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1.  How “healthy” should children be when selecting reference samples for spirometry? 
The European respiratory journal  2015;45(6):1576-1581.
Question
How ‘healthy’ do children need to be when selecting reference samples for spirometry?
Methods
Anthropometry and spirometry were measured at school in an unselected, multi-ethnic population of London children aged 5-11yrs, with follow-up assessments 1yr later. Parents provided information on children’s birth data and health status. FEV1 and FVC were adjusted for sex, age, height and ethnicity using the GLI-2012 equations, and the effects of potential exclusion criteria on the z-score distributions were examined.
Results
After exclusions for current and chronic lung disease, acceptable data were available for 1901 children on 2767 occasions. “Healthy” children were defined as those without prior asthma or hospitalisation for respiratory problems, born full-term with birthweight ≥2.5kg and asymptomatic at test. Mean(SD) z-scores for FEV1 and FVC approximated 0(1) indicating the GLI-2012 equations were appropriate for this “healthy” population. However, if children born preterm, or with low birthweight, prior asthma or mildly symptomatic at test were included in the reference, results overall were similar to those for “healthy” children, while increasing the sample size by 25%.
Answer
With the exception of clear-cut factors such as current and chronic respiratory disease, paediatric reference samples for spirometry can be relatively inclusive and hence more generalisable to the target population.
doi:10.1183/09031936.00223814
PMCID: PMC4452263  PMID: 25700391
2.  Life course epidemiology: recognising the importance of adolescence 
doi:10.1136/jech-2014-205300
PMCID: PMC4515995  PMID: 25646208
ADOLESCENTS CG; EPIDEMIOLOGY; CHILD HEALTH
3.  Relationships of maternal and paternal anthropometry with neonatal body size, proportions and adiposity in an Australian cohort 
The patterns of association between maternal or paternal and neonatal phenotype may offer insight into how neonatal characteristics are shaped by evolutionary processes, such as conflicting parental interests in fetal investment and obstetric constraints. Paternal interests are theoretically served by maximizing fetal growth, and maternal interests by managing investment in current and future offspring, but whether paternal and maternal influences act on different components of overall size is unknown. We tested whether parents' prepregnancy height and body mass index (BMI) were related to neonatal anthropometry (birthweight, head circumference, absolute and proportional limb segment and trunk lengths, subcutaneous fat) among 1,041 Australian neonates using stepwise linear regression. Maternal and paternal height and maternal BMI were associated with birthweight. Paternal height related to offspring forearm and lower leg lengths, maternal height and BMI to neonatal head circumference, and maternal BMI to offspring adiposity. Principal components analysis identified three components of variability reflecting neonatal “head and trunk skeletal size,” “adiposity,” and “limb lengths.” Regression analyses of the component scores supported the associations of head and trunk size or adiposity with maternal anthropometry, and limb lengths with paternal anthropometry. Our results suggest that while neonatal fatness reflects environmental conditions (maternal physiology), head circumference and limb and trunk lengths show differing associations with parental anthropometry. These patterns may reflect genetics, parental imprinting and environmental influences in a manner consistent with parental conflicts of interest. Paternal height may relate to neonatal limb length as a means of increasing fetal growth without exacerbating the risk of obstetric complications. Am J Phys Anthropol 156:625–636, 2015.
doi:10.1002/ajpa.22680
PMCID: PMC4404025  PMID: 25502164
neonatal anthropometry; birthweight; limb length; parental height; parental BMI
4.  From trial to population: a study of a family-based community intervention for childhood overweight implemented at scale 
Objectives
To assess how outcomes associated with participation in a family-based weight management intervention (MEND 7-13 - Mind, Exercise, Nutrition…Do it) for childhood overweight or obesity implemented at scale in the community vary by child, family, neighbourhood and MEND programme characteristics.
