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1.  Grip Strength across the Life Course: Normative Data from Twelve British Studies 
PLoS ONE  2014;9(12):e113637.
Epidemiological studies have shown that weaker grip strength in later life is associated with disability, morbidity, and mortality. Grip strength is a key component of the sarcopenia and frailty phenotypes and yet it is unclear how individual measurements should be interpreted. Our objective was to produce cross-sectional centile values for grip strength across the life course. A secondary objective was to examine the impact of different aspects of measurement protocol.
We combined 60,803 observations from 49,964 participants (26,687 female) of 12 general population studies in Great Britain. We produced centile curves for ages 4 to 90 and investigated the prevalence of weak grip, defined as strength at least 2.5 SDs below the gender-specific peak mean. We carried out a series of sensitivity analyses to assess the impact of dynamometer type and measurement position (seated or standing).
Our results suggested three overall periods: an increase to peak in early adult life, maintenance through to midlife, and decline from midlife onwards. Males were on average stronger than females from adolescence onwards: males’ peak median grip was 51 kg between ages 29 and 39, compared to 31 kg in females between ages 26 and 42. Weak grip strength, defined as strength at least 2.5 SDs below the gender-specific peak mean, increased sharply with age, reaching a prevalence of 23% in males and 27% in females by age 80. Sensitivity analyses suggested our findings were robust to differences in dynamometer type and measurement position.
This is the first study to provide normative data for grip strength across the life course. These centile values have the potential to inform the clinical assessment of grip strength which is recognised as an important part of the identification of people with sarcopenia and frailty.
PMCID: PMC4256164  PMID: 25474696
2.  Modifiable early-life risk factors for childhood adiposity and overweight: an analysis of their combined impact and potential for prevention1234 
Background: Early life may be a “critical period” when appetite and regulation of energy balance are programmed, with lifelong consequences for obesity risk. Insight into the potential impact of modifying early-life risk factors on later obesity can be gained by evaluating their combined effects.
Objective: The objective was to examine the relation between the number of early-life risk factors and obesity outcomes among children in a prospective birth cohort (Southampton Women's Survey).
Design: Five risk factors were defined: maternal obesity [prepregnant body mass index (BMI; in kg/m2) >30], excess gestational weight gain (Institute of Medicine, 2009), smoking during pregnancy, low maternal vitamin D status (<64 nmol/L), and short duration of breastfeeding (none or <1 mo). Obesity outcomes examined when the children were aged 4 and 6 y were BMI, dual-energy X-ray absorptiometry–assessed fat mass, overweight, or obesity (International Obesity Task Force). Data were available for 991 mother-child pairs, with children born between 1998 and 2003.
Results: Of the children, 148 (15%) had no early-life risk factors, 330 (33%) had 1, 296 (30%) had 2, 160 (16%) had 3, and 57 (6%) had 4 or 5. At both 4 and 6 y, there were positive graded associations between number of early-life risk factors and each obesity outcome (all P < 0.001). After taking account of confounders, the relative risk of being overweight or obese for children who had 4 or 5 risk factors was 3.99 (95% CI: 1.83, 8.67) at 4 y and 4.65 (95% CI: 2.29, 9.43) at 6 y compared with children who had none (both P < 0.001).
Conclusions: Having a greater number of early-life risk factors was associated with large differences in adiposity and risk of overweight and obesity in later childhood. These findings suggest that early intervention to change these modifiable risk factors could make a significant contribution to the prevention of childhood obesity.
PMCID: PMC4307207  PMID: 25646335
adiposity; childhood obesity; early life; obesity; lifecourse; prevention
3.  Childhood bone mineral content is associated with methylation status of the RXRA promoter at birth 
Maternal vitamin D deficiency has been associated with reduced offspring bone mineral accrual. Retinoid-X Receptor-alpha (RXRA) is an essential cofactor in the action of 1,25(OH)2-vitamin D, and RXRA methylation in umbilical cord DNA has been associated with later offspring adiposity. We tested the hypothesis that RXRA methylation in umbilical cord DNA collected at birth is associated with offspring skeletal development, assessed by dual-energy X-ray absorptiometry, in a population-based mother-offspring cohort (Southampton Women’s Survey). Relationships between maternal plasma 25(OH)-vitamin D concentrations and cord RXRA methylation were also investigated. In 230 children aged 4 years, higher % methylation at 4 out of 6 RXRA CpG sites measured was correlated with lower offspring % bone mineral content (%BMC) (β=−0.02 to −0.04%/SD, p=0.002 to 0.043) and BMC corrected for body size (β=−2.1 to −3.4g/SD, p=0.002 to 0.047), with a further site associated with %BMC only. Similar relationships for %BMC were observed in a second independent cohort (n=64). Maternal free 25(OH)-vitamin D index was negatively associated with methylation at one of these RXRA CpG sites (β=−3.3 SD/unit, p=0.03). In addition to the mechanistic insights afforded by associations between maternal free 25(OH)-vitamin D index, RXRA methylation in umbilical cord DNA, and childhood BMC, such epigenetic marks in early life might represent novel biomarkers for adverse bone outcomes in the offspring.
