Applied causal inference methods for sequential mediators.

BACKGROUND: Mediation analysis aims at estimating to what extent the effect of an exposure on an outcome is explained by a set of mediators on the causal pathway between the exposure and the outcome. The total effect of the exposure on the outcome can be decomposed into an indirect effect, i.e. the effect explained by the mediators jointly, and a direct effect, i.e. the effect unexplained by the mediators. However finer decompositions are possible in presence of independent or sequential mediators. METHODS: We review four statistical methods to analyse multiple sequential mediators, the inverse odds ratio weighting approach, the inverse probability weighting approach, the imputation approach and the extended imputation approach. These approaches are compared and implemented using a case-study with the aim to investigate the mediating role of adverse reproductive outcomes and infant respiratory infections in the effect of maternal pregnancy mental health on infant wheezing in the Ninfea birth cohort. RESULTS: Using the inverse odds ratio weighting approach, the direct effect of maternal depression or anxiety in pregnancy is equal to a 59% (95% CI: 27%,94%) increased prevalence of infant wheezing and the mediated effect through adverse reproductive outcomes is equal to a 3% (95% CI: -6%,12%) increased prevalence of infant wheezing. When including infant lower respiratory infections in the mediation pathway, the direct effect decreases to 57% (95% CI: 25%,92%) and the indirect effect increases to 5% (95% CI: -5%,15%). The estimates of the effects obtained using the weighting and the imputation approaches are similar. The extended imputation approach suggests that the small joint indirect effect through adverse reproductive outcomes and lower respiratory infections is due entirely to the contribution of infant lower respiratory infections, and not to an increased prevalence of adverse reproductive outcomes. CONCLUSIONS: The four methods revealed similar results of small mediating role of adverse reproductive outcomes and early respiratory tract infections in the effect of maternal pregnancy mental health on infant wheezing. The choice of the method depends on what is the effect of main interest, the type of the variables involved in the analysis (binary, categorical, count or continuous) and the confidence in specifying the models for the exposure, the mediators and the outcome.

Impact of maternal body mass index and gestational weight gain on pregnancy complications: an individual participant data meta-analysis of European, North American and Australian cohorts.

OBJECTIVE: To assess the separate and combined associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact. DESIGN: Individual participant data meta-analysis of 39 cohorts. SETTING: Europe, North America, and Oceania. POPULATION: 265 270 births. METHODS: Information on maternal pre-pregnancy BMI, gestational weight gain, and pregnancy complications was obtained. Multilevel binary logistic regression models were used. MAIN OUTCOME MEASURES: Gestational hypertension, pre-eclampsia, gestational diabetes, preterm birth, small and large for gestational age at birth. RESULTS: Higher maternal pre-pregnancy BMI and gestational weight gain were, across their full ranges, associated with higher risks of gestational hypertensive disorders, gestational diabetes, and large for gestational age at birth. Preterm birth risk was higher at lower and higher BMI and weight gain. Compared with normal weight mothers with medium gestational weight gain, obese mothers with high gestational weight gain had the highest risk of any pregnancy complication (odds ratio 2.51, 95% CI 2.31- 2.74). We estimated that 23.9% of any pregnancy complication was attributable to maternal overweight/obesity and 31.6% of large for gestational age infants was attributable to excessive gestational weight gain. CONCLUSIONS: Maternal pre-pregnancy BMI and gestational weight gain are, across their full ranges, associated with risks of pregnancy complications. Obese mothers with high gestational weight gain are at the highest risk of pregnancy complications. Promoting a healthy pre-pregnancy BMI and gestational weight gain may reduce the burden of pregnancy complications and ultimately the risk of maternal and neonatal morbidity. TWEETABLE ABSTRACT: Promoting a healthy body mass index and gestational weight gain might reduce the population burden of pregnancy complications.

Socioeconomic inequalities in weight, height and body mass index from birth to 5 years.