Methods/Subjects
Intervention evaluation using prospective service level data. Families (N=21 132) with overweight children are referred, or self-refer, to MEND. Families (participating child and one parent/carer) attend two sessions/week for 10 weeks (N=13 998; N=9 563 with complete data from 1 788 programmes across England). Sessions address diet and physical activity through education, skills training and motivational enhancement. MEND was shown to be effective in obese children in a randomised controlled trial (RCT). Outcomes were mean change in body mass index (BMI), age and sex standardised BMI (zBMI), self-esteem (Rosenberg scale), and psychological distress (Strengths and Difficulties Questionnaire, SDQ) after the 10-week programme. Relationships between the outcome and covariates were tested in multilevel models adjusted for the outcome at baseline.
Results
After adjustment for covariates, BMI reduced by mean 0·76 kg/m2 (standard error (se)=0.021, p<0.0001), zBMI reduced by mean 0.18 (se=0.0038, p<0.0001), self-esteem score increased by 3·53 units (se=0.13, p<0.0001) psychological distress score decreased by 2·65 units (se=0.31, p<0.0001). Change in outcomes varied by participant, family, neighbourhood and programme factors. Generally, outcomes improved less amongst children from less advantaged backgrounds and in Asian compared to white children. BMI reduction under service conditions was slightly but not statistically significantly less than in the earlier RCT.
Conclusions
The MEND intervention, when delivered at scale, is associated with improved BMI and psychosocial outcomes on average, but may work less well for some groups of children, and so has the potential to widen inequalities in these outcomes. Such public health interventions should be implemented to achieve sustained impact for all groups.
doi:10.1038/ijo.2014.103
PMCID: PMC4175967  PMID: 24919564
Childhood obesity; Intervention; Implementation; Inequalities; Weight management
5.  Identifying the best body mass index metric to assess adiposity change in children 
Archives of Disease in Childhood  2014;99(11):1020-1024.
Objective
Although dual-energy X-ray absorptiometry (DEXA) is the preferred method to estimate adiposity, body mass index (BMI) is often used as a proxy. However, the ability of BMI to measure adiposity change among youth is poorly evidenced. This study explored which metrics of BMI change have the highest correlations with different metrics of DEXA change.
Methods
Data were from the Quebec Adipose and Lifestyle Investigation in Youth cohort, a prospective cohort of children (8–10 years at recruitment) from Québec, Canada (n=557). Height and weight were measured by trained nurses at baseline (2008) and follow-up (2010). Metrics of BMI change were raw (ΔBMIkg/m2), adjusted for median BMI (ΔBMIpercentage) and age-sex-adjusted with the Centers for Disease Control and Prevention growth curves expressed as centiles (ΔBMIcentile) or z-scores (ΔBMIz-score). Metrics of DEXA change were raw (total fat mass; ΔFMkg), per cent (ΔFMpercentage), height-adjusted (fat mass index; ΔFMI) and age-sex-adjusted z-scores (ΔFMz-score). Spearman's rank correlations were derived.
Results
Correlations ranged from modest (0.60) to strong (0.86). ΔFMkg correlated most highly with ΔBMIkg/m2 (r = 0.86), ΔFMI with ΔBMIkg/m2 and ΔBMIpercentage (r = 0.83–0.84), ΔFMz-score with ΔBMIz-score (r = 0.78), and ΔFMpercentage with ΔBMIpercentage (r = 0.68). Correlations with ΔBMIcentile were consistently among the lowest.
Conclusions
In 8–10-year-old children, absolute or per cent change in BMI is a good proxy for change in fat mass or FMI, and BMI z-score change is a good proxy for FM z-score change. However change in BMI centile and change in per cent fat mass perform less well and are not recommended.
doi:10.1136/archdischild-2013-305163
PMCID: PMC4215345  PMID: 24842797
6.  Blood pressure centiles for Great Britain 
Archives of Disease in Childhood  2006;92(4):298-303.
Objective
To produce representative cross‐sectional blood pressure reference centiles for children and young people living in Great Britain.