PMCID: PMC3836689  PMID: 23907847
Epigenetic; methylation; umbilical cord; RXRA; vitamin D; DXA
4.  Association of early childhood abdominal circumference and weight gain with blood pressure at 36 months of age: secondary analysis of data from a prospective cohort study 
BMJ Open  2014;4(7):e005412.
To assess whether changes in measures of fat distribution and body size during early life are associated with blood pressure at 36 months of age.
Analysis of data collected from a prospective cohort study.
Community-based investigation in Southampton, UK.
761 children with valid blood pressure measurements, born to women participating in the Southampton Women’s Survey.
Primary and secondary outcome measures
Anthropometric measurements were collected at 0, 6, 12, 24 and 36 months and conditional changes between the time points calculated. Blood pressure was measured at 36 months. Factors possibly influencing the blood pressure were assessed using linear regression. All independent variables of interest and confounding variables were included in stepwise multiple regression to identify the model that best predicted blood pressure at 36 months.
Greater conditional gains in abdominal circumference (AC) between 0–6 and 24–36 months were associated with higher systolic and diastolic blood pressures at 36 months (p<0.001). Subscapular skinfold and height gains were weakly associated with higher blood pressures, while greater weight gains between 0–6, 12–24 and 24–36 months were more strongly associated, but the dominant influences were AC gains, particularly from 0–6 to 24–36 months. Thus one SD score increases in AC between 0–6 and 24–36 months were associated with 1.59 mm Hg (95% CI 0.97 to 2.21) and 1.84 mm Hg (1.24 to 2.46) higher systolic blood pressures, respectively, and 1.04 mm Hg (0.57 to 1.51) and 1.02 mm Hg (0.56, 1.48) higher diastolic pressures, respectively.
Conditional gains in abdominal circumference, particularly within 6 months of birth and in the year preceding measurement, were more positively associated with blood pressure at 36 months than gains in other anthropometric measures. Above-average AC gains in early childhood may contribute to adult hypertension and increased cardiovascular disease risk.
PMCID: PMC4091398  PMID: 24993768
5.  Maternal antenatal vitamin D status and offspring muscle development: findings from the Southampton Women’s Survey 
The Journal of clinical endocrinology and metabolism  2013;99(1):10.1210/jc.2013-3241.
Maternal 25-hydroxy-vitamin D [25(OH)D] status in pregnancy has been associated with offspring bone development and adiposity. Vitamin D has also been implicated in postnatal muscle function but little is known about a role for antenatal 25(OH)D exposure in programming muscle development.
We investigated the associations between maternal plasma 25(OH)D status at 34 weeks gestation and offspring lean mass and muscle strength at 4 years of age.
Design and setting
A prospective UK population-based mother-offspring cohort: the Southampton Women’s Survey (SWS).
12583 non-pregnant women were initially recruited into SWS, of which 3159 had singleton pregnancies. 678 mother-child pairs were included in this analysis.
Main Outcomes Measured
At 4 years of age, offspring assessments included hand grip strength (Jamar Dynamometer) and whole body DXA (Hologic Discovery) yielding lean mass and %lean mass. Physical activity was assessed by 7-day accelerometry (Actiheart) in a subset of children (n=326).
Maternal serum 25(OH)D concentration in pregnancy was positively associated with offspring height-adjusted hand grip strength (β=0.10 SD/SD, p=0.013), which persisted after adjustment for maternal confounding factors, duration of breastfeeding and child’s physical activity at 4 years (β=0.13 SD/SD, p=0.014). Maternal 25(OH)D was also positively associated with offspring %lean mass (β=0.11 SD/SD, p=0.006), but not total lean mass (β=0.06, p=0.15). This however did not persist after adjustment for confounding factors (β=0.09 SD/SD, p=0.11).
This observational study suggests that intrauterine exposure to 25(OH)D during late pregnancy might influence offspring muscle development through an effect primarily on muscle strength rather than muscle mass.
PMCID: PMC3880861  PMID: 24178796
vitamin D; grip strength; muscle mass; fetal programming
6.  Preterm birth, infant weight gain, and childhood asthma risk: A meta-analysis of 147,000 European children 
Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results.
We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years).
First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes.
Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27).
Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth.
PMCID: PMC4024198  PMID: 24529685
Gestational age; low birth weight; infant growth; wheezing; asthma; children; cohort studies; epidemiology; BMI, Body mass index; ISAAC, International Study on Asthma and Allergy in Childhood; OR, Odds ratio; pOR, Pooled odds ratio; SDS, Standard deviation scores
7.  Prenatal development is linked to bronchial reactivity: epidemiological and animal model evidence 
Scientific Reports  2014;4:4705.
