that group-level bias in protein and potassium (for women) collected with 24-h recalls does not vary across centers and to a certain extent varies for potassium in men. BMI and study design aspects, rather than center-level characteristics, affected the biases across centers.

Effect of folate intake on health outcomes in pregnancy: a systematic review and meta-analysis on birth weight, placental weight and length of gestation.

The beneficial effect of folic acid supplementation before and shortly after conception is well recognized, whereas the effect of supplementation during the second and third trimesters is controversial and poorly documented. Our aims were to systematically review randomized controlled trials (RCTs) investigating the effect of folate supplementation on birth weight, placental weight and length of gestation and to assess the dose-response relationship between folate intake (folic acid plus dietary folate) and health outcomes. The MEDLINE, EMBASE and Cochrane Library CENTRAL databases were searched from inception to February 2010 for RCTs in which folate intake and health outcomes in pregnancy were investigated. We calculated the overall intake-health regression coefficient (ß^) by using random-effects meta-analysis on a log(e)-log(e) scale. Data of 10 studies from 8 RCTs were analyzed. We found significant dose-response relationship between folate intake and birth weight (P=0.001), the overall ß^ was 0.03 (95% confidence interval (CI): 0.01, 0.05). This relationship indicated 2% increase in birth weight for every two-fold increase in folate intake. In contrast, we did not find any beneficial effect of folate supplementation on placental weight or on length of gestation. There is a paucity of well-conducted RCTs investigating the effect of folate supplementation on health outcomes in pregnancy. The dose-response methodology outlined in the present systematic review may be useful for designing clinical studies on folate supplementation and for developing recommendations for pregnant women.

Uncertainty in intake due to portion size estimation in 24-hour recalls varies between food groups.

Portion size estimation is expected to be one of the largest sources of uncertainty in dietary assessment of the individual. Therefore, we demonstrated a method to quantify uncertainty due to portion size estimation in the usual intake distributions of vegetables, fruit, bread, protein, and potassium. Dutch participants of the European Food Consumption Validation study completed 2 nonconsecutive 24-h recall interviews. In short, the uncertainty analysis consists of Monte Carlo simulations drawing values for portion size from lognormal uncertainty distributions. The uncertainty of the usual intake distribution and accompanying parameters (IQR and the shrinkage factor) were estimated. For the food groups, portion size uncertainty had the greatest effect for vegetables and the least for fruit: the relative 95% uncertainty interval (UI) of the IQR of the usual intake distribution was 0.61-1.35 for vegetables, 0.77-1.24 for bread, and 0.99-1.10 for fruit. For protein and potassium, the resulting relative width of the UI of the IQR for portion size uncertainty are similar: 0.88-1.14 for protein and 0.86-1.14 for potassium. Furthermore, a sensitivity analysis illustrated the importance of the specified uncertainty distributions. The examples show that uncertainty in portion sizes may be more important for some foods such as vegetables. This may reflect differential quantification errors by food groups that deserve further consideration. In conclusion, the presented methodology allows the important quantification of portion size uncertainty and extensions to include other sources of uncertainty is straightforward.

Two non-consecutive 24 h recalls using EPIC-Soft software are sufficiently valid for comparing protein and potassium intake between five European centres--results from the European Food Consumption Validation (EFCOVAL) study.

The use of two non-consecutive 24 h recalls using EPIC-Soft for standardised dietary monitoring in European countries has previously been proposed in the European Food Consumption Survey Method consortium. Whether this methodology is sufficiently valid to assess nutrient intake in a comparable way, among populations with different food patterns in Europe, is the subject of study in the European Food Consumption Validation consortium. The objective of the study was to compare the validity of usual protein and K intake estimated from two non-consecutive standardised 24 h recalls using EPIC-Soft between five selected centres in Europe. A total of 600 adults, aged 45-65 years, were recruited in Belgium, the Czech Republic, France, The Netherlands and Norway. From each participant, two 24 h recalls and two 24 h urines were collected. The mean and distribution of usual protein and K intake, as well as the ranking of intake, were compared with protein and K excretions within and between centres. Underestimation of protein (range 2-13%) and K (range 4-17%) intake was seen in all centres, except in the Czech Republic. We found a fair agreement between prevalences estimated based on the intake and excretion data at the lower end of the usual intake distribution (< 10% difference), but larger differences at other points. Protein and K intake was moderately correlated with excretion within the centres (ranges = 0·39-0·67 and 0·37-0·69, respectively). These were comparable across centres. In conclusion, two standardised 24 h recalls (EPIC-Soft) appear to be sufficiently valid for assessing and comparing the mean and distribution of protein and K intake across five centres in Europe as well as for ranking individuals.

Estimating effects of rare haplotypes on failure time using a penalized Cox proportional hazards regression model.