BACKGROUND/OBJECTIVES: Studies in high-income countries show that despite the positive association of weight with socioeconomic position at birth, an inverse socioeconomic gradient in overweight (OW) appears later in childhood. The objectives were to understand the natural history of socioeconomic inequalities in weight, height and body mass index (BMI), by investigating their associations with maternal educational level between birth and 5 years, separately in boys and girls. SUBJECTS/METHODS: A published work of growth modelling between birth and 5 years allowed us to calculate predicted weight, height and BMI at 1 month, 6 months, 1, 3 and 5 years for 1735 children from the French EDEN mother-child cohort. Associations between maternal education and predicted measures of body size were analysed with marginal linear and logistic models, stratified by sex. RESULTS: In girls, despite a positive association between maternal education and birthweight, an inverse socioeconomic gradient was observed as early as 1 month for BMI. Girls whose mothers had low education levels were shorter on the whole than their counterparts with better-educated mothers, despite their similar weights. In boys, no socioeconomic gradient in BMI was observed at any age, including birth, but positive associations were found as early as 1 month for both weight and height. CONCLUSIONS: The emergence of an inverse socioeconomic gradient in BMI and OW apparently results from a complex pattern of socioeconomic inequalities in weight and height from 1 month onwards. The very start of life thus appears to be an important window of opportunity for addressing socioeconomic inequalities in growth.

To which mixtures are French pregnant women mainly exposed? A combination of the second French total diet study with the EDEN and ELFE cohort studies.

Pregnant women and their unborn child are exposed to a large number of substances during pregnancy. Some of these substances may cross the placenta, resulting in exposure of the foetus. There is growing evidence that certain substances could interact to produce a mixture effect. It is therefore essential to identify the main mixtures mothers are exposed to. This study aimed to identify the major mixtures French pregnant women included in EDEN and ELFE cohorts were exposed to, on the basis of the 441 substances analysed in the second French total diet study. Exposure systems and the composition of substances were identified from co-exposures using sparse non-negative matrix under-approximation to generate the main mixtures. Individuals were clustered to define clusters with similar co-exposure profiles. Six clusters associated with eight mixtures were identified. For example in ELFE, cluster 2 comprising 10% of the population was characterised by mixtures "Pest-1" mainly contains pesticides and "TE-F-PAH″ contains trace elements, furans and polycyclic aromatic hydrocarbons. Five other clusters were also described with their associated mixtures. Similar results were observed for EDEN. This study helps to prioritise mixtures for which it is crucial to investigate possible toxicological effects and to recommend epidemiological studies concerning health effects.

Influence of infant feeding patterns over the first year of life on growth from birth to 5 years.

OBJECTIVES: As early-life feeding experiences may influence later health, we aimed to examine relations between feeding patterns over the first year of life and child's growth in the first 5 years of life. METHODS: Our analysis included 1022 children from the EDEN mother-child cohort. Three feeding patterns were previously identified, i.e. 'Later dairy products introduction and use of ready-prepared baby foods' (pattern-1), 'Long breastfeeding, later main meal food introduction and use of home-made foods' (pattern-2) and 'Use of ready-prepared adult foods' (pattern-3). Associations between the feeding patterns and growth [weight, height and body mass index {BMI}] were analysed by multivariable linear regressions. Anthropometric changes were assessed by the final value adjusted for the initial value. RESULTS: Even though infant feeding patterns were not related to anthropometric measurements at 1, 3 and 5 years, high scores on pattern-1 were associated with higher 1-3 years weight and height changes. High scores on pattern-2 were related to lower 0-1 year weight and height changes, higher 1-5 years weight and height changes but not to BMI changes, after controlling for a wide range of potential confounding variables including parental BMI. Scores on pattern-3 were not significantly related to growth. Additional adjustment for breastfeeding duration reduced the strength of the associations between pattern-2 and growth but not those between pattern-1 and height growth. CONCLUSION: Our findings emphasize the relevance of considering infant feeding patterns including breastfeeding duration, age of complementary foods introduction as well as type of foods used when examining effects of early infant feeding practices on later health. © 2017 World Obesity Federation.

Maternal weight prior and during pregnancy and offspring's BMI and adiposity at 5-6 years in the EDEN mother-child cohort.