Chronic cardiorespiratory disease is associated with low birthweight suggesting the importance of the developmental environment. Prenatal factors affecting fetal growth are believed important, but the underlying mechanisms are unknown. The influence of developmental programming on bronchial hyperreactivity is investigated in an animal model and evidence for comparable associations is sought in humans. Pregnant Wistar rats were fed either control or protein-restricted diets throughout pregnancy. Bronchoconstrictor responses were recorded from offspring bronchial segments. Morphometric analysis of paraffin-embedded lung sections was conducted. In a human mother-child cohort ultrasound measurements of fetal growth were related to bronchial hyperreactivity, measured at age six years using methacholine. Protein-restricted rats' offspring demonstrated greater bronchoconstriction than controls. Airway structure was not altered. Children with lesser abdominal circumference growth during 11–19 weeks' gestation had greater bronchial hyperreactivity than those with more rapid abdominal growth. Imbalanced maternal nutrition during pregnancy results in offspring bronchial hyperreactivity. Prenatal environmental influences might play a comparable role in humans.
PMCID: PMC3989559  PMID: 24740086
8.  Objectively measured physical activity in four-year-old British children: a cross-sectional analysis of activity patterns segmented across the day 
Little is known about preschool-aged children’s levels of physical activity (PA) over the course of the day. Using time-stamped data, we describe the levels and patterns of PA in a population-based sample of four-year-old British children.
Within the Southampton Women’s Survey the PA levels of 593 4-year-old children (51% female) were measured using (Actiheart) accelerometry for up to 7 days. Three outcome measures: minutes spent sedentary (<20 cpm); in light (LPA: ≥20 – 399 cpm) and in moderate-to-vigorous activity (MVPA: ≥400 cpm) were derived. Average daily activity levels were calculated and then segmented across the day (morning, afternoon and evening). MVPA was log-transformed. Two-level random intercept models were used to analyse associations between activity level and temporal and demographic factors.
Children were active for 67% (mean 568.5 SD 79.5 minutes) of their daily registered time on average, with 88% of active time spent in LPA. All children met current UK guidelines of 180 minutes of daily activity. There were no differences in children’s average daily levels of sedentary activity and LPA by temporal and demographic factors: differences did emerge when activity was segmented across the day. Sex differences were largest in the morning, with girls being more sedentary, spending fewer minutes in LPA and 18% less time in MVPA than boys. Children were more sedentary and less active (LPA and MVPA) in the morning if they attended childcare full-time compared to part-time, and on weekend mornings compared to weekdays. The reverse was true for weekend afternoons and evenings. Children with more educated mothers were less active in the evenings. Children were less sedentary and did more MVPA on summer evenings compared to winter evenings.
Preschool-aged children meet current physical activity guidelines, but with the majority of their active time spent in LPA, investigation of the importance of activity intensity in younger children is needed. Activity levels over the day differed by demographic and temporal factors, highlighting the need to consider temporality in future interventions. Increasing girls’ morning activity and providing opportunities for daytime activity in winter months may be worthwhile.
PMCID: PMC3896827  PMID: 24405936
9.  Validation of novel wheeze phenotypes using longitudinal airway function and atopic sensitisation data in the first 6 years of life: Evidence from the Southampton Women’s Survey. 
Pediatric pulmonology  2013;48(7):683-692.
In 1995 the Tucson Children’s Respiratory Study (TCRS) identified clinically distinct phenotypes amongst early wheezers; the Avon Longitudinal Study of Parents And Children (ALSPAC) has recently re-examined these.
To validate statistically derived ALSPAC phenotypes in the Southampton Women’s Survey (SWS) using infant and 6 year lung function, and allergic sensitisation at 1, 3 and 6 years, comparing these with TCRS phenotypes.
Complete 6 year follow-up data were available for 926 children, selected from 1973 infants born to 12,579 women characterised pre-conception. 95 children had V’maxFRC and FEV0.4 measured age 5-14 weeks using rapid compression/raised volume techniques. At 6 years we performed spirometry (n=791), fractional exhaled nitric oxide (FeNO, n=589) and methacholine challenge (n=234). Skin prick testing was performed at 12m, 3 and 6 years (n=1494, 1255, 699, respectively). Using wheeze status questionnaire data at 6m, 12m, 2, 3 and 6 years we classified children into TCRS (never, transient early, persistent, late-onset) and ALSPAC based groups (never, early, transient, intermediate-onset, late-onset, persistent).
Amongst ALSPAC groups, persistent and late-onset wheeze were associated with atopy at 3 and 6 years, whilst intermediate-onset wheeze showed earlier atopic association at 1 year; all three were associated with FeNO at 6 years. Persistent wheezers had lower infant (V’maxFRC p<0.05) and 6 year lung function (FEV1, FEV1/FVC and FEF25-75, p<0.05), whilst late and intermediate-onset wheezers showed no lung function deficits. Transient wheezers were non-atopic but showed persistent lung function deficits (V’maxFRC in infancy, FEV1 and FEF25-75 at 6 years, all p<0.05). Those who wheezed only in the first year (early phenotype) showed no lung function deficits. No associations were seen with 6 years bronchial hyper-responsiveness or infancy FEV0.4.
