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1.  Growth trajectories in the children of mothers with eating disorders: a longitudinal study 
BMJ Open  2014;4(3):e004453.
Objective
The aim of this study was to examine longitudinal patterns of growth trajectories in children of women with eating disorders (ED): anorexia nervosa (AN) and bulimia nervosa (BN).
Design
Prospective longitudinal birth cohort; Avon Longitudinal Study of Parents and Children (ALSPAC).
Setting
South West England, UK.
Participants
The sample consisted of women and their children (n=10 190) from ALSPAC. Patterns of growth among children of women reporting a history of AN (n=137), BN (n=165), both AN and BN (n=68) and other psychiatric disorders (n=920) were compared with an unexposed group of children (n=8900).
Main outcome measures
Height and weight data, from birth to 10 years, were extracted from health visitor records, parental report from questionnaires and clinic attendances. Growth trajectories were analysed using mixed-effects models and constructed separately for male and female children.
Results
Between birth and 10 years, male children of women with BN were taller than children in the unexposed group. Male children of women with a history of AN and BN, and female children of women with AN, were shorter throughout childhood. Between the ages of 2 and 5, higher body mass index (BMI) was observed in male children in all maternal ED groups. Conversely, female children of women with AN had a BMI of −0.35 kg/m2 lower at 2 years compared with the unexposed group, with catch-up by age 10.
Conclusions
Early childhood growth has been found to predict weight gain in adolescence and adulthood, and may be a risk factor for the development of an ED. These findings therefore have public health implications in relation to the prevention of weight-related and eating-related disorders later in life.
doi:10.1136/bmjopen-2013-004453
PMCID: PMC3975767  PMID: 24674996
Epidemiology; Psychiatry; Public Health
2.  Associations of postnatal weight and length/height gain with wheeze, asthma and atopy: The PROBIT Study 
Background
It has been hypothesised that postnatal weight and length/height gain are variously related to wheeze, asthma and atopy, however supporting evidence is limited and inconsistent.
Methods
Weights and lengths/heights of 12,171 term-infants were measured from birth to 12 months and at 6.5 years, and extracted from polyclinic records prospectively obtained between 12 and 60 months. Atopic phenotypes were ascertained at 6.5 years with the International Study of Asthma and Allergy in Childhood questionnaire and skin-prick tests. Logistic regression models investigated whether rates of weight and length/height gain from infancy to mid-childhood were associated with atopy phenotypes that have occurred ever or in the last 12 months.
Results
After controlling for confounders and prior weight and length/height gain, all weight gain variables except birthweight were positively associated with ever having wheezed (p<0.1). A one SD increase in weight gain rate between 0–3 months was associated with a 12% increase (2%–23%) in allergic rhinitis ever. No other consistent patterns of association were found for weight gain or length/height gain rate between 0–60 months with atopic outcomes at 6.5 years. In contrast, all atopy outcomes except for ever having asthma were associated with current weight and height, even after controlling for prior growth.
Conclusion
Current height and weight are more strongly associated with the development of atopic phenotypes in childhood than patterns of infant and early childhood growth, which may well reflect reverse causality (atopy effects on growth) or residual confounding by an unknown common cause of growth and atopy.
doi:10.1111/pai.12049
PMCID: PMC3711479  PMID: 23374010
wheeze; asthma; atopy; postnatal growth; weight gain; length gain
3.  Joint modelling rationale for chained equations 
Background
Chained equations imputation is widely used in medical research. It uses a set of conditional models, so is more flexible than joint modelling imputation for the imputation of different types of variables (e.g. binary, ordinal or unordered categorical). However, chained equations imputation does not correspond to drawing from a joint distribution when the conditional models are incompatible. Concurrently with our work, other authors have shown the equivalence of the two imputation methods in finite samples.
Methods
Taking a different approach, we prove, in finite samples, sufficient conditions for chained equations and joint modelling to yield imputations from the same predictive distribution. Further, we apply this proof in four specific cases and conduct a simulation study which explores the consequences when the conditional models are compatible but the conditions otherwise are not satisfied.
Results
We provide an additional “non-informative margins” condition which, together with compatibility, is sufficient. We show that the non-informative margins condition is not satisfied, despite compatible conditional models, in a situation as simple as two continuous variables and one binary variable. Our simulation study demonstrates that as a consequence of this violation order effects can occur; that is, systematic differences depending upon the ordering of the variables in the chained equations algorithm. However, the order effects appear to be small, especially when associations between variables are weak.
Conclusions
Since chained equations is typically used in medical research for datasets with different types of variables, researchers must be aware that order effects are likely to be ubiquitous, but our results suggest they may be small enough to be negligible.
doi:10.1186/1471-2288-14-28
PMCID: PMC3936896  PMID: 24559129
Chained equations imputation; Gibbs sampling; Joint modelling imputation; Multiple imputation; Multivariate missing data
4.  Association of a Body Mass Index Genetic Risk Score with Growth throughout Childhood and Adolescence 
PLoS ONE  2013;8(11):e79547.
Background
While the number of established genetic variants associated with adult body mass index (BMI) is growing, the relationships between these variants and growth during childhood are yet to be fully characterised. We examined the association between validated adult BMI associated single nucleotide polymorphisms (SNPs) and growth trajectories across childhood. We investigated the timing of onset of the genetic effect and whether it was sex specific.
Methods
Children from the ALSPAC and Raine birth cohorts were used for analysis (n = 9,328). Genotype data from 32 adult BMI associated SNPs were investigated individually and as an allelic score. Linear mixed effects models with smoothing splines were used for longitudinal modelling of the growth parameters and measures of adiposity peak and rebound were derived.