BACKGROUND: This paper describes a likelihood approach to model the relation between failure time and haplotypes in studies with unrelated individuals where haplotype phase is unknown, while dealing with the problem of unstable estimates due to rare haplotypes by considering a penalized log-likelihood. RESULTS: The Cox model presented here incorporates the uncertainty related to the unknown phase of multiple heterozygous individuals as weights. Estimation is performed with an EM algorithm. In the E-step the weights are estimated, and in the M-step the parameter estimates are estimated by maximizing the expectation of the joint log-likelihood, and the baseline hazard function and haplotype frequencies are calculated. These steps are iterated until the parameter estimates converge. Two penalty functions are considered, namely the ridge penalty and a difference penalty, which is based on the assumption that similar haplotypes show similar effects. Simulations were conducted to investigate properties of the method, and the association between IL10 haplotypes and risk of target vessel revascularization was investigated in 2653 patients from the GENDER study. CONCLUSION: Results from simulations and real data show that the penalized log-likelihood approach produces valid results, indicating that this method is of interest when studying the association between rare haplotypes and failure time in studies of unrelated individuals.

Polymorphisms in APOA1 and LPL genes are statistically independently associated with fasting TG in men with CAD.

The objective of this paper was to identify the single nucleotide polymorphisms (SNPs) that show unshared effects on plasma triglyceride (TG) levels and to investigate whether these SNPs show statistically independent effects on plasma TG levels. In total, 59 polymorphisms in 20 genes involved in lipid metabolism were investigated. Polymorphisms were selected for a multivariate ANOVA model if they showed an univariate association with TG (after adjustment for HDL-C and LDL-C) in more than 50% of bootstrap samples that were made from the original data. The multivariate model included 512 men with coronary artery disease from the REGRESS study who were completely genotyped for eight polymorphisms selected in the univariate procedure (ie, APOA1 G(-75)A, ABCA1 C(-477)T, ABCA1 G1051A, APOC3 T3206G, APOE Arg158Cys, LIPC C(-514)T, LPL Asn291Ser and LPL Ser447Stop). The gene variants APOA1 G(-75)A (P=0.04) and LPL Asn291Ser (P=0.03) were significantly associated with plasma TG levels in this multivariate analysis. The eight polymorphisms explained 8.9% of the variation in plasma TG levels. In conclusion, this study showed statistically independent effects of gene variants in the APOA1 and LPL genes on fasting plasma levels of TG. Nevertheless, only a small part of variation in TG levels could be explained by the polymorphisms.

Biomarker responses to folic acid intervention in healthy adults: a meta-analysis of randomized controlled trials.

BACKGROUND: The task of revising dietary folate recommendations for optimal health is complicated by a lack of data quantifying the biomarker response that reliably reflects a given folate intake. OBJECTIVE: We conducted a dose-response meta-analysis in healthy adults to quantify the typical response of recognized folate biomarkers to a change in folic acid intake. DESIGN: Electronic and bibliographic searches identified 19 randomized controlled trials that supplemented with folic acid and measured folate biomarkers before and after the intervention in apparently healthy adults aged ≥18 y. For each biomarker response, the regression coefficient (ß) for individual studies and the overall pooled ß were calculated by using random-effects meta-analysis. RESULTS: Folate biomarkers (serum/plasma and red blood cell folate) increased in response to folic acid in a dose-response manner only up to an intake of 400 µg/d. Calculation of the overall pooled ß for studies in the range of 50 to 400 µg/d indicated that a doubling of folic acid intake resulted in an increase in serum/plasma folate by 63% (71% for microbiological assay; 61% for nonmicrobiological assay) and red blood cell folate by 31% (irrespective of whether microbiological or other assay was used). Studies that used the microbiological assay indicated lower heterogeneity compared with studies using nonmicrobiological assays for determining serum/plasma (I(2) = 13.5% compared with I(2) = 77.2%) and red blood cell (I(2) = 45.9% compared with I(2) = 70.2%) folate. CONCLUSIONS: Studies administering >400 µg folic acid/d show no dose-response relation and thus will not yield meaningful results for consideration when generating dietary folate recommendations. The calculated folate biomarker response to a given folic acid intake may be more robust with the use of a microbiological assay rather than alternative methods for blood folate measurement.

A statistical method to base nutrient recommendations on meta-analysis of intake and health-related status biomarkers.

Nutrient recommendations in use today are often derived from relatively old data of few studies with few individuals. However, for many nutrients, including vitamin B-12, extensive data have now become available from both observational studies and randomized controlled trials, addressing the relation between intake and health-related status biomarkers. The purpose of this article is to provide new methodology for dietary planning based on dose-response data and meta-analysis. The methodology builds on existing work, and is consistent with current methodology and measurement error models for dietary assessment. The detailed purposes of this paper are twofold. Firstly, to define a Population Nutrient Level (PNL) for dietary planning in groups. Secondly, to show how data from different sources can be combined in an extended meta-analysis of intake-status datasets for estimating PNL as well as other nutrient intake values, such as the Average Nutrient Requirement (ANR) and the Individual Nutrient Level (INL). For this, a computational method is presented for comparing a bivariate lognormal distribution to a health criterion value. Procedures to meta-analyse available data in different ways are described. Example calculations on vitamin B-12 requirements were made for four models, assuming different ways of estimating the dose-response relation, and different values of the health criterion. Resulting estimates of ANRs and less so for INLs were found to be sensitive to model assumptions, whereas estimates of PNLs were much less sensitive to these assumptions as they were closer to the average nutrient intake in the available data.