SWS cohort data validates the statistically derived ALSPAC 6-class model. In particular, lung function and atopy successfully differentiate persistent, late-onset and intermediate-onset wheeze, whilst the Tucson ‘transient early’ wheeze phenotype can be sub-classified into groups that reflect early lung function. Since the 4-class model fails to adequately differentiate phenotypes based on lung function and atopy, we propose that strong consideration be given to using the 6-class paradigm for longitudinal outcome work in wheezing with onset in early life.
PMCID: PMC3689612  PMID: 23401430
Wheeze; asthma; phenotype; lung function; cohort; atopy
10.  Fetal and infant growth predict hip geometry at six years old: Findings from the Southampton Women’s Survey 
Pediatric research  2013;74(4):450-456.
We investigated relationships between early growth and proximal femoral geometry at age six years in a prospective population-based cohort, the Southampton Women’s Survey.
In 493 mother-offspring pairs we assessed linear size (individual measure dependent on developmental stage) using high-resolution ultrasound at 11, 19 and 34 weeks gestation (femur length) and at birth, 1, 2, 3, 4 and 6 years (crown-heel length/height). Standard deviation (SD)-scores were created and conditional regression modelling generated mutually independent growth variables. Children underwent hip DXA (Dual X-ray absorptiometry) at 6 years (Hologic Discovery, Hologic Inc., MA); hip structure analysis software yielded measures of geometry and strength.
There were strong associations between early linear growth and femoral neck section modulus (Z) at 6 years, with the strongest relationships observed for femur growth from 19-34 weeks gestation (β=0.26 cm3/SD, p<0.0001), and for height growth from birth to 1 year (β=0.25 cm3/SD, p<0.0001) and 1-2 years (β=0.33 cm3/SD, p<0.0001), with progressively weaker relationships over years 3 (β=0.23 cm3/SD, p=0.0002) and 4 (β=0.10 cm3/SD, p=0.18).
These results demonstrate that growth before age 3 years predicts proximal femoral geometry at six years old. The data suggest critical periods in which there is capacity for long term influence on the later skeletal growth trajectory.
PMCID: PMC3797011  PMID: 23857297
11.  Different Indices of Fetal Growth Predict Bone Size and Volumetric Density at 4 Years of Age 
We have demonstrated previously that higher birth weight is associated with greater peak and later-life bone mineral content and that maternal body build, diet, and lifestyle influence prenatal bone mineral accrual. To examine prenatal influences on bone health further, we related ultrasound measures of fetal growth to childhood bone size and density. We derived Z-scores for fetal femur length and abdominal circumference and conditional growth velocity from 19 to 34 weeks’ gestation from ultrasound measurements in participants in the Southampton Women’s Survey. A total of 380 of the offspring underwent dual-energy X-ray absorptiometry (DXA) at age 4 years [whole body minus head bone area (BA), bone mineral content (BMC), areal bone mineral density (aBMD), and estimated volumetric BMD (vBMD)]. Volumetric bone mineral density was estimated using BMC adjusted for BA, height, and weight. A higher velocity of 19- to 34-week fetal femur growth was strongly associated with greater childhood skeletal size (BA: r = 0.30, p < .0001) but not with volumetric density (vBMD: r = 0.03, p = .51). Conversely, a higher velocity of 19- to 34-week fetal abdominal growth was associated with greater childhood volumetric density (vBMD: r = 0.15, p = .004) but not with skeletal size (BA: r = 0.06, p = .21). Both fetal measurements were positively associated with BMC and aBMD, indices influenced by both size and density. The velocity of fetal femur length growth from 19 to 34 weeks’ gestation predicted childhood skeletal size at age 4 years, whereas the velocity of abdominal growth (a measure of liver volume and adiposity) predicted volumetric density. These results suggest a discordance between influences on skeletal size and volumetric density.
PMCID: PMC3793299  PMID: 20437610
12.  Maternal awareness of young children’s physical activity: levels and cross-sectional correlates of overestimation 
BMC Public Health  2013;13:924.
Factors associated with parental awareness of children’s physical activity (PA) levels have not been explored in preschool-aged children. This paper investigates maternal awareness of preschool-aged children’s PA levels and determined correlates associated with maternal overestimation of PA.
Data from the Southampton Women’s Survey, a UK population-based study, were collected March 2006 through June 2009. Daily minutes of moderate-to-vigorous PA (MVPA) were derived using accelerometry in 478 4-year-old children. Mothers who were realistic or overestimated their child’s PA were identified. Log-binomial regression was used to analyse correlates of maternal overestimation of PA levels in children whose mothers perceived them to be active (n = 438).
40.8% of children were classified as inactive: 89.7% of these were perceived to be active by their mothers (over-estimators). These mothers were more likely to think their child sometimes lacked skills required to be physically active (RR (95% CI) = 1.29(1.03-1.63)) and their child was more likely to attend nursery full-time (RR = 1.53(1.14-2.04)). They were less likely to have older children at home (RR = 0.71(0.56-0.90)).