Design
Analysis of blood pressure data from seven nationally representative surveys: Health Surveys for England 1995–8, Scottish Health Surveys 1995 and 1998, and National Diet & Nutrition Survey 1997.
Methods
Blood pressure was measured using the Dinamap 8100 with the same protocol throughout. Weight and height were also measured. Data for 11 364 males and 11 537 females aged 4–23 years were included in the analysis, after excluding 0.3% missing or outlying data. Centiles were derived for systolic, diastolic, mean arterial and pulse pressure using the latent moderated structural (LMS) equations method.
Results
Blood pressure in the two sexes was similar in childhood, rising progressively with age and more rapidly during puberty. Systolic pressure rose faster and was appreciably higher in adult men than in adult women. After adjustment for age, blood pressure was related more to weight than height, the effect being stronger for systolic blood pressure. Pulse pressure peaked at 18 years in males and 16 years in females.
Conclusions
These centiles increase our knowledge of blood pressure norms in contemporary British children and young people. High blood pressure for age should be defined as blood pressure above the 98th centile, and high‐normal blood pressure for age as blood pressure between the 91st and 98th centiles. The centiles identify children and young people with increased blood pressure, and will be of benefit to both clinical practice and research.
doi:10.1136/adc.2005.081216
PMCID: PMC2083671  PMID: 16905566
7.  Relationships between Neonatal Weight, Limb Lengths, Skinfold Thicknesses, Body Breadths and Circumferences in an Australian Cohort 
PLoS ONE  2014;9(8):e105108.
Background
Low birth weight has been consistently associated with adult chronic disease risk. The thrifty phenotype hypothesis assumes that reduced fetal growth impacts some organs more than others. However, it remains unclear how birth weight relates to different body components, such as circumferences, adiposity, body segment lengths and limb proportions. We hypothesized that these components vary in their relationship to birth weight.
Methods
We analysed the relationship between birth weight and detailed anthropometry in 1270 singleton live-born neonates (668 male) from the Mater-University of Queensland Study of Pregnancy (Brisbane, Australia). We tested adjusted anthropometry for correlations with birth weight. We then performed stepwise multiple regression on birth weight of: body lengths, breadths and circumferences; relative limb to neck-rump proportions; or skinfold thicknesses. All analyses were adjusted for sex and gestational age, and used logged data.
Results
Circumferences, especially chest, were most strongly related to birth weight, while segment lengths (neck-rump, thigh, upper arm, and especially lower arm and lower leg) were relatively weakly related to birth weight, and limb lengths relative to neck-rump length showed no relationship. Skinfolds accounted for 36% of birth weight variance, but adjusting for size (neck-rump, thigh and upper arm lengths, and head circumference), this decreased to 10%. There was no evidence that heavier babies had proportionally thicker skinfolds.
Conclusions
Neonatal body measurements vary in their association with birth weight: head and chest circumferences showed the strongest associations while limb segment lengths did not relate strongly to birth weight. After adjusting for body size, subcutaneous fatness accounted for a smaller proportion of birth weight variance than previously reported. While heavier babies had absolutely thicker skinfolds, this was proportional to their size. Relative limb to trunk length was unrelated to birth weight, suggesting that limb proportions at birth do not index factors relevant to prenatal life.
doi:10.1371/journal.pone.0105108
PMCID: PMC4146506  PMID: 25162658
8.  Is BMI Alone a Sufficient Outcome To Evaluate Interventions for Child Obesity? 
Childhood Obesity  2013;9(4):350-356.
Abstract
Background
BMI is often used to evaluate the effectiveness of childhood obesity interventions, but such interventions may have additional benefits independent of effects on adiposity. We investigated whether benefits to health outcomes following the Mind, Exercise, Nutrition…Do It! (MEND) childhood obesity intervention were independent of or associated with changes in zBMI.
Methods
A total of 79 obese children were measured at baseline; 71 and 42 participants were followed-up at 6 and 12 months respectively, and split into four groups depending on magnitude of change in zBMI. Differences between groups for waist circumference, cardiovascular fitness, physical and sedentary activities, and self-esteem were investigated.