Results
The allelic score was associated with BMI growth throughout childhood, explaining 0.58% of the total variance in BMI in females and 0.44% in males. The allelic score was associated with higher BMI at the adiposity peak (females  =  0.0163 kg/m2 per allele, males  =  0.0123 kg/m2 per allele) and earlier age (-0.0362 years per allele in males and females) and higher BMI (0.0332 kg/m2 per allele in females and 0.0364 kg/m2 per allele in males) at the adiposity rebound. No gene:sex interactions were detected for BMI growth.
Conclusions
This study suggests that known adult genetic determinants of BMI have observable effects on growth from early childhood, and is consistent with the hypothesis that genetic determinants of adult susceptibility to obesity act from early childhood and develop over the life course.
doi:10.1371/journal.pone.0079547
PMCID: PMC3823612  PMID: 24244521
5.  Gestational weight gain as a risk factor for hypertensive disorders of pregnancy 
American Journal of Obstetrics and Gynecology  2013;209(4):327.e1-327.e17.
Objective
Pregnancy interventions to limit gestational weight gain (GWG) have been proposed as a means of preventing hypertensive disorders of pregnancy (HDP); however, it is currently unclear whether GWG has a causal influence on the development of HDP. Thus, we aimed to determine whether GWG in early pregnancy is a risk factor for preeclampsia and gestational hypertension and whether GWG precedes the increases in blood pressure in normotensive women across pregnancy.
Study Design
We examined repeat antenatal clinic measurements of weight and blood pressure (median of 12 and 14 per woman, respectively) of 12,522 women in the Avon Longitudinal Study of Parents and Children.
Results
Greater prepregnancy weight was associated with an increased risk of gestational hypertension and preeclampsia per 10 kg of prepregnancy weight: odds ratio (OR), 1.80; 95% confidence interval (CI), 1.70–1.91 and OR, 1.71; 95% CI, 1.49–1.95, respectively, for women weighing 90 kg or less before pregnancy; OR, 1.24; 95% CI, 1.03–1.49 and OR, 1.61; 95% CI, 1.18–2.19 for women weighing more than 90 kg. Fully adjusted odds ratios for gestational hypertension and preeclampsia per 200 g per week GWG up to 18 weeks were OR, 1.26; 95% CI, 1.16–1.38 and OR, 1.31; 95% CI, 1.07–1.62. In normotensive women, GWG in early pregnancy was associated positively with blood pressure change in midpregnancy and negatively with blood pressure change in late pregnancy. In all gestational periods, GWG was positively associated with concurrent blood pressure change. However, there was no evidence that blood pressure changes in any period were associated with subsequent GWG.
Conclusion
These findings suggest that GWG in early pregnancy may be a potential target for interventions aimed at reducing the risk of HDP.
doi:10.1016/j.ajog.2013.05.042
PMCID: PMC3807791  PMID: 23711667
Avon Longitudinal Study of Parents and Children; blood pressure; gestational weight gain; hypertensive disorder of pregnancy; preeclampsia
6.  Area Deprivation Across the Life Course and Physical Capability in Midlife: Findings From the 1946 British Birth Cohort 
American Journal of Epidemiology  2013;178(3):441-450.
Physical capability in later life is influenced by factors occurring across the life course, yet exposures to area conditions have only been examined cross-sectionally. Data from the National Survey of Health and Development, a longitudinal study of a 1946 British birth cohort, were used to estimate associations of area deprivation (defined as percentage of employed people working in partly skilled or unskilled occupations) at ages 4, 26, and 53 years (residential addresses linked to census data in 1950, 1972, and 1999) with 3 measures of physical capability at age 53 years: grip strength, standing balance, and chair-rise time. Cross-classified multilevel models with individuals nested within areas at the 3 ages showed that models assessing a single time point underestimate total area contributions to physical capability. For balance and chair-rise performance, associations with area deprivation in midlife were robust to adjustment for individual socioeconomic position and prior area deprivation (mean change for a 1-standard-deviation increase: balance, −7.4% (95% confidence interval (CI): −12.8, −2.8); chair rise, 2.1% (95% CI: −0.1, 4.3)). In addition, area deprivation in childhood was related to balance after adjustment for childhood socioeconomic position (−5.1%, 95% CI: −8.7, −1.6). Interventions aimed at reducing midlife disparities in physical capability should target the socioeconomic environment of individuals—for standing balance, as early as childhood.
doi:10.1093/aje/kwt003
PMCID: PMC3727343  PMID: 23788665
geography; Great Britain; health status disparities; longitudinal studies; multilevel analysis; physical endurance; residence characteristics; socioeconomic factors
7.  Associations of Maternal Weight Gain in Pregnancy With Offspring Cognition in Childhood and Adolescence: Findings From the Avon Longitudinal Study of Parents and Children 
American Journal of Epidemiology  2013;177(5):402-410.
An association of gestational weight gain (GWG) with offspring cognition has been postulated. We used data from the Avon Longitudinal Study of Parents and Children, a United Kingdom prospective cohort (1990 through the present) with a median of 10 maternal weight measurements in pregnancy. These were used to allocate participants to 2009 Institute of Medicine weight-gain categories and in random effect linear spline models. Outcomes were School Entry Assessment score (age, 4 years; n = 5,832), standardized intelligence quotient assessed by Wechsler Intelligence Scale for Children (age, 8 years; n = 5,191), and school final-examination results (age, 16 years; n = 7,339). Offspring of women who gained less weight than recommended had a 0.075 standard deviation lower mean School Entry Assessment score (95% confidence interval: −0.127, −0.023) and were less likely to achieve adequate final-examination results (odds ratio = 0.88, 95% confidence interval: 0.78, 0.99) compared with offspring of women who gained as recommended. GWG in early pregnancy (defined as 0–18 weeks on the basis of a knot point at 18 weeks) and midpregnancy (defined as 18–28 weeks on the basis of knot points at 18 and 28 weeks) was positively associated with School Entry Assessment score and intelligence quotient. GWG in late pregnancy (defined as 28 weeks onward on the basis of a knot point at 28 weeks) was positively associated with offspring intelligence quotient and with increased odds of offspring achieving adequate final-examination results in mothers who were overweight prepregnancy. Findings support small positive associations between GWG and offspring cognitive development, which may have lasting effects on educational attainment up to age 16 years.