Systematic review using meta-analyses to estimate dose-response relationships between iodine intake and biomarkers of iodine status in different population groups.

The objective of this systematic review was to identify studies investigating iodine intake and biomarkers of iodine status, to assess the data of the selected studies, and to estimate dose-response relationships using meta-analysis. All randomized controlled trials, prospective cohort studies, nested case-control studies, and cross-sectional studies that supplied or measured dietary iodine and measured iodine biomarkers were included. The overall pooled regression coefficient (ß) and the standard error of ß were calculated by random-effects meta-analysis on a double-log scale, using the calculated intake-status regression coefficient (ß) for each individual study. The results of pooled randomized controlled trials indicated that the doubling of dietary iodine intake increased urinary iodine concentrations by 14% in children and adolescents, by 57% in adults and the elderly, and by 81% in pregnant women. The dose-response relationship between iodine intake and biomarkers of iodine status indicated a 12% decrease in thyroid-stimulating hormone and a 31% decrease in thyroglobulin in pregnant women. The model of dose-response quantification used to describe the relationship between iodine intake and biomarkers of iodine status may be useful for providing complementary evidence to support recommendations for iodine intake in different population groups.

Systematic review with dose-response meta-analyses between vitamin B-12 intake and European Micronutrient Recommendations Aligned's prioritized biomarkers of vitamin B-12 including randomized controlled trials and observational studies in adults and elderly persons.

BACKGROUND: Many randomized controlled trials (RCTs) and observational studies have provided information on the association between vitamin B-12 intake and biomarkers. The use of these data to estimate dose-response relations provides a useful means to summarize the body of evidence. OBJECTIVE: We systematically reviewed studies that investigated vitamin B-12 intake and biomarkers of vitamin B-12 status and estimated dose-response relations with the use of a meta-analysis. DESIGN: This systematic review included all RCTs, prospective cohort studies, nested case-control studies, and cross-sectional studies in healthy adult populations published through January 2010 that supplied or measured dietary vitamin B-12 intake and measured vitamin B-12 status as serum or plasma vitamin B-12, methylmalonic acid (MMA), or holotranscobalamin. We calculated an intake-status regression coefficient ( ) for each individual study and calculated the overall pooled and SE ( ) by using random-effects meta-analysis on a double-log scale. RESULTS: The meta-analysis of observational studies showed a weaker slope of dose-response relations than the meta-analysis of RCTs. The pooled dose-response relation of all studies between vitamin B-12 intake and status indicated that a doubling of the vitamin B-12 intake increased vitamin B-12 concentrations by 11% (95% CI: 9.4%, 12.5%). This increase was larger for studies in elderly persons (13%) than in studies in adults (8%). The dose-response relation between vitamin B-12 intake and MMA concentrations indicated a decrease in MMA of 7% (95% CI: -10%, -4%) for every doubling of the vitamin B-12 intake. The assessment of risk of bias within individual studies and across studies indicated risk that was unlikely to seriously alter these results. CONCLUSION: The obtained dose-response estimate between vitamin B-12 intake and status provides complementary evidence to underpin recommendations for a vitamin B-12 intake of populations.

The relationship between zinc intake and serum/plasma zinc concentration in pregnant and lactating women: a systematic review with dose-response meta-analyses.

Recommendations for zinc intake during pregnancy and lactation vary widely across Europe. Using data on zinc intake and biomarkers of zinc status reported in randomized controlled trials (RCTs) and observational studies can provide estimates of dose-response relationships that may be used for underpinning zinc reference values. This systematic review included all RCTs, prospective cohort studies, nested case-control studies and cross-sectional studies in healthy pregnant and lactating populations published by February 2010 which provided data on zinc intake and biomarkers of zinc status. An intake-status regression coefficient (߈) was calculated for each individual study and calculated the overall pooled ߈ and SE (߈) using random effects meta-analysis on a double log scale. The pooled dose-response relationship between zinc intake and zinc status found that a doubling of zinc intake was associated with an increase in serum/plasma zinc status by 3% in pregnant women and by 1% in lactating women. These modest associations are likely to reflect the low-moderate zinc bioavailability dietary patterns and the widespread use of other micronutrients in the populations included in this review, physiologic adjustments of zinc homeostasis, insensitivity of serum/plasma zinc as a biomarker of zinc status, and wide heterogeneity between study results which reflect real uncertainty in the current evidence base. Although this review provides useful information for dietary zinc requirements in populations vulnerable to zinc deficiency, it also highlights a need for further studies in pregnant and lactating women with different dietary patterns in order to provide useful complementary evidence that can be utilized when setting zinc recommendations as a basis for nutrition policies in Europe.