BACKGROUND: Beyond pre-pregnancy BMI, maternal weight change before and during pregnancy may also affect offspring adiposity. OBJECTIVE: To investigate the relationship between maternal weight history before and during pregnancy with children's adiposity at 5-6 years. METHODS: In 1069 mother-child dyads from the EDEN Cohort, we examined by linear regression the associations of children's BMI, fat mass and abdominal adiposity at 5-6 years with maternal pre-pregnancy BMI, pre-pregnancy average yearly weight change from age 20 and gestational weight gain. The shapes of relationships were investigated using splines and polynomial functions were tested. RESULTS: Children's BMI and adiposity parameters were positively associated with maternal pre-pregnancy BMI, but these relationships were mainly seen in thin mothers, with no substantial variation for maternal BMI ranging from 22 to 35 kg/m2 . Gestational weight gain was positively associated with children's BMI Z-score, but again more so in thin mothers. We found no association with pre-pregnancy weight change. CONCLUSIONS: Before the adiposity rebound, maternal pre-pregnancy thinness explains most of the relationship with children's BMI. The relationship may emerge at older ages in children of overweight and obese mothers, and this latency may be an obstacle to early prevention.

Prospective associations between energy balance-related behaviors at 2 years of age and subsequent adiposity: the EDEN mother-child cohort.

BACKGROUND/OBJECTIVES: Sedentary behavior, physical activity and dietary behavior are formed early during childhood and tend to remain relatively stable into later life. No longitudinal studies have assessed the independent influence of these three energy balance-related behaviors during toddlerhood on later adiposity. We aimed to analyze the associations between TV/DVD watching time, outdoor play time and dietary patterns at the age of 2 years and child adiposity at the age of 5 years, in boys and girls separately. SUBJECTS/METHODS: This study included 883 children from the French EDEN mother-child cohort. TV/DVD watching time, outdoor play time and dietary intakes were reported by parents in questionnaires when the child was aged 2 years. Two dietary patterns, labeled 'Guidelines' and 'Processed, fast foods', were identified in a previous study. The percentage of body fat (%BF) based on bioelectrical impedance analysis and body mass index were measured at the age of 5 years. RESULTS: In boys, TV/DVD watching time at the age of 2 years was positively associated with %BF at the age of 5 years (ß=0.50 (95% confidence interval: 0.001, 1.00) for those boys with ⩾60 min per day of TV/DVD watching time vs those with ⩽15 min per day, P-value for trend 0.05). In girls, outdoor play was inversely associated with %BF (ß=-0.96 (95% confidence interval: -1.60, -0.32) for those in the highest tertile of outdoor play time vs those in the lowest tertile, P=0.001). Overall, at the age of 2 years, dietary patterns were associated with both TV/DVD watching time and outdoor play time, but no significant and independent association was observed between dietary patterns and later adiposity. CONCLUSION: This study shows longitudinal and gender-differentiated relations between both TV/DVD watching time and outdoor play time in toddlerhood and later adiposity, whereas evidence for a relation between dietary patterns and subsequent fat development was less conclusive. Early childhood-by the age of 2 years-should be targeted as a critical time for promoting healthy energy balance-related behaviors.

Early factors related to carbohydrate and fat intake at 8 and 12 months: results from the EDEN mother-child cohort.

BACKGROUND/OBJECTIVES: Few studies have examined the factors explaining the variability in fat and carbohydrate intake during infancy. We aimed to describe infants' fat and carbohydrate intake and analyse the associations with infant and maternal characteristics and feeding practices. SUBJECTS/METHODS: This study included 1275 infants aged 8 months from the French EDEN mother-child cohort. Carbohydrate intake, fat intake, added fat (vegetable oils and animal fats) and added sugar (honey, white sugar, brown sugar, jam and sweetened beverages) consumption were calculated at 8 and 12 months. Associations between these variables and infant and maternal characteristics as well as maternal dietary patterns during pregnancy, breast-feeding duration and age at complementary feeding introduction were analysed using multivariable linear and logistic regressions. RESULTS: Less than 5% of non-breast-fed infants reached the recommendation of consuming at least 40% of total energy from fat, whereas more than 95% of them reached 45% of energy from carbohydrates. Overall, infant and maternal characteristics and maternal diet during pregnancy were marginally associated with both carbohydrate/added sugar and fat/added fat intake. Nevertheless, age at complementary feeding introduction was associated with all outcomes. CONCLUSIONS: Our results suggest that only a small proportion of non-breast-fed infants at 8 and 12 months reached the recommendations for fat intake, whereas a majority of them reached the recommendations for carbohydrate intake. As subgroups of infants with a higher risk of inadequate diet were not identified, the present results call for an improved dissemination of information regarding infant-specific dietary fat needs in the entire population.