doi:10.1093/aje/kws239
PMCID: PMC3581073  PMID: 23388581
ALSPAC; cognition; gestational weight gain
8.  BLOOD PRESSURE CHANGE IN NORMOTENSIVE, GESTATIONAL HYPERTENSIVE, PREECLAMPTIC AND ESSENTIAL HYPERTENSIVE PREGNANCIES 
Hypertension  2012;59(6):1241-1248.
We compared patterns of blood pressure (BP) change between normotensive women, women who developed gestational hypertension or preeclampsia and women who had essential hypertension to examine how distinct these conditions are and whether rates of BP change may help to identify women at risk of hypertensive disorders. We used antenatal clinic BP measurements (median 14 per woman) of 13,016 women from the Avon Longitudinal Study of Parents and Children (ALSPAC) who had a singleton or twin live birth surviving until at least 1 year. Linear spline models were used to describe changes in systolic and diastolic BP in different periods of pregnancy (8-18, 18-30, 30-36 and 36+ weeks gestation). Women who had essential hypertension, and those who developed gestational hypertension or preeclampsia had higher BP at 8 weeks gestation (baseline) compared with normotensive women. The decrease in BP until 18 weeks was smaller in gestational hypertensive compared with normotensive pregnancies. BP rose more rapidly from 18 weeks onwards in gestational hypertensive and preeclamptic pregnancies and from 30 weeks onwards in essential hypertensive compared with normotensive pregnancies. Women who developed preeclampsia had a more rapid increase in BP from 30 weeks onwards than those who developed gestational hypertension or had essential hypertension. Our findings indicate notable patterns of BP change that distinguish women with essential hypertension, gestational hypertension and preeclampsia from each other and from normotensive women, even from early pregnancy. These distinct patterns may be useful for identifying women at risk of developing a hypertensive disorder later in pregnancy.
doi:10.1161/HYPERTENSIONAHA.111.187039
PMCID: PMC3378662  PMID: 22526257
blood pressure; preeclampsia; gestational hypertension; pregnancy; ALSPAC
9.  Association of maternal weight gain in pregnancy with offspring obesity and metabolic and vascular traits in childhood 
Circulation  2010;121(23):2557-2564.
Background
We aimed to examine the association of gestational weight gain (GWG) and pre-pregnancy weight with offspring adiposity and cardiovascular risk factors.
Methods and results
Data from 5,154 (for adiposity and blood pressure) and 3,457 (for blood assays) mother-offspring pairs from a UK prospective pregnancy cohort were used. Random effects multilevel models were used to assess incremental GWG (median and range of repeat weight measures per woman: 10 (1, 17)). Women who exceeded the 2009 Institute of Medicine recommended GWG were more likely to have offspring with greater body mass index, waist, fat mass, leptin, systolic blood pressure, CRP and IL-6 levels, and lower HDLc and Apolipoprotein A1 levels. Children of women who gained less than the recommended amounts had lower levels of adiposity, but other cardiovascular risk factor tended to be similar in this group to offspring of women gaining recommended amounts. When examined in more detail greater pre-pregnancy weight was associated with greater offspring adiposity and more adverse cardiovascular risk factors at age 9. GWG in early pregnancy (0 to 14 weeks) was positively associated with offspring adiposity across the entire distribution, but strengthened in women gaining more than 500g/week. By contrast, between 14 and 36 weeks GWG was only associated with offspring adiposity in women gaining at least 500g/week. GWG between 14-36 weeks was positively and linearly associated with adverse lipid and inflammatory profiles with these associations largely mediated by the associations with offspring adiposity.
Conclusions
Greater maternal pre-pregnancy weight and GWG up to 36 weeks gestation are associated with greater offspring adiposity and adverse cardiovascular risk factors. Before implementing any GWG recommendations, the balance of risks and benefits of attempts to control GWG for short- and long-term outcomes in mother and child should be ascertained.
doi:10.1161/CIRCULATIONAHA.109.906081
PMCID: PMC3505019  PMID: 20516377
Pregnancy; Gestational Weight Gain; Offspring cardiovascular risk factors; ALSPAC
10.  Is infant weight associated with childhood blood pressure? Analysis of the Promotion of Breastfeeding Intervention Trial (PROBIT) cohort 
Background Weight gain during infancy may programme later health outcomes, but examination of this hypothesis requires appropriate lifecourse methods and detailed weight gain measures during childhood. We examined associations between weight gain in infancy and early childhood and blood pressure at the age of 6.5 years in healthy children born at term.
Methods We carried out an observational analysis of data from a cluster-randomized breastfeeding promotion trial in Belarus. Of 17 046 infants enrolled between June 1996 and December 1997, 13 889 (81.5%) had systolic and diastolic blood pressure measured at 6.5 years; 10 495 children with complete data were analysed. A random-effects linear spline model with three knot points was used to estimate each individual's birthweight and weight gain from birth to 3 months, 3 months to 1 year and 1–5 years. Path analysis was used to separate direct effects from those mediated through subsequent weight gain.