Results
Apart from waist circumference and its z-score, there were no differences or trends across zBMI subgroups for any outcome. Independent of the degree of zBMI change, benefits in several parameters were observed in children participating in this obesity intervention.
Conclusion
We concluded that isolating a single parameter like zBMI change and neglecting other important outcomes is restrictive and may undermine the evaluation of childhood obesity intervention effectiveness.
doi:10.1089/chi.2013.0019
PMCID: PMC3728723  PMID: 23767805
9.  Associations between infant feeding and the size, tempo and velocity of infant weight gain: SITAR analysis of the Gemini twin birth cohort 
Objective
Infant growth trajectories, in terms of size, tempo and velocity, may program lifelong obesity risk. Timing of breastfeeding cessation and weaning are both implicated in rapid infant growth; we examined the association of both simultaneously with a range of growth parameters.
Design
Longitudinal population-based twin birth cohort
Subjects
The Gemini cohort provided data on 4680 UK infants with a median of 10 (IQR 8-15) weight measurements between birth and a median of 6.5 months. Age at breastfeeding cessation and weaning were reported by parents at mean age 8.2 months (SD 2.2, range 4-20). Growth trajectories were modelled using SITAR to generate three descriptors of individual growth relative to the average trajectory: size (grams), tempo (weeks, indicating the timing of the peak growth rate), and velocity (% difference from average, reflecting mean growth rate). Complex-samples general linear models adjusting for family clustering and confounders examined associations between infant feeding and SITAR parameters.
Results
Longer breastfeeding (> 4 months vs. never) was independently associated with lower growth velocity by 6.8% (SE 1.3%), and delayed growth tempo by 1.0 (SE 0.2 weeks), but not with smaller size. Later weaning (≥ 6 months vs. < 4 months) was independently associated with lower growth velocity by 4.9% (SE 1.1%) and smaller size by 102g (SE 25g).
Conclusions
Infants breastfed for longer grew slower for longer after birth (later peak growth rate) but were no different in size, while infants weaned later grew slower overall and were smaller but the timing of peak growth did not differ. Slower trajectories with a delayed peak in growth may have beneficial implications for programming later obesity risk. Replication in cohorts with longer follow-up, alternative confounding structures or randomised controlled trials are required to confirm the long-term effects and directionality, and to rule out residual confounding.
doi:10.1038/ijo.2014.61
PMCID: PMC4088337  PMID: 24722545
weight gain; growth; infancy; feeding; weaning; breastfeeding; SITAR; Gemini
10.  Prenatal Influences on Size, Velocity and Tempo of Infant Growth: Findings from Three Contemporary Cohorts 
PLoS ONE  2014;9(2):e90291.
Background
Studying prenatal influences of early life growth is relevant to life-course epidemiology as some of its features have been linked to the onset of later diseases.
Methods
We studied the association between prenatal maternal characteristics (height, age, parity, education, pre-pregnancy body mass index (BMI), smoking, gestational diabetes and hypertension) and offspring weight trajectories in infancy using SuperImposition by Translation And Rotation (SITAR) models, which parameterize growth in terms of three biologically interpretable parameters: size, velocity and tempo. We used data from three contemporary cohorts based in Portugal (GXXI, n = 738), Italy (NINFEA, n = 2,925), and Chile (GOCS, n = 959).
Results
Estimates were generally consistent across the cohorts for maternal height, age, parity and pre-pregnancy overweight/obesity. Some exposures only affected one growth parameter (e.g. maternal height (per cm): 0.4% increase in size (95% confidence interval (CI):0.3; 0.5)), others were either found to affect size and velocity (e.g. pre-pregnancy underweight vs normal weight: smaller size (−4.9%, 95% CI:−6.5; −3.3), greater velocity (5.9%, 95% CI:1.9;10.0)), or to additionally influence tempo (e.g. pre-pregnancy overweight/obesity vs normal weight: increased size (7.9%, 95% CI:4.9;10.8), delayed tempo (0.26 months, 95% CI:0.11;0.41), decreased velocity (−4.9%, 95% CI: −10.8;0.9)).