Dietary acrylamide intake during pregnancy and anthropometry at birth in the French EDEN mother-child cohort study.

BACKGROUND AND AIM: Acrylamide is a contaminant formed in a wide variety of carbohydrate-containing foods during frying or baking at high temperatures. Recent studies have suggested reduced foetal growth after exposure to high levels of acrylamide during pregnancy. OBJECTIVE: To study the relationship between maternal dietary acrylamide intake during pregnancy and their offspring's anthropometry at birth. DESIGN: In our population of 1471 mother-child pairs from two French cities, Nancy and Poitiers, dietary acrylamide intake during pregnancy was assessed by combining maternal food frequency questionnaires with data on food contamination at the national level, provided by the second "French Total Diet Study". Newborns weighing less than the 10th percentile, according to a customised definition, were defined as small for gestational age (SGA). Linear and logistic regression models were used to study continuous and binary outcomes respectively, adjusting for the study centre, maternal age at delivery, height, education, parity, smoking during pregnancy, the newborn's gestational age at birth and sex. RESULTS: The median and interquartile range of dietary acrylamide intake were 19.2µg/day (IQR, 11.8;30.3). Each 10µg/day increase in acrylamide intake was associated with an odds-ratio for SGA of 1.11 (95% Confidence Interval: 1.03,1.21), birth length change of -0.05cm (95% CI: -0.11,0.00) and birth weight change of -9.8g (95% CI: -21.3,1.7). CONCLUSIONS: Our results, consistent with both experimental and epidemiological studies, add to the evidence of an effect of acrylamide exposure on the risk of SGA and suggest an effect on foetal growth, for both weight and length.

Impact on obstetric outcome of third-trimester screening for small-for-gestational-age fetuses.

OBJECTIVES: To evaluate the performance of screening for small-for-gestational-age (SGA) fetuses by ultrasound biometry at 30-35 weeks' gestation, and to determine the impact of screening on obstetric and neonatal outcomes. METHODS: For this prospective cohort study, pregnant women were recruited from two French university maternity centers between 2003 and 2006. Performance measures of third-trimester biometry for the prediction of SGA, defined as estimated fetal weight < 10(th) centile, were analyzed. Obstetric outcomes and neonatal health status were compared, first, between SGA neonates diagnosed correctly at ultrasound examination (true positive (TP); n = 45) and SGA neonates that went undiagnosed (false negative (FN); n = 110) and, second, between non-SGA neonates identified as normal at ultrasound examination (true negative (TN); n = 1641) and non-SGA neonates diagnosed incorrectly as SGA (false positive (FP); n = 101). RESULTS: In the prediction of SGA, third-trimester ultrasound had a sensitivity of 29.0% (95% CI, 22.5-36.6%) and specificity of 94.2% (95% CI, 93.0-95.2%). Positive and negative predictive values were 30.8% (95% CI, 23.9-38.7%) and 93.7% (95% CI, 92.5-94.8%), respectively. One hundred and ten SGA neonates went undiagnosed at ultrasound. Compared to the TN neonates considered as of normal weight at ultrasound, planned preterm delivery (before 37 weeks) and elective Cesarean section for a fetal growth indication were 2.4 (P = 0.01) and 2.85 (P = 0.003) times more likely to occur, respectively, in the FP group of non-SGA neonates, diagnosed incorrectly as SGA during the antenatal period. There was no statistically significant difference in 5-min Apgar score < 7, cord blood pH at birth < 7.15 and need for neonatal resuscitation between the two subgroups (TN vs FP and TP vs FN). CONCLUSIONS: The performance of third-trimester ultrasound screening for SGA seems poor, as it misses the diagnosis of a large number of SGA neonates. The consequences of routine screening for SGA in a low-risk population may lead to unnecessary planned preterm deliveries and elective Cesarean sections in FP pregnancies, without improved neonatal outcome in the FN pregnancies.