Results In boys, after controlling for confounders and prior weight gain, the change in systolic blood pressure per z-score increase in weight gain was 0.09 mmHg [95% confidence interval (95% CI) −0.14 to 0.31] for birthweight; 0.41 mmHg (95% CI 0.19–0.64) for birth to 3 months; 0.69 mmHg (95% CI 0.47–0.92) for 3 months to 1 year and 0.82 mmHg (95% CI 0.58–1.06) for 1–5 years. Most of the associations between weight gain and blood pressure were mediated through weight at the age of 6.5 years. Findings for girls and diastolic blood pressure were similar.
Conclusions Children who gained weight faster than their peers, particularly at later ages, had higher blood pressure at the age of 6.5 years, with no association between birthweight and blood pressure.
doi:10.1093/ije/dyr119
PMCID: PMC3383097  PMID: 22039193
Birthweight; blood pressure; lifetime; multi-level model; path analysis; weight gain
11.  Cohort Profile: The Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort 
Summary The Avon Longitudinal Study of Children and Parents (ALSPAC) was established to understand how genetic and environmental characteristics influence health and development in parents and children. All pregnant women resident in a defined area in the South West of England, with an expected date of delivery between 1st April 1991 and 31st December 1992, were eligible and 13 761 women (contributing 13 867 pregnancies) were recruited. These women have been followed over the last 19–22 years and have completed up to 20 questionnaires, have had detailed data abstracted from their medical records and have information on any cancer diagnoses and deaths through record linkage. A follow-up assessment was completed 17–18 years postnatal at which anthropometry, blood pressure, fat, lean and bone mass and carotid intima media thickness were assessed, and a fasting blood sample taken. The second follow-up clinic, which additionally measures cognitive function, physical capability, physical activity (with accelerometer) and wrist bone architecture, is underway and two further assessments with similar measurements will take place over the next 5 years. There is a detailed biobank that includes DNA, with genome-wide data available on >10 000, stored serum and plasma taken repeatedly since pregnancy and other samples; a wide range of data on completed biospecimen assays are available. Details of how to access these data are provided in this cohort profile.
doi:10.1093/ije/dys066
PMCID: PMC3600619  PMID: 22507742
12.  Challenges in examining area effects across the life course on physical capability in mid-life: Findings from the 1946 British Birth Cohort 
Health & Place  2012;18(2-2):366-374.
A major limitation of past work linking area socioeconomic conditions to health in mid-life has been the reliance on single point in time measurement of area. Using the MRC National Survey of Health and Development, this study for the first time linked place of residence at three major life periods of childhood (1950), young adulthood (1972), and mid-life (1999) to area-socioeconomic data from the nearest census years. Using objective measures of physical capability as the outcome, the purpose of this study was to highlight four methodological challenges of attrition bias, secular changes in socio-economic measures, historical data availability, and changing reporting units over time. In general, standing balance and chair rise time showed clear cross-sectional associations with residing in areas with high deprivation. However, it was the process of overcoming the methodological challenges, which led to the conclusion that in this example percent low social class occupations was the most appropriate measure to use when extending cross-sectional analysis of standing balance and chair rise to life course investigation.
doi:10.1016/j.healthplace.2011.11.007
PMCID: PMC3315018  PMID: 22209408
Life course; Area; Capability; Methodology; Deprivation
13.  Maternal smoking during pregnancy and offspring trajectories of height and adiposity: comparing maternal and paternal associations 
Background Maternal smoking during pregnancy is associated with reduced offspring birth length and has been postulated as a risk factor for obesity. Causality for obesity is not established. Causality is well-supported for birth length, but evidence on persistence of height deficits is inconsistent.
Methods We examined the association between maternal smoking during pregnancy and trajectories of offspring height (0–10 years, N = 9424), ponderal index (PI) (0–2 years, N = 9321) and body mass index (BMI) (2–10 years, N = 8887) in the Avon Longitudinal Study of Parents and Children. To strengthen inference, measured confounders were controlled for, maternal and partner smoking associations were compared, dose–response and associations with post-natal smoking were examined.
Results Maternal smoking during pregnancy was associated with shorter birth length, faster height growth in infancy and slower growth in later childhood. By 10 years, daughters of women who smoke during pregnancy are on average 1.11 cm (SE = 0.27) shorter after adjustment for confounders and partner smoking; the difference is 0.22 cm (SE = 0.22) for partner's smoking. Maternal smoking was associated with lower PI at birth, faster PI increase in infancy, but not with BMI changes 2–10 years. Associations were stronger for maternal than partner smoking for PI at birth and PI changes in infancy, but not for BMI changes after 2 years. A similar dose–response in both maternal and partner smoking was seen for BMI change 2–10 years.
Conclusion Maternal smoking during pregnancy has an intrauterine effect on birth length, and possibly on adiposity at birth and changes in height and adiposity in infancy. We do not find evidence of a specific intrauterine effect on height or adiposity changes after the age of 2 years.