Conclusions
By disentangling the growth parameters of size, velocity and tempo, we found that prenatal maternal characteristics, especially maternal smoking, pre-pregnancy overweight and underweight, parity and gestational hypertension, are associated with different aspects of infant weight growth. These results may offer insights into the mechanisms governing infant growth.
doi:10.1371/journal.pone.0090291
PMCID: PMC3937389  PMID: 24587314
11.  Childhood obesity and overweight prevalence trends in England: evidence for growing socio-economic disparities 
International journal of obesity (2005)  2009;34(1):10.1038/ijo.2009.217.
Objective
Previous data indicate a rapidly increasing prevalence of obesity and overweight among English children and an emerging socioeconomic gradient in prevalence. The main aim of this study was to update prevalence trends among school-age children and assess the changing socioeconomic gradient.
Design
A series of nationally representative household-based health surveys conducted between 1997 and 2007 in England.
Subjects
15,271 white children (7880 boys) aged 5 to 10 years with measured height and weight.
Measurements
Height and weight were directly measured by trained fieldworkers. Overweight (including obesity) and obesity prevalence were calculated using the international body mass index cut-offs. Socioeconomic position (SEP) score was a composite score based on income and social class. Multiple linear regression assessed the prevalence odds with time point (1997/8, 2000/1, 2002/3, 2004/5, 2006/7) as the main exposure. Linear interaction terms of time by SEP were also tested for.
Results
There are signs that the overweight and obesity trend has levelled off from 2002/3 to 2006/7. The odds ratio (OR) for overweight in 2006/7 compared to 2002/3 was 0.99 (95% CI 0.88 to 1.11) and for obesity OR = 1.06 (0.86 to 1.29). The socioeconomic gradient has increased in recent years, particularly 2006/7. Compared to 1997/8, the 2006/7 age and sex-adjusted OR for overweight was 1.88 (1.52 to 2.33) in low SEP, 1.25 (1.04 to 1.50) in middle SEP, and 1.13 (0.86 to 1.48) in high SEP children.
Conclusion
Childhood obesity and overweight prevalence among school-age children in England has stabilised in recent years, but children from lower socio-economic strata have not benefited from this trend. There is an urgent need to reduce socio-economic disparities in childhood overweight and obesity.
doi:10.1038/ijo.2009.217
PMCID: PMC3865596  PMID: 19884892
Obesity; overweight; children; trends; England; socioeconomic status; socioeconomic position; income
12.  The effect of prepubertal calcium carbonate supplementation on the age of peak height velocity in Gambian adolescents1234 
Background: Limited evidence suggests that calcium intake before puberty influences adolescent height growth and the timing of puberty. Such an effect might be particularly marked in populations in whom low calcium intake, stunting, and delayed puberty are common.
Objective: The objective was to test whether 12 mo of calcium supplementation at age 8–12 y to increase intakes toward international recommendations had long-term effects on adolescent growth and pubertal development in rural Gambian children.
Design: This was a longitudinal study of 160 Gambian boys (n = 80) and girls (n = 80) who had participated in a 12-mo, randomized, double-blind, placebo-controlled, calcium carbonate supplementation trial (1000 mg Ca/d, 5 d/wk) at age 8–12 y. Anthropometric measures were made every 1–2 y until age 21–25 y; pubertal status and menarche data were collected. Repeated-measures ANCOVA and Superimposition by Translation and Rotation Method (SITAR) growth models were used to assess the effects of treatment.
Results: In boys, midadolescent height growth was advanced in the calcium group, which resulted in greater stature at a mean age of 15.5 y (mean ± SEM: 2.0 ± 0.8 cm; P = 0.01) and an earlier age of peak height velocity by 7.4 ± 2.9 mo. Subsequently, the calcium group stopped growing earlier (P = 0.02) and was 3.5 ± 1.1 cm shorter (P = 0.002) at a mean age of 23.5 y. Weight and midupper arm circumference paralleled height. No significant effects were observed in girls, but a sex-by-supplement interaction on height growth could not be confirmed.