Almost 90% of mothers of inactive preschool-aged children perceive their child to be active. Nursery-school attendance and having older siblings at home may be important to consider when designing behavioural interventions to increase PA in preschool children.
PMCID: PMC3852941  PMID: 24090173
Physical activity; Awareness; Preschool children
Thorax  2013;68(4):372-379.
Obesity and asthma have increased in westernised countries. Maternal obesity may increase childhood asthma risk. If this relation is causal it may be mediated through factors associated with maternal adiposity, such as fetal development, pregnancy complications or infant adiposity. We investigated the relationships of maternal BMI and fat mass with childhood wheeze and examined the influences of infant weight gain and childhood obesity.
Maternal pre-pregnancy BMI and estimated fat mass (from skinfold thicknesses) were related to asthma, wheeze and atopy in 940 children. Transient or persistent/late wheeze was classified using questionnaire data collected at ages 6, 12, 24 and 36 months and 6 years. At 6 years, skin prick testing was conducted and exhaled nitric oxide and spirometry measured. Infant adiposity gain was calculated from skinfold thickness at birth and 6 months.
Greater maternal BMI and fat mass were associated with increased childhood wheeze (RR 1.08 per 5 kg m−2, p=0.006; RR 1.09 per 10 kg, p=0.003); these reflected associations with transient wheeze (RR 1.11, p=0.003; RR 1.13, p=0.002, respectively) but not with persistent wheeze or asthma. Infant adiposity gain was associated with persistent wheeze but not significantly. Adjusting for infant adiposity gain or BMI at 3 or 6 years did not reduce the association between maternal adiposity and transient wheeze. Maternal adiposity was not associated with offspring atopy, exhaled nitric oxide, or spirometry.
Greater maternal adiposity is associated with transient wheeze but not asthma or atopy, suggesting effects upon airway structure/function but not allergic predisposition.
PMCID: PMC3661999  PMID: 23291350
adiposity; body mass index; obesity; asthma; allergic sensitisation
14.  Physical activity intensity, sedentary time, and body composition in preschoolers123 
Detailed associations between physical activity (PA) subcomponents, sedentary time, and body composition in preschoolers remain unclear.
We examined the magnitude of associations between objectively measured PA subcomponents and sedentary time with body composition in 4-y-old children.
We conducted a cross-sectional study in 398 preschool children recruited from the Southampton Women’s Survey. PA was measured by using accelerometry, and body composition was measured by using dual-energy X-ray absorptiometry. Associations between light physical activity, moderate physical activity (MPA), vigorous physical activity (VPA), and moderate-to-vigorous physical activity (MVPA) intensity; sedentary time; and body composition were analyzed by using repeated-measures linear regression with adjustment for age, sex, birth weight, maternal education, maternal BMI, smoking during pregnancy, and sleep duration. Sedentary time and PA were also mutually adjusted for one another to determine whether they were independently related to adiposity.
VPA was the only intensity of PA to exhibit strong inverse associations with both total adiposity [P < 0.001 for percentage of body fat and fat mass index (FMI)] and abdominal adiposity (P = 0.002 for trunk FMI). MVPA was inversely associated with total adiposity (P = 0.018 for percentage of body fat; P = 0.022 for FMI) but only because of the contribution of VPA, because MPA was unrelated to fatness (P ≥ 0.077). No associations were shown between the time spent sedentary and body composition (P ≥ 0.11).
In preschoolers, the time spent in VPA is strongly and independently associated with lower adiposity. In contrast, the time spent sedentary and in low-to-moderate–intensity PA was unrelated to adiposity. These results indicate that efforts to challenge pediatric obesity may benefit from prioritizing VPA.
PMCID: PMC3785144  PMID: 23553158
15.  Correlates of Light and Moderate-to-Vigorous Objectively Measured Physical Activity in Four-Year-Old Children 
PLoS ONE  2013;8(9):e74934.
Correlates of physical activity (PA) are hypothesized to be context and behaviour specific, but there is limited evidence of this in young children. The aim of the current study is to investigate associations between personal, social and environmental factors and objectively measured light and moderate-to-vigorous PA (LPA and MVPA, respectively) in four-year-old children.
Cross-sectional data were used from the Southampton Women’s Survey, a UK population-based longitudinal study. Four-year old children (n = 487, 47.0% male) had valid PA data assessed using accelerometry (Actiheart) and exposure data collected with a validated maternal questionnaire (including data on child personality, family demographics, maternal behaviour, rules and restrictions, and perceived local environment). Linear regression modelling was used to analyse associations with LPA and MVPA separately, interactions with sex were explored.
LPA minutes were greater in children whose mothers reported more PA (vs. inactive: regression coefficient±standard error: 6.70±2.94 minutes), and without other children in the neighbourhood to play with (−6.33±2.44). MVPA minutes were greater in children with older siblings (vs. none: 5.81±2.80) and those whose mothers used active transport for short trips (vs. inactive: 6.24±2.95). Children accumulated more MVPA in spring (vs. winter: 9.50±4.03) and, in boys only, less MVPA with availability of other children in the neighbourhood (−3.98±1.70).