doi:10.1093/ije/dys025
PMCID: PMC3396309  PMID: 22407859
Smoking; growth; obesity; pregnancy; child; ALSPAC
14.  Patterns of Alcohol Use in Early Adolescence Predict Problem Use at Age 16 
Aims: Teenagers in the UK report some of the highest rates of alcohol use in Europe. We identify patterns of alcohol use in early adolescence and relate these to hazardous and harmful alcohol use at age 16. Methods: In a UK birth cohort, we analysed repeated measures of alcohol use from age 13 to 15 in a sample of 7100 adolescents. Data on drinking frequency and typical consumption when drinking were modelled separately using a pair of latent class models. Classes of alcohol-use behaviour were contrasted across a range of risk factors and then to hazardous and harmful alcohol use as assessed using the Alcohol Use Disorders Identification Test scale at age 16. Results: Heterogeneity in drinking frequency and consumption could each be captured with three classes corresponding to low, medium and high levels. In total, 14.2% were classified as high-frequency and 8.9% as high consumption alcohol users. Socio-demographic factors, maternal substance use and the young persons' use of tobacco and cannabis were associated with class membership. At age 16, 29% were drinking hazardously and a further 5.6% were assessed as harmful drinkers. Young people in the high drinking frequency or consumption class had a 9-fold increased risk of reporting harmful drinking at age 16. Conclusions: By the age of 16, a substantial proportion of teenagers in this sample were drinking at levels that could be considered hazardous or harmful for an adult. Patterns of alcohol exposure in early adolescence were strongly associated with later alcohol use. Altering drinking patterns in middle adolescence has the potential to reduce harmful use in later adolescence.
doi:10.1093/alcalc/agr156
PMCID: PMC3284685  PMID: 22215001
15.  Relationships of Risk Factors for Pre-Eclampsia with Patterns of Occurrence of Isolated Gestational Proteinuria during Normal Term Pregnancy 
PLoS ONE  2011;6(7):e22115.
Background
Isolated gestational proteinuria may be part of the pre-eclampsia disease spectrum. Confirmation of its association with established pre-eclampsia risk factors and higher blood pressure in uncomplicated pregnancies would support this concept.
Methods
Data from 11,651 women from the Avon Longitudinal Study of Parents and Children who had a term live birth but did not have pre-existing hypertension or diabetes or develop gestational diabetes or preeclampsia were used. Proteinuria was assessed repeatedly (median 12 measurements per woman) by dipstick and latent class analysis was used to identify subgroups of the population with different patterns of proteinuria in pregnancy.
Results
Higher maternal pre-pregnancy body mass index (BMI), younger age, nulliparity and twin pregnancy were independently associated with increased odds of any proteinuria in pregnancy. Women who experienced proteinuria showed five patterns: proteinuria in early pregnancy only (≤20 weeks gestation), and onset at 21–28 weeks, 29–32 weeks, 33–36 weeks and ≥37 weeks gestation. There were higher odds of proteinuria onset after 33 weeks in obese women and after 37 weeks in nulliparous women compared with normal weight and multiparous women respectively. Smoking in pregnancy was weakly negatively associated with odds of proteinuria onset after 37 weeks. Twin pregnancies had higher odds of proteinuria onset from 29 weeks. In women with proteinuria onset after 33 weeks blood pressure was higher in early pregnancy and at the end of pregnancy.
Conclusions
Established pre-eclampsia risk factors were related to proteinuria occurrence in late gestation in healthy term pregnancies, supporting the hypothesis that isolated gestational proteinuria may represent an early manifestation of pre-eclampsia.
doi:10.1371/journal.pone.0022115
PMCID: PMC3138774  PMID: 21789220
16.  Adult height variants affect birth length and growth rate in children 
Human Molecular Genetics  2011;20(20):4069-4075.
Previous studies identified 180 single nucleotide polymorphisms (SNPs) associated with adult height, explaining ∼10% of the variance. The age at which these begin to affect growth is unclear. We modelled the effect of these SNPs on birth length and childhood growth. A total of 7768 participants in the Avon Longitudinal Study of Parents and Children had data available. Individual growth trajectories from 0 to 10 years were estimated using mixed-effects linear spline models and differences in trajectories by individual SNPs and allelic score were determined. The allelic score was associated with birth length (0.026 cm increase per ‘tall’ allele, SE = 0.003, P = 1 × 10−15, equivalent to 0.017 SD). There was little evidence of association between the allelic score and early infancy growth (0–3 months), but there was evidence of association between the allelic score and later growth. This association became stronger with each consecutive growth period, per ‘tall’ allele per month effects were 0.015 SD (3 months–1 year, SE = 0.004), 0.023 SD (1–3 years, SE = 0.003) and 0.028 SD (3–10 years, SE = 0.003). By age 10, the mean height difference between individuals with ≤170 versus ≥191 ‘tall’ alleles (the top and bottom 10%) was 4.7 cm (0.8 SD), explaining ∼5% of the variance. There was evidence of associations with specific growth periods for some SNPs (rs3791675, EFEMP1 and rs6569648, L3MBTL3) and supportive evidence for previously reported age-dependent effects of HHIP and SOCS2 SNPs. SNPs associated with adult height influence birth length and have an increasing effect on growth from late infancy through to late childhood. By age 10, they explain half the height variance (∼5%) of that explained in adults (∼10%).
doi:10.1093/hmg/ddr309
PMCID: PMC3177650  PMID: 21757498
17.  Associations of gestational weight gain with maternal body mass index, waist circumference, and blood pressure measured 16 y after pregnancy: the Avon Longitudinal Study of Parents and Children (ALSPAC)1234 
Background: Little is known about associations of gestational weight gain (GWG) with long-term maternal health.
Objective: We aimed to examine associations of prepregnancy weight and GWG with maternal body mass index (BMI; in kg/m2), waist circumference (WC), systolic blood pressure (SBP), and diastolic blood pressure (DBP) 16 y after pregnancy.
Design: This is a prospective study in 2356 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC)—a population-based pregnancy cohort.