Conclusion: Calcium supplementation of boys in late childhood advanced the age of peak height velocity and resulted in shorter adult stature in a population in whom low calcium intakes and delayed puberty are common. This trial was registered at isrctn.org as ISRCTN28836000.
doi:10.3945/ajcn.112.037481
PMCID: PMC3642996  PMID: 22990031
13.  MULTI-ETHNIC REFERENCE VALUES FOR SPIROMETRY FOR THE 3–95 YEAR AGE RANGE: THE GLOBAL LUNG FUNCTION 2012 EQUATIONS 
The European respiratory journal  2012;40(6):1324-1343.
Objective
Derive continuous prediction equations and their lower limits of normal for spirometric indices, which are applicable globally.
Material
Over 160,000 data points from 72 centres in 33 countries were shared with the European Respiratory Society Global Lung Function Initiative. Eliminating data that could not be used (mostly missing ethnic group, some outliers) left 97,759 records of healthy nonsmokers (55.3% females) aged 2.5–95 years.
Methods
Lung function data were collated, and prediction equations derived using the LMS (λ, µ, σ) method, which allows simultaneous modelling of the mean (mu), the coefficient of variation (sigma) and skewness (lambda) of a distribution family.
Results
After discarding 23,572 records, mostly because they could not be combined with other ethnic or geographic groups, reference equations were derived for healthy individuals from 3–95 years for Caucasians (N=57,395), African Americans (N=3,545), and North (N=4,992) and South East Asians (N=8,255). FEV1 and FVC between ethnic groups differed proportionally from that in Caucasians, such that FEV1/FVC remained virtually independent of ethnic group. For individuals not represented by these four groups, or of mixed ethnic origins, a composite equation taken as the average of the above equations is provided to facilitate interpretation until a more appropriate solution is developed.
Conclusion
Spirometric prediction equations for the 3–95 age range are now available that include appropriate age-dependent lower limits of normal. They can be applied globally to different ethnic groups. Additional data from the Indian subcontinent, Arab, Polynesian, Latin American countries, and Africa will further improve these equations in the future.
doi:10.1183/09031936.00080312
PMCID: PMC3786581  PMID: 22743675
14.  Randomized, placebo-controlled, calcium supplementation trial in pregnant Gambian women accustomed to a low calcium intake: effects on maternal blood pressure and infant growth1234 
Background: Dietary calcium intake in rural Gambian women is very low (∼350 mg/d) compared with international recommendations. Studies have suggested that calcium supplementation of women receiving low-calcium diets significantly reduces risk of pregnancy hypertension.
Objective: We tested the effects on blood pressure (BP) of calcium carbonate supplementation (1500 mg Ca/d) in pregnant, rural Gambian women.
Design: The study was a randomized, double-blind, parallel, placebo-controlled supplementation trial from 20 wk of gestation (P20) until delivery (calcium: n = 330; placebo; n = 332). BP and anthropometric measures were taken at P20 and then 4 weekly until 36 wk of gestation (P36), and infant anthropometric measures were taken at 2, 13, and 52 wk postdelivery.
Results: A total of 525 (calcium: n = 260; placebo: n = 265) women had BP measured at P36 and subsequently delivered a healthy term singleton infant. Mean compliance was 97%, and urinary calcium measures confirmed the group allocation. At P20, the mean (±SD) systolic blood pressure (SBP) was 101.2 ± 9.0 and 102.1 ± 9.3 mm Hg, and diastolic blood pressure (DBP) was 54.5 ± 7.3 and 55.8 ± 7.8 mm Hg, in the calcium and placebo groups, respectively. The intention-to-treat analysis that was adjusted for confounders showed no significant effect of calcium supplementation on the change between P20 and P36 (calcium compared with placebo; mean ± SEM) in SBP (−0.64 ± 0.65%; P = 0.3) or DBP (−0.22 ± 1.15%; P = 0.8). There was no significant effect of supplementation on BP, pregnancy weight gain, weight postpartum, or infant weight, length, and other measures of growth. However, the comparability of the original randomly assigned groups may have been compromised by the exclusion of 20.7% of women from the final analysis.