Impact of objectively measured sedentary behaviour on changes in insulin resistance and secretion over 3 years in the RISC study: interaction with weight gain.

AIMS: The importance of reducing sedentary time is increasingly being recognized in the prevention of diabetes and cardiovascular disease. Despite this, the prospective association between sedentary time and physical activity with insulin sensitivity and cardiometabolic risk factors has been little studied. METHODS: In an analysis of data from the European RISC study, sedentary time and time spent in activity of moderate or vigorous intensity were assessed by accelerometry at baseline in 313 men and 414 women, aged 30-60 years, with insulin sensitivity as measured by euglycaemic-hyperinsulinaemic clamp. Three years later, cardiometabolic risk factors (anthropometry, glucose, insulin, lipids) were available for 549 participants. RESULTS: In cross-sectional analyses using baseline data, after adjusting for age, gender, recruitment centre and time spent in activity of moderate or vigorous intensity, significant unfavourable associations were observed between higher sedentary time with body weight, HDL cholesterol, triglycerides, clamp-measured insulin sensitivity and insulin secretion (all P(trend)<0.002). Sedentary time remained significantly associated with insulin secretion after adjusting for insulin sensitivity (P(trend)=0.02). In longitudinal analyses, higher baseline sedentary time was associated with 3-year increases in fasting glucose, fasting insulin and the HOMA insulin-resistance index score for the 50% of the study population who increased their BMI by at least 0.3 kg/m(2) (all P(trend)<0.01); these relationships remained significant after adjusting for time spent in activity of moderate or vigorous intensity. The 3-year increase in insulin secretion was lower in those spending more time doing activity of moderate or vigorous intensity (P(trend)=0.03). CONCLUSION: These prospective data suggest that less sedentary behaviour may partly counteract some of the negative effects of increasing body weight on glucose-insulin homoeostasis.

Infant feeding patterns over the first year of life: influence of family characteristics.

BACKGROUND/OBJECTIVES: Early eating patterns and behaviors can determine later eating habits and food preferences and they have been related to the development of childhood overweight and obesity. We aimed to identify patterns of feeding in the first year of life and to examine their associations with family characteristics. SUBJECTS/METHODS: Our analysis included 1004 infants from the EDEN mother-child cohort. Feeding practices were assessed through maternal self-report at birth, 4, 8 and 12 months. Principal component analysis was applied to derive patterns from breastfeeding duration, age at complementary food (CF) introduction and type of food used at 1 year. Associations between patterns and family characteristics were analyzed by linear regressions. RESULTS: The main source of variability in infant feeding was characterized by a pattern labeled 'late CF introduction and use of ready-prepared baby foods'. Older, more educated, primiparous women with high monthly income ranked high on this pattern. The second pattern, labeled 'longer breastfeeding, late CF introduction and use of home-made foods' was the closest to infant feeding guidelines. Mothers ranking high on this pattern were older and more educated. The third pattern, labeled 'use of adults' foods' suggests a less age-specific diet for the infants. Mothers ranking high on this pattern were often younger and multiparous. Recruitment center was related to all patterns. CONCLUSIONS: Not only maternal education level and age, but also parity and region are important contributors to the variability in patterns. Further studies are needed to describe associations between these patterns and infant growth and later food preferences.

Pre-pregnancy body mass index and weight gain during pregnancy: relations with gestational diabetes and hypertension, and birth outcomes.