Results: Women with low GWG by Institute of Medicine recommendations had a lower mean BMI (−1.56; 95% CI: −2.12, −1.00) and WC (−3.37 cm; −4.91, −1.83 cm) than did women who gained weight as recommended. Women with a high GWG had a greater mean BMI (2.90; 2.27, 3.52), WC (5.84 cm; 4.15, 7.54 cm), SBP (2.87 mm Hg; 1.22, 4.52 mm Hg), and DBP (1.00 mm Hg; −0.02, 2.01 mm Hg). Analyses were adjusted for age, offspring sex, social class, parity, smoking, physical activity and diet in pregnancy, mode of delivery, and breastfeeding. Women with a high GWG had 3-fold increased odds of overweight and central adiposity. On the basis of estimates from random-effects multilevel models, prepregnancy weight was positively associated with all outcomes. GWG in all stages of pregnancy was positively associated with later BMI, WC, increased odds of overweight or obesity, and central adiposity. GWG in midpregnancy (19–28 wk) was associated with later greater SBP, DBP, and central adiposity but only in women with a normal prepregnancy BMI.
Conclusions: Results support initiatives aimed at optimizing prepregnancy weight. Recommendations on optimal GWG need to balance contrasting associations with different outcomes in both mothers and offspring.
doi:10.3945/ajcn.110.008326
PMCID: PMC3095501  PMID: 21471282
18.  Development of a New Method for Monitoring Prostate-Specific Antigen Changes in Men with Localised Prostate Cancer: A Comparison of Observational Cohorts 
European urology  2009;57(3):446-452.
Background
Prostate-specific antigen (PSA) measurements are increasingly used to monitor men with localised prostate cancer (PCa), but there is little consensus about the method to use.
Objective
To apply age-specific predictions of PSA level (developed in men without cancer) to one cohort of men with clinically identified PCa and one cohort of men with PSA-detected PCa. We hypothesise that among men with clinically identified cancer, the annual increase in PSA level would be steeper than in men with PSA-detected cancer.
Design, setting, and participants
The Scandinavian Prostatic Cancer Group 4 (SPCG-4) cohort consisted of 321 men assigned to the watchful waiting arm of the SPCG-4 trial. The UK cohort consisted of 320 men with PSA-detected PCa in the Prostate Testing for Cancer and Treatment (ProtecT) study in nine UK centres between 1999 and 2007 who opted for monitoring rather than treatment. Multilevel models describing changes in PSA level were fitted to the two cohorts, and average PSA level at age 50, change in PSA level with age, and predicted PSA values were derived.
Measurements
PSA level.
Results and limitations
In the SPCG-4 cohort, mean PSA at age 50 was similar to the cancer-free cohort but with a steeper yearly increase in PSA level (16.4% vs 4.0%). In the UK cohort, mean PSA level was higher than that in the cancer-free cohort (due to a PSA biopsy threshold of 3.0 ng/ml) but with a similar yearly increase in PSA level (4.1%). Predictions were less accurate for the SPCG-4 cohort (median observed minus predicted PSA level: −2.0 ng/ml; interquartile range [IQR]: −7.6–0.7 ng/ml) than for the UK cohort (median observed minus predicted PSA level: −0.8 ng/ml; IQR: −2.1–0.1 ng/ml).
Conclusions
In PSA-detected men, yearly change in PSA was similar to that in cancer-free men, whereas in men with symptomatic PCa, the yearly change in PSA level was considerably higher. Our method needs further evaluation but has promise for refining active monitoring protocols.
doi:10.1016/j.eururo.2009.03.023
PMCID: PMC2910432  PMID: 19303695
active surveillance; localised prostate cancer; PSA doubling time; PSA velocity; reference ranges
19.  Changes in Ponderal Index and Body Mass Index across Childhood and Their Associations with Fat Mass and Cardiovascular Risk Factors at Age 15 
PLoS ONE  2010;5(12):e15186.
Background
Little is known about whether associations between childhood adiposity and later adverse cardiovascular health outcomes are driven by tracking of overweight from childhood to adulthood and/or by vascular and metabolic changes from childhood overweight that persist into adulthood. Our objective is to characterise associations between trajectories of adiposity across childhood and a wide range of cardiovascular risk factors measured in adolescence, and explore the extent to which these are mediated by fat mass at age 15.
Methods and Findings
Using data from the Avon Longitudinal Study of Parents and Children, we estimated individual trajectories of ponderal index (PI) from 0–2 years and BMI from 2–10 years using random-effects linear spline models (N = 4601). We explored associations between PI/BMI trajectories and DXA-determined total-body fat-mass and cardiovascular risk factors at 15 years (systolic and diastolic blood pressure, fasting LDL- and HDL-cholesterol, triglycerides, C-reactive protein, glucose, insulin) with and without adjustment for confounders. Changes in PI/BMI during all periods of infancy and childhood were associated with greater DXA-determined fat-mass at age 15. BMI changes in childhood, but not PI changes from 0–2 years, were associated with most cardiovascular risk factors in adolescence; associations tended to be strongest for BMI changes in later childhood (ages 8.5–10), and were largely mediated by fat mass at age 15.
Conclusion
Changes in PI/BMI from 0–10 years were associated with greater fat-mass at age 15. Greater increases in BMI from age 8.5–10 years are most strongly associated with cardiovascular risk factors at age 15, with much of these associations mediated by fat-mass at this age. We found little evidence supporting previous reports that rapid PI changes in infancy are associated with future cardiovascular risk. This study suggests that associations between early overweight and subsequent adverse cardiovascular health are largely due to overweight children tending to remain overweight.
doi:10.1371/journal.pone.0015186
PMCID: PMC2999567  PMID: 21170348
20.  Association between general and central adiposity in childhood, and change in these, with cardiovascular risk factors in adolescence: prospective cohort study 
Objectives To examine the prospective associations between body mass index (BMI), waist circumference, and fat mass in childhood and cardiovascular risk factors at age 15-16.
Design Prospective cohort study.
Setting Avon Longitudinal Study of Parents and Children.
Participants 5235 children aged 9-12 at start of study.