Young children’s LPA and MVPA have differing associations with a number of social and environmental variables. Interventions targeting PA promotion in young children outside of formal care settings should consider including intensity specific factors.
PMCID: PMC3764204  PMID: 24040365
17.  New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism 
Horikoshi, Momoko | Yaghootkar, Hanieh | Mook-Kanamori, Dennis O. | Sovio, Ulla | Taal, H. Rob | Hennig, Branwen J. | Bradfield, Jonathan P. | St. Pourcain, Beate | Evans, David M. | Charoen, Pimphen | Kaakinen, Marika | Cousminer, Diana L. | Lehtimäki, Terho | Kreiner-Møller, Eskil | Warrington, Nicole M. | Bustamante, Mariona | Feenstra, Bjarke | Berry, Diane J. | Thiering, Elisabeth | Pfab, Thiemo | Barton, Sheila J. | Shields, Beverley M. | Kerkhof, Marjan | van Leeuwen, Elisabeth M. | Fulford, Anthony J. | Kutalik, Zoltán | Zhao, Jing Hua | den Hoed, Marcel | Mahajan, Anubha | Lindi, Virpi | Goh, Liang-Kee | Hottenga, Jouke-Jan | Wu, Ying | Raitakari, Olli T. | Harder, Marie N. | Meirhaeghe, Aline | Ntalla, Ioanna | Salem, Rany M. | Jameson, Karen A. | Zhou, Kaixin | Monies, Dorota M. | Lagou, Vasiliki | Kirin, Mirna | Heikkinen, Jani | Adair, Linda S. | Alkuraya, Fowzan S. | Al-Odaib, Ali | Amouyel, Philippe | Andersson, Ehm Astrid | Bennett, Amanda J. | Blakemore, Alexandra I.F. | Buxton, Jessica L. | Dallongeville, Jean | Das, Shikta | de Geus, Eco J. C. | Estivill, Xavier | Flexeder, Claudia | Froguel, Philippe | Geller, Frank | Godfrey, Keith M. | Gottrand, Frédéric | Groves, Christopher J. | Hansen, Torben | Hirschhorn, Joel N. | Hofman, Albert | Hollegaard, Mads V. | Hougaard, David M. | Hyppönen, Elina | Inskip, Hazel M. | Isaacs, Aaron | Jørgensen, Torben | Kanaka-Gantenbein, Christina | Kemp, John P. | Kiess, Wieland | Kilpeläinen, Tuomas O. | Klopp, Norman | Knight, Bridget A. | Kuzawa, Christopher W. | McMahon, George | Newnham, John P. | Niinikoski, Harri | Oostra, Ben A. | Pedersen, Louise | Postma, Dirkje S. | Ring, Susan M. | Rivadeneira, Fernando | Robertson, Neil R. | Sebert, Sylvain | Simell, Olli | Slowinski, Torsten | Tiesler, Carla M.T. | Tönjes, Anke | Vaag, Allan | Viikari, Jorma S. | Vink, Jacqueline M. | Vissing, Nadja Hawwa | Wareham, Nicholas J. | Willemsen, Gonneke | Witte, Daniel R. | Zhang, Haitao | Zhao, Jianhua | Wilson, James F. | Stumvoll, Michael | Prentice, Andrew M. | Meyer, Brian F. | Pearson, Ewan R. | Boreham, Colin A.G. | Cooper, Cyrus | Gillman, Matthew W. | Dedoussis, George V. | Moreno, Luis A | Pedersen, Oluf | Saarinen, Maiju | Mohlke, Karen L. | Boomsma, Dorret I. | Saw, Seang-Mei | Lakka, Timo A. | Körner, Antje | Loos, Ruth J.F. | Ong, Ken K. | Vollenweider, Peter | van Duijn, Cornelia M. | Koppelman, Gerard H. | Hattersley, Andrew T. | Holloway, John W. | Hocher, Berthold | Heinrich, Joachim | Power, Chris | Melbye, Mads | Guxens, Mònica | Pennell, Craig E. | Bønnelykke, Klaus | Bisgaard, Hans | Eriksson, Johan G. | Widén, Elisabeth | Hakonarson, Hakon | Uitterlinden, André G. | Pouta, Anneli | Lawlor, Debbie A. | Smith, George Davey | Frayling, Timothy M. | McCarthy, Mark I. | Grant, Struan F.A. | Jaddoe, Vincent W.V. | Jarvelin, Marjo-Riitta | Timpson, Nicholas J. | Prokopenko, Inga | Freathy, Rachel M.
Nature genetics  2012;45(1):76-82.
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes, and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study (up to 69,308 individuals of European descent from 43 studies), we have now extended the number of genome-wide significant loci to seven, accounting for a similar proportion of variance to maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes; ADRB1 with adult blood pressure; and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
PMCID: PMC3605762  PMID: 23202124
18.  Monitoring head size and growth using the new UK-World Health Organization growth standard 
Archives of disease in childhood  2011;96(4):386-388.