To study the relationship between pre-pregnancy body mass index (BMI) and weight gain during pregnancy with pregnancy and birth outcomes, with a focus on gestational diabetes and hypertension and their role in the association with fetal growth. We studied 1,884 mothers and offspring from the Eden mother-child cohort. Weight before pregnancy (W1) and weight after delivery (W2) were collected and we calculated BMI and net gestational weight gain (netGWG = (W2 - W1)/(weeks of gestation)). Gestational diabetes, hypertension gestational age and birth weight were collected. We used multivariate linear or logistic models to study the association between BMI, netGWG and pregnancy and birth outcomes, adjusting for center, maternal age and height, parity and average number of cigarettes smoked per day during pregnancy. High BMI was more strongly related to the risk of giving birth to a large-for-gestational-age (LGA) baby than high netGWG (odds ratio OR [95% CI] of 3.23 [1.86-5.60] and 1.61 [0.91-2.85], respectively). However, after excluding mothers with gestational diabetes or hypertension the ORs for LGA, respectively weakened (OR 2.57 [1.29-5.13]) for obese women and strengthened for high netGWG (OR 2.08 [1.14-3.80]). Low in comparison to normal netGWG had an OR of 2.18 [1.20-3.99] for pre-term birth, which became stronger after accounting for blood pressure and glucose disorders (OR 2.70 [1.37-5.34]). Higher net gestational weight gain was significantly associated with an increased risk of LGA only after accounting for blood pressure and glucose disorders. High gestational weight gain should not be neglected in regard to risk of LGA in women without apparent risk factors.

A genetic study of the ghrelin and growth hormone secretagogue receptor (GHSR) genes and stature.

Growth and nutrition are interrelated and influenced by multiple genetic and environmental factors. We studied whether common variants in ghrelin and ghrelin receptor (GHSR) genes could play a role in stature variation in the general population and in families ascertained for obesity. Selected tagging SNPs in the ghrelin and GHSR genes were genotyped in 263 Caucasian families recruited for childhood obesity (1,275 subjects), and in 287 families from a general population (1,072 subjects). We performed familial testing for associations in the entire population and in a sub-set of the samples selected for a case-control study. In the case-control study for height (cases were selected from the obese cohort with mean ZH = 3.17 +/- 0.15 confidence interval (CI) versus controls with mean ZH 0.14 +/- 0.09), we found an association with a 2 base-pair intronic deletion in the GHSR gene (rs10618418) (p = 0.006, odds ratio (OR) 1.86, 95% CI [1.26;2.74] under additive model), although when adjusting for BMI, the association disappeared (p = 0.06). Individuals carrying no deletion or who were heterozygous were significantly more frequent among the tall obese population (52% vs. 36% in controls, p = 0.007, OR 1.97, 95%CI [1.22;3.18]). However, the association was not maintained after correcting for multiple testing. Familial association testing of the ghrelin and GHSR genes and their interaction testing failed to show that any combination of SNPs had any significant effect. Thus, our results suggest that common variants of the ghrelin and GHSR genes are not major contributors to height variation in a French population.

Association analysis of the IGF1 gene with childhood growth, IGF-1 concentrations and type 1 diabetes.

AIMS/HYPOTHESIS: Insulin-like growth factor-1 is a major childhood growth factor and promotes pancreatic islet cell survival and growth in vitro. We hypothesised that genetic variation in IGF1 might be associated with childhood growth, glucose metabolism and type 1 diabetes risk. We therefore examined the association between common genetic variation in IGF1 and predisposition to type 1 diabetes, childhood growth and metabolism. MATERIALS AND METHODS: Variants in IGF1 were identified by direct resequencing of the exons, exon-intron boundaries and 5' and 3' regions in 32 unrelated type 1 diabetes patients. A tagging subset of these variants was genotyped in a collection of type 1 diabetes families (3,121 parent-child trios). We also genotyped a previously reported CA repeat in the region 5' to IGF1. A subset of seven tag single nucleotide polymorphism (SNPs) that captured variants with minor allele frequency (MAF) > or =0.05 was genotyped in 902 children from the Avon Longitudinal Study of Parents And Children with data on growth, IGF-1 concentrations, insulin secretion and insulin action. RESULTS: Resequencing detected 27 SNPs in IGF1, of which 11 had a MAF > 0.05 and were novel. Variants with MAF > or = 0.10 were captured by a set of four tag-SNPs. These SNPs showed no association with type 1 diabetes. In children, global variation in IGF1 was weakly associated with IGF-1 concentrations, but not with other phenotypes. The CA repeat in the region 5' to IGF1 showed no association with any phenotype. CONCLUSIONS/INTERPRETATION: Common genetic variation in IGF1 alters IGF-1 concentrations but is not associated with growth, glucose metabolism or type 1 diabetes.