Conclusions: Calcium supplementation did not affect BP in pregnancy. This result may have been because the Gambian women were adapted to a low dietary calcium intake, and/or obesity, high gestational weight gain, high underlying BP, tobacco use, alcohol consumption, and sedentary lifestyles were rare. This trial was registered at the International Standard Randomized Controlled Trial Register (www.controlled-trials.com/mrct/) as ISRCTN96502494.
doi:10.3945/ajcn.113.059923
PMCID: PMC3778867  PMID: 24004887
15.  Unexpected long-term effects of calcium supplementation in pregnancy on maternal bone outcomes in women with a low calcium intake: a follow-up study123 
Background: Calcium supplementation of pregnant Gambian women with a low calcium intake results in lower maternal bone mineral content in the subsequent lactation.
Objective: The objective was to investigate whether the lower bone mineral content persists long term.
Design: All women in the calcium supplementation trial (International Trial Registry ISRCTN96502494) who had been scanned with dual-energy X-ray absorptiometry at 52 wk of lactation (L52; n = 79) were invited for follow-up when neither pregnant nor lactating for ≥3 mo (NPNL) or at 52 wk postpartum in a future lactation (F52). Bone scans and anthropometric and dietary assessments were conducted.
Results: Sixty-eight women participated (35 at both NPNL and F52 and 33 at only one time point): n = 59 NPNL (n = 31 calcium, n = 28 placebo) and n = 44 F52 (n = 24 calcium, n = 20 placebo). The mean (±SD) time from L52 was 4.9 ± 1.9 y for NPNL and 5.0 ± 1.3 y for F52. Size-adjusted bone mineral content (SA-BMC) was greater at NPNL than at L52 in the placebo group (P ≤ 0.001) but not in the calcium group (P for time-by-group interaction: lumbar spine, 0.002; total hip, 0.03; whole body, 0.03). No significant changes in SA-BMC from L52 to F52 were observed in either group. Consequently, the lower SA-BMC in the calcium group at L52 persisted at NPNL and F52 (P ≤ 0.001): NPNL (lumbar spine, −7.5 ± 0.7%; total hip, −10.5 ± 1.0%; whole body, −3.6 ± 0.5%) and F52 (lumbar spine, −6.2 ± 0.9%; total hip, −10.3 ± 1.4%; whole body, −3.2 ± 0.6%).
Conclusion: In rural Gambian women with a low-calcium diet, a calcium supplement of 1500 mg/d during pregnancy resulted in lower maternal bone mineral content in the subsequent lactation that persisted long term. This trial was registered at www/controlled-trials.com/mrct/ as ISRCTN96502494.
doi:10.3945/ajcn.113.061630
PMCID: PMC3743734  PMID: 23902782
16.  How active are our children? Findings from the Millennium Cohort Study 
BMJ Open  2013;3(8):e002893.
Objective
To describe levels of physical activity, sedentary time and adherence to Chief Medical Officers (CMO) physical activity guidelines among primary school-aged children across the UK using objective accelerometer-based measurements.
Design
Nationally representative prospective cohort study.
Setting
Children born across the UK, between 2000 and 2002.
Participants
6497 7-year-old to 8-year-old singleton children for whom reliable accelerometer data were available for at least 10 h a day for at least 2 days.
Main outcome measures
Physical activity in counts per minute (cpm); time spent in sedentary and moderate-to-vigorous intensity physical activity (MVPA); proportion of children meeting CMO guidelines (≥60 min/day MVPA); average daily steps.