In order to assess the extent to which children in the United Kingdom (UK) will follow the UK-WHO head circumference standard, we used head circumference data from the Southampton Women’s Survey (SWS; n=3159) and the Avon Longitudinal Study of Parents and Children (ALSPAC; n=15,208) in children age 0-36 months, converted into z-scores using both the UK-WHO or UK1990 references. Rapid head growth was defined as crossing upwards through 2 major centile bands (1.33 SD). The UK-WHO standard identified many more infants with heads above the 98th centile compared to the UK1990 reference (UK-WHO 6% to 16% of infants at various ages, UK1990 1% to 4%). Rapid head growth in the first 6 to 9 months was also much more common using the UK-WHO standard (UK-WHO: 14.6% to 15.3%; UK1990: 4.8% to 5.1%). Practitioners should be aware of these findings to avoid unnecessary referrals.
PMCID: PMC3685130  PMID: 21285227
ALSPAC; head circumference; growth charts; macrocephaly; microcephaly; hydrocephalus
19.  The long term effects of prenatal development on growth and metabolism 
Seminars in reproductive medicine  2011;29(3):257-265.
People who were small at birth and had poor infant growth have an increased risk of adult cardiovascular disease, osteoporosis and type 2 diabetes, particularly if their restricted early growth is followed by increased childhood weight gain. These relations extend across the normal range of birth size in a graded manner, so reduced size is not a prerequisite. In addition larger birth size is associated with risks of obesity and type 2 diabetes. The associations appear to reflect developmental plastic responses made by the fetus and infant based on cues about the environment, influenced by maternal characteristics including diet, body composition, stress and exercise levels. These responses involve epigenetic processes which modify the offspring’s phenotype. Vulnerability to ill-health results if the environment in infancy, childhood and later life is mismatched to the phenotype induced in development, informed by the developmental cues. This mismatch may arise through unbalanced diet or body composition of the mother, or change in lifestyle factors between generations. These insights offer new possibilities for early diagnosis and prevention of chronic disease.
PMCID: PMC3685133  PMID: 21769765
Nutrition; fetal growth; metabolic disease; epigenetics
21.  Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years 
Thorax  2010;65(12):1099-1106.
Little is known about whether patterns of growth are associated with altered respiratory and immune development. This study relates prenatal and infant growth patterns to wheeze and atopy at age 3 years
Birth weight and length were measured in 1548 children born at term. Conditional fetal head and abdominal circumference growth velocities were calculated from antenatal ultrasound measurements. Conditional postnatal growth velocities were calculated from infant weight, length and adiposity data. .Measures of size and conditional growth were related to parentally-reported infant and early childhood wheeze and to atopic status at age 3.
Atopy risk increased by 46% per standard deviation (SD) increase in abdominal circumference growth velocity from 11-19 weeks’ gestation but by 20% per SD decrease in abdominal growth velocity from 19-34 weeks (p=0.007 and p=0.011). Atopic wheeze risk increased by 20% per SD decrease in 19-34 week abdominal growth (p=0.046). Non-atopic wheeze risk increased by 10% per SD decrease in 11-19 week head circumference growth. Greater relative infant weight and adiposity gains were associated with both atopic and non-atopic wheeze.
Rapid growth during 11-19 weeks’ gestation followed by growth faltering is associated with atopy, suggesting that influences affecting fetal growth may also alter immune development. A lower early fetal growth trajectory is associated with non-atopic wheeze, possibly reflecting an association with smaller airways. An association between postnatal adiposity gain and wheeze may partly reflect prenatal influences that cause fetal growth to falter but are then followed by postnatal adiposity gain.
PMCID: PMC3685135  PMID: 20956394
asthma; preschool-wheeze; allergic sensitisation; growth; nutrition
22.  Maternal late-pregnancy serum 25-hydroxyvitamin D in relation to childhood wheeze and atopic outcomes 
Thorax  2012;67(11):950-956.
Studies exploring the relationship between prenatal vitamin D exposure and childhood asthma have yielded conflicting results. Higher vitamin D intake during pregnancy has been shown to lower the risk of childhood wheeze, yet a study of maternal late-pregnancy serum 25-hydroxyvitamin D suggested higher serum concentrations may be associated with increased childhood asthma.
To assess the relationship between mothers’ serum 25-hydroxyvitamin D status and asthma and wheeze phenotypes in their children at age 6 years. Secondly, to explore the relationship between maternal 25-hydroxyvitamin D status and objective measures of childhood atopy and lung function.
Serum 25-hydroxyvitamin D was measured at 34 weeks’ gestation in the mothers of 860 children born at term. Wheeze was classified as either transient or persistent/late using questionnaire data collated from 6, 12, 24 and 36 months and 6 years. At 6 years spirometry was performed and atopic status was determined by skin prick testing, exhaled nitric oxide was measured in 451 and bronchial hyperresponsiveness in 216 children.