Relationship between gamma-glutamyltransferase and fat mass in a general population of 8-17 years old children. The FLVS II study.

AIM: Elevated gamma-glutamyltransferase (GGT) is positively associated with severity of obesity in obese children and with increased BMI and waist circumference in general populations of adults. We aimed to study the relationships between GGT and anthropometric parameters in a general population of children. METHODS: This cross-sectional study was conducted in 219 boys and 214 girls included in the Fleurbaix Laventie Ville Santé II study. Weight, height, four skinfolds and waist circumference were measured. We compared the means of GGT activity according to gender and Tanner stage, and according to overweight status (IOTF definition) and quartiles of anthropometric parameters. We then calculated partial Pearson correlations by gender between GGT and anthropometric parameters taking age and Tanner stage into account. RESULTS: GGT activity was higher in boys than in girls as soon as puberty started (P<0.001). The higher difference was observed for Tanner stage III (GGT=10.2 UI/L, CI95% of mean (9.5, 11.1) vs. 7.8 UI/L (7.2, 8.4)). Anthropometric parameters were significantly associated with GGT, particularly waist circumference (r=0.28 in boys; r=0.24 in girls). After an additional adjustment for sum of skinfolds, this correlation disappeared in boys (r=0.06), and was still significant in girls (r=0.19). CONCLUSION: In a general population of children, overweight and abdominal fat distribution were associated with increased GGT. As some studies have shown that GGT could predict the metabolic syndrome in children and type 2 diabetes in adults, the modest elevation of GGT observed in overweight children may be of pathophysiological importance in the long term.

Single nucleotide polymorphisms in the neuropeptide Y2 receptor (NPY2R) gene and association with severe obesity in French white subjects.

AIMS/HYPOTHESIS: Genetic variants of genes for peptide YY (PYY), neuropeptide Y2 receptor (NPY2R) and pancreatic polypeptide (PPY) were investigated for association with severe obesity. SUBJECTS AND METHODS: The initial screening of the genes for variants was performed by sequencing in a group of severely obese subjects (n=161). Case-control analysis of the common variants was then carried out in 557 severely obese adults, 515 severely obese children and 1,163 non-obese/non-diabetic control subjects. Rare variants were genotyped in 700 obese children and the non-obese/non-diabetic control subjects (n=1,163). RESULTS: Significant association was found for a 5' variant (rs6857715) in the NPY2R gene with both severe adult obesity (p=0.002) and childhood obesity (p=0.02). This significant association was further supported by a pooled allelic analysis of all obese cases (adults and children, n=928) vs the control subjects (n=938) (p=0.0004, odds ratio=1.3, 95% CI 1.1-1.5). Quantitative trait analysis of BMI and WHR was performed and significant association was observed for SNP rs1047214 in NPY2R with an increase in WHR in the severely obese children (co-dominant model p=0.005, recessive model p=0.001). Association was also observed for an intron 3 variant (rs162430) in the PYY gene with childhood obesity (p=0.04). No significant associations were observed for PPY variants. Only one rare variant in the NPY2R gene (C-5641T) was not found in lean individuals and this was found to co-segregate with obesity in one family. CONCLUSIONS/INTERPRETATION: These results provide evidence of association for NPY2R and PYY gene variants with obesity and none for PPY variants. A rare variant of the NPY2R gene showed evidence of co-segregation with obesity and its contribution to obesity should be investigated further.

High plasma leptin predicts an increase in subcutaneous adiposity in children and adults.