Main exposures BMI, waist circumference, and fat mass determined by dual energy x ray absorptiometry, assessed at age 9-12 and at age 15-16.
Main outcome measures Systolic and diastolic blood pressure and concentrations of fasting glucose, insulin, triglycerides, low density lipoprotein cholesterol, and high density lipoprotein cholesterol assessed at age 15-16.
Results In girls a 1 SD greater BMI at age 9-12 was associated with cardiovascular risk factors at age 15-16 in fully adjusted models: odds ratio 1.23 (95% confidence interval 1.10 to 1.38) for high systolic blood pressure (≥130 mm Hg); 1.19 (1.03 to 1.38) for high concentration of low density lipoprotein cholesterol (≥2.79 mmol/l); 1.43 (1.06 to 1.92) for high concentration of triglycerides (≥1.7 mmol/l); 1.25 (1.08 to 1.46) for low concentration of high density lipoprotein cholesterol (<1.03 mmol/l); and 1.45 (1.22 to 1.73) for high concentration of insulin (≥16.95 IU/l). Equivalent results in boys were 1.24 (1.13 to 1.37) for systolic blood pressure; 1.30 (1.07 to 1.59) for low density lipoprotein cholesterol; 1.96 (1.51 to 2.55) for triglycerides; 1.39 (1.22 to 1.57) for high density lipoprotein cholesterol, and 1.84 (1.56 to 2.17) for insulin. BMI was associated with high fasting glucose (≥5.6 mmol/l) only in boys (1.18, 1.03 to 1.36). With these binary outcomes there was statistical evidence that associations differed between girls and boys for fasting glucose (P=0.03) and insulin (P<0.001). When risk factors were examined as continuous outcomes there was evidence for stronger associations of BMI with more adverse levels in boys than girls for fasting insulin, glucose, and triglyceride concentrations (all interaction P≤0.03). BMI, waist circumference, and fat mass were all strongly correlated with each other (r=0.89-0.94), and associations of the three with cardiovascular outcomes were of similar magnitude with statistical evidence of consistency in associations (all P>0.2 for heterogeneity). When waist circumference or fat mass or both were added to models including BMI they did not increase the variation in cardiovascular risk factors already explained by BMI and confounders alone. Girls who were overweight/obese at age 9-12 but were normal weight by 15-16 had similar odds of adverse levels of risk factors to those who were normal weight at both ages. In boys odds of high systolic blood pressure, high concentrations of triglycerides and insulin, and low concentrations of high density lipoprotein cholesterol remained higher in this group compared with those who were normal weight at both ages but were lower than in those who remained overweight/obese at both ages.
Conclusions Measurements of waist circumference or directly assessed fat mass in childhood do not seem to be associated with cardiovascular risk factors in adolescence any more strongly than BMI. Girls who favourably alter their overweight status between childhood and adolescence have cardiovascular risk profiles broadly similar to those who were normal weight at both time points, but boys who change from overweight to normal show risk factor profiles intermediate between those seen in boys who are normal weight at both ages or overweight at both ages.
doi:10.1136/bmj.c6224
PMCID: PMC2992109  PMID: 21109577
21.  Objective measurement of levels and patterns of physical activity 
Archives of Disease in Childhood  2007;92(11):963-969.
Objective
To measure the levels and patterns of physical activity, using accelerometers, of 11‐year‐old children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC).
Design
Cross‐sectional analysis.
Setting
ALSPAC is a birth cohort study located in the former county of Avon, in the southwest of England. This study used data collected when the children were 11 years old.
Participants
5595 children (2662 boys, 2933 girls). The children are the offspring of women recruited to a birth cohort study during 1991–2. The median age (95% CI) of the children is now 11.8 (11.6 to 11.9) years.
Methods
Physical activity was measured over a maximum of 7 consecutive days using the MTI Actigraph accelerometer.
Main outcome measures
Level and pattern of physical activity.
Results
The median physical activity level was 580 counts/min. Boys were more active than girls (median (IQR) 644 (528–772) counts/min vs 529 (444–638) counts/min, respectively). Only 2.5% (95% CI 2.1% to 2.9%) of children (boys 5.1% (95% CI 4.3% to 6.0%), girls 0.4% (95% CI 0.2% to 0.7%) met current internationally recognised recommendations for physical activity. Children were most active in summer and least active in winter (difference = 108 counts/min). Both the mother and partner's education level were inversely associated with activity level (p for trend <0.001 (both mother and partner)). The association was lost for mother's education (p for trend = 0.07) and attenuated for partner's education (p for trend = 0.02), after adjustment for age, sex, season, maternal age and social class.
Conclusions
A large majority of children are insufficiently active, according to current recommended levels for health.
doi:10.1136/adc.2006.112136
PMCID: PMC2083612  PMID: 17855437
22.  Socioeconomic differences in childhood growth trajectories: at what age do height inequalities emerge? 
Background
Socioeconomic differentials in adult height are frequently observed, but the age at which these inequalities emerge and the patterns they follow through childhood are unknown.
Subjects and Methods
Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), height trajectories from birth to 10 years (N=12366) were modelled. Individual trajectories were estimated using mixed-effects models. Differences in trajectories by socioeconomic position (SEP) were investigated.
Results
There was a clear gradient in birth length across categories of maternal education; average birth length in boys was 0.41 cm lower in the lowest maternal education category compared with the highest, which is 0.9% of the average birth length for the highest SEP category (equivalent results for girls 0.65 cm, 1.3%). Socioeconomic differences in childhood growth were small, and only resulted in minimal widening of the height inequality with increasing age. By the age of 10 years, the mean difference between children in the lowest and highest maternal education categories was 1.4 cm for boys and 1.7 cm for girls; similar proportionate differences to those seen at birth (1.0% for boys and 1.2% for girls). Patterns were the same when father's education or household occupational social class were used to measure SEP.