There were no significant associations between maternal late-pregnancy 25-hydroxyvitamin D status and either asthma or wheeze at age 6 years. Maternal vitamin D status was not associated with transient or persistent/late wheeze; no significant association was found between persistent/late wheeze when subdivided according to atopic status. No associations were found with skin sensitisation or lung function.
This study provides no evidence that exposure to higher concentrations of 25-hydroxyvitamin D in maternal serum during late pregnancy increases the risk of childhood asthma, wheeze or atopy.
PMCID: PMC3679514  PMID: 22707522
asthma epidemiology; asthma; paediatric asthma
23.  Correction of unexpected distributions of P values from analysis of whole genome arrays by rectifying violation of statistical assumptions 
BMC Genomics  2013;14:161.
Statistical analysis of genome-wide microarrays can result in many thousands of identical statistical tests being performed as each probe is tested for an association with a phenotype of interest. If there were no association between any of the probes and the phenotype, the distribution of P values obtained from statistical tests would resemble a Uniform distribution. If a selection of probes were significantly associated with the phenotype we would expect to observe P values for these probes of less than the designated significance level, alpha, resulting in more P values of less than alpha than expected by chance.
In data from a whole genome methylation promoter array we unexpectedly observed P value distributions where there were fewer P values less than alpha than would be expected by chance. Our data suggest that a possible reason for this is a violation of the statistical assumptions required for these tests arising from heteroskedasticity. A simple but statistically sound remedy (a heteroskedasticity–consistent covariance matrix estimator to calculate standard errors of regression coefficients that are robust to heteroskedasticity) rectified this violation and resulted in meaningful P value distributions.
The statistical analysis of ‘omics data requires careful handling, especially in the choice of statistical test. To obtain meaningful results it is essential that the assumptions behind these tests are carefully examined and any violations rectified where possible, or a more appropriate statistical test chosen.
PMCID: PMC3610227  PMID: 23496791
P values; Distributions; Statistical analysis; Statistical assumptions; Whole genome methylation promoter arrays; Epigenome
24.  Postpartum depressive symptoms: the B-vitamin link 
Objective This study examined longitudinal relationships between maternal red-cell folate status and dietary intakes of vitamins B6, B12 and folate before and during pregnancy and subsequent postpartum depressive symptoms.
Study design and setting Within a cohort study of women aged 20–34 years (the Southampton Women's Survey) dietary data were obtained before pregnancy and at 11 and 34 weeks' gestation. Red-cell folate was measured before pregnancy and at 11 weeks' gestation. We derived relative risks of postpartum depressive symptoms using an Edinburgh Postnatal Depression Scale (EPDS) score of ≥ 13 administered from 6 months to 1 year postpartum.
Results No significant differences were found between those with postpartum depressive symptoms (n = 905) and those without (n = 1951) in relation to red-cell folate concentration or dietary intake of folate, vitamin B12 and vitamin B6, before or during pregnancy. A prior history of mental illness (relative risk (RR) 1.83; 95% confidence interval (CI) 1.53–2.19) was associated with postpartum depressive symptoms, and women who breastfed until 6 months were less likely to experience postpartum depressive symptoms (RR 0.68; 95% CI 0.55–0.84).
Conclusion This study suggests that folate status and dietary folate, B6 and B12 intakes before and during pregnancy are not associated with postpartum depressive symptoms. A history of mental illness, however, was a strong risk factor.
PMCID: PMC3487611  PMID: 23277793
B-vitamin intake; folate status; postpartum depression
25.  Maternal Plasma Phosphatidylcholine Fatty Acids and Atopy and Wheeze in the Offspring at Age of 6 Years 
Variation in exposure to polyunsaturated fatty acids (PUFAs) might influence the development of atopy, asthma, and wheeze. This study aimed to determine whether differences in PUFA concentrations in maternal plasma phosphatidylcholine are associated with the risk of childhood wheeze or atopy. For 865 term-born children, we measured phosphatidylcholine fatty acid composition in maternal plasma collected at 34 weeks' gestation. Wheezing was classified using questionnaires at 6, 12, 24, and 36 months and 6 years. At age of 6 years, the children underwent skin prick testing, fractional exhaled nitric oxide (FENO) measurement, and spirometry. Maternal n-6 fatty acids and the ratio of n-3 to n-6 fatty acids were not associated with childhood wheeze. However, higher maternal eicosapentaenoic acid, docosahexaenoic acid, and total n-3 fatty acids were associated with reduced risk of non-atopic persistent/late wheeze (RR 0.57, 0.67 and 0.69, resp. P = 0.01, 0.015, and 0.021, resp.). Maternal arachidonic acid was positively associated with FENO (P = 0.024). A higher ratio of linoleic acid to its unsaturated metabolic products was associated with reduced risk of skin sensitisation (RR 0.82, P = 0.013). These associations provide some support for the hypothesis that variation in exposure to n-6 and n-3 fatty acids during pregnancy influences the risk of childhood wheeze and atopy.
PMCID: PMC3463812  PMID: 23049600

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