OBJECTIVE: To investigate the hypothesis that plasma leptin may predict adiposity changes. DESIGN: A population-based cohort study. SETTING: Fleurbaix and Laventie, in the north of France. SUBJECTS: In all, 1175 subjects participated, of whom 946 completed measurements at baseline (1999) and follow-up (2001). After excluding 64 subjects obese at baseline, 882 subjects (478 adults, 404 children 8 years and over) were included in the analysis. INTERVENTIONS: We measured plasma leptin concentrations at baseline and various adiposity parameters at baseline and follow-up. Partial correlation coefficients (r(p)) between baseline plasma leptin and each adiposity indicator at follow-up were calculated with adjustment for baseline age, pubertal stage, adiposity and familial correlations between siblings. RESULTS: Changes in body mass index and percentage body fat were not related to baseline plasma leptin. High baseline plasma leptin predicted an increase (r(p) (P-value)) in the sum of the four skinfolds (0.18 (<0.0001)), the waist circumference (0.16 (0.0003)) and the waist-to-hip ratio (0.29 (<0.0001)) in adults only, and in the hip circumference in adults (0.20 (<0.0001)) and children (0.22 (<0.0001)). After adjustment for a set of four adiposity variables at baseline (percentage body fat, skinfolds, waist and hip circumferences), baseline plasma leptin predicted only changes in the sum of the four skinfolds in adults (0.15 (0.001)), with similar tendency although not significant in children (0.08 (0.13)). CONCLUSIONS: A high leptin relative to baseline fat mass predicts fat mass gain over time, mainly in the subcutaneous location.

Growth curves of anthropometric indices in a general population of French children and comparison with reference data.

BACKGROUND: The description of growth patterns of the different anthropometric measurements mainly used in epidemiological studies is useful to better understand the development of obesity in children and its consequences. OBJECTIVE: Our aim was to establish growth curves of anthropometric indices in a general population of French children born during the 1980s and to compare them with the French reference curves based on children born in the 1950s. DESIGN: As part of the Fleurbaix Laventie Ville Santé Studies I and II (FLVS), 441 girls and 467 boys were examined at least twice between 1993 and 2001. Height, weight and four skinfold thicknesses were measured. Body mass index (BMI), sum of peripheral and truncal skinfolds and truncal-to-peripheral ratio were calculated. Mean growth curves from ages 5 to 17 years were assessed for these indices, calculating means and 95% confidence interval per 1 year age group and by gender. RESULTS: Trajectories with age differed importantly according to the index considered; BMI was the one with the smallest difference between genders and the most linear shape with age. From the age of 5 years and after, the FLVS children were on average taller and had a higher subcutaneous adiposity than children born 30 years earlier. Truncal-to-peripheral ratio was higher in our population; this difference became more marked with puberty in girls. DISCUSSION: This study suggests the existence of a secular trend towards a precocious accelerated growth, and a more truncal adiposity distribution, especially in girls. It is a disquieting trend considering its expected consequences on adult health.

Reliability of bioimpedance analysis compared with other adiposity measurements in children: the FLVS II Study.

OBJECTIVE: To evaluate the reproducibility of the measurement of% body fat by bipedal biometrical impedance analysis (BIA) compared with anthropometric measurements of adiposity in children and the correlations between these methods in children and adults. METHODS: A cross-sectional study in a total of 1080 adults and children enrolled in 1999 in the Fleurbaix-Laventie Ville Santé II (FLVS II) population-based study in northern France. The reproducibility of anthropometrical and BIA methods was determined by a nested analysis of variance of repeated measurements by 2 investigators and a bipedal BIA device (Tanita TBF 310) in 64 pupils of two 5th grade classes. The correlation of BIA and anthropometric adiposity measurements with the unknown relative fat mass or volume of the body estimated by a latent adiposity variable (LAV) was established by the triads' method in 1080 subjects of the FLVS II cohort. RESULTS: The reproducibility was similar for the sum of skinfolds, waist circumference and BIA% fat measurements (intraclass correlation coefficients: 0.979-0.992). Correlation coefficient between BIA body fat% and the LAV was higher than 0.86 in all sex and Tanner stage related groups, and similar in children and adults, except in pubertal boys (0.76). CONCLUSION: With a high level of reproducibility, foot-to-foot BIA analysis provides a valuable measurement of total% fat for epidemiologic studies in children. However further studies are needed before extrapolating these results to overweight children.