Conclusions
The socioeconomic differential in height during childhood in this cohort of children born in the UK in the 1990s arises largely through inequalities in birth length, with small increases in the inequality from differences in growth in later childhood.
doi:10.1136/jech.2010.113068
PMCID: PMC3245896  PMID: 20724285
ALSPAC; growth; growth in infancy; height; inequalities SI; inequality; socioeconomic
23.  Metabolic imbalance and prostate cancer progression 
There is substantial evidence implicating environmental factors in the progression of prostate cancer. The metabolic consequences of a western lifestyle, such as obesity, insulin resistance and abnormal hormone production have been linked to prostate carcinogenesis through multiple overlapping pathways. Insulin resistance results in raised levels of the mitogens insulin and insulin-like growth factor-1, both of which may affect prostate cancer directly, or through their effect on other metabolic regulators. Obesity is associated with abnormal levels of adipocyte-derived peptides (adipokines), sex hormones and inflammatory cytokines. Adipokines have been shown to influence prostate cancer in both cell culture studies and observational, population level studies. Testosterone appears to have a complex relationship with prostate carcinogenesis, and it has been suggested that the lower levels associated with obesity may select for more aggressive androgen independent prostate cancer cells. Prostatic inflammation, caused by infection, urinary reflux or dietary toxins, frequently occurs prior to cancer development and may influence progression to advanced disease. High levels of ω-6 fatty acids in the diet may lead to the production of further inflammatory molecules that may influence prostate cancer. Increased fatty acid metabolism occurs within tumour cells, providing a potential target for prostate cancer therapies. Aberrations in amino acid metabolism have also been identified in prostate cancer tissue, particularly in metastatic cancer. This evidence indicates lifestyle interventions may be effective in reducing the incidence of clinical disease. However, much more research is needed before recommendations are made.
PMCID: PMC3076778  PMID: 21532839
Prostate cancer; obesity; adipokines; insulin-like growth factors; diabetes; inflammation; metabolism
24.  Reproducibility measures and their effect on diet–cancer associations in the Boyd Orr cohort 
Objectives
To quantify measurement error in the estimation of family diet intakes using 7‐day household food inventories and to investigate the effect of measurement‐error adjustment on diet–disease associations.
Design and setting
Historical cohort study in 16 districts in England and Scotland, between 1937 and 1939.
Subjects
4999 children from 1352 families in the Carnegie Survey of Diet and Health. 86.6% of these children were traced as adults and form the Boyd Orr cohort. The reproducibility analysis was based on 195 families with two assessments of family diet recorded 3–15 months apart.
Methods
Intraclass correlation coefficients (ICCs) were calculated for a variety of nutrients and food groups. Diet–cancer associations reported previously in the Boyd Orr cohort were reassessed using two methods: (a) the ICC and (b) the regression calibration.
Main results
The ICCs for the dietary intakes ranged from 0.44 (β carotene) to 0.85 (milk and milk products). The crude fully adjusted hazard ratio (HR) for cancer mortality per 1 MJ/day increase in energy intake was 1.15 (95% CI 1.06 to 1.24). After adjustment using the ICC for energy (0.80) the HR (95% CI) increased to 1.19 (1.08 to 1.31), and the estimate from regression calibration was 1.14 (0.98 to 1.32). The crude fully adjusted odds ratio (OR) for cancer incidence per 40 g/day increase in fruit intake was 0.84 (95% CI 0.73 to 0.97). After adjustment using the fruit ICC (0.78) it became 0.81 (0.67 to 0.96) and the OR derived from regression calibration was 0.81 (0.59 to 1.10).
Conclusions
The diet–disease relationships for the dietary intakes with low measurement error were robust to adjustment for measurement error.
doi:10.1136/jech.2006.046524
PMCID: PMC2465690  PMID: 17435211
25.  Predicting ambient ultraviolet from routine meteorological data; its potential use as an instrumental variable for vitamin D status in pregnancy in a longitudinal birth cohort in the UK 
Background
Maternal vitamin D status in pregnancy has been postulated to have important effects on intrauterine development. UVB radiation is not commonly measured but is the prime determinant of circulating 25-hydroxyvitamin-D [25-(OH)D] and is highly dependent on regional weather including cloud cover, ozone and sunshine hours.
Methods
Using linear regression we described the relationship between estimated ambient-erythemal ultraviolet (eUV) exposure in Oxford (1990–95) and total hours of sunshine and month in order to forecast eUV in nearby regions, whilst adjusting for regional variations in weather. The forecast was validated with empirical data collected from Cornwall and then predicted for the Avon region. Total 98-day prenatal ambient-eUV was then predicted in 355 expectant mothers in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort and its relationship with maternal vitamin D status was determined.
Results
Estimated ambient-eUV was strongly associated with measured ambient-eUV (r2=0.989) with a near 1:1 prediction for the validation data set [β=0.99, 95% confidence interval (CI) 0.913, 1.067 r2=0.980]; strong seasonal associations were observed between eUV in the last trimester of pregnancy and maternal serum 25-(OH)D concentrations (r2=0.40).
Conclusion
This technique of prediction could be applied to existing cohorts allowing the relationship between maternal vitamin D status and the health of the offspring to be studied via instrumental variable analysis.
doi:10.1093/ije/dyp237
PMCID: PMC2788530  PMID: 19564248
Epidemiology; maternal exposure; pregnancy; prenatal exposure delayed effects; seasons; ultraviolet rays; vitamin D; instrumental variable; ALSPAC

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