Explanatory measures
Gender, ethnicity, maternal current/most recent occupation, lone parenthood status, number of children in the household and country/region of residence.
Results
The median daily physical activity level was 595 cpm (IQR 507, 697). Children spent a median of 60 min (IQR 47–76) in MVPA/day and were sedentary for a median of 6.4 h/day (IQR 6–7). Only 51% met CMO guidelines, with girls (38%) less active than boys (63%). Children took an average of 10 229 (95% CI (8777 to 11 775)) steps each day. Children of Indian ethnicity were significantly less active overall than all other ethnic groups. Children of Bangladeshi origin and those living in Northern Ireland were least likely to meet CMO guidelines.
Conclusions
Only half of 7-year-old children in the UK achieve recommended levels of physical activity, with significant gender, ethnic and geographic variations. Longitudinal studies are needed to better understand the relevance of these (in)activity patterns for long-term health and well-being. In the meantime population-wide efforts to boost physical activity among young people are needed which are likely to require a broad range of policy interventions.
doi:10.1136/bmjopen-2013-002893
PMCID: PMC3752053  PMID: 23965931
Public Health; Sports Medicine; Paediatrics
17.  Designing the new UK-WHO growth charts to enhance assessment of growth around birth 
The decision to adopt the new WHO standard in the UK necessitated substantial changes to the neonatal section of the chart, including separation of the preterm UK birthweight reference from the WHO standard. The evidence-based design process has led to several novel features that could be generally applied in other chart designs, and revealed uncertainties leading to inconsistencies in charting. Failing to plot birthweight of term infants at age 0 can lead to spurious centile crossing in the early weeks of life, particularly among infants at the extreme of gestation. Users will need training to use the charts, but this should improve overall understanding and use of charts.
doi:10.1136/adc.2010.205864
PMCID: PMC3546314  PMID: 21398325
18.  Human Life History Evolution Explains Dissociation between the Timing of Tooth Eruption and Peak Rates of Root Growth 
PLoS ONE  2013;8(1):e54534.
We explored the relationship between growth in tooth root length and the modern human extended period of childhood. Tooth roots provide support to counter chewing forces and so it is advantageous to grow roots quickly to allow teeth to erupt into function as early as possible. Growth in tooth root length occurs with a characteristic spurt or peak in rate sometime between tooth crown completion and root apex closure. Here we show that in Pan troglodytes the peak in root growth rate coincides with the period of time teeth are erupting into function. However, the timing of peak root velocity in modern humans occurs earlier than expected and coincides better with estimates for tooth eruption times in Homo erectus. With more time to grow longer roots prior to eruption and smaller teeth that now require less support at the time they come into function, the root growth spurt no longer confers any advantage in modern humans. We suggest that a prolonged life history schedule eventually neutralised this adaptation some time after the appearance of Homo erectus. The root spurt persists in modern humans as an intrinsic marker event that shows selection operated, not primarily on tooth tissue growth, but on the process of tooth eruption. This demonstrates the overarching influence of life history evolution on several aspects of dental development. These new insights into tooth root growth now provide an additional line of enquiry that may contribute to future studies of more recent life history and dietary adaptations within the genus Homo.
doi:10.1371/journal.pone.0054534
PMCID: PMC3544739  PMID: 23342167
19.  Trade-Offs in Relative Limb Length among Peruvian Children: Extending the Thrifty Phenotype Hypothesis to Limb Proportions 
PLoS ONE  2012;7(12):e51795.
Background and Methods
Both the concept of ‘brain-sparing’ growth and associations between relative lower limb length, childhood environment and adult disease risk are well established. Furthermore, tibia length is suggested to be particularly plastic under conditions of environmental stress. The mechanisms responsible are uncertain, but three hypotheses may be relevant. The ‘thrifty phenotype’ assumes that some components of growth are selectively sacrificed to preserve more critical outcomes, like the brain. The ‘distal blood flow’ hypothesis assumes that blood nutrients decline with distance from the heart, and hence may affect limbs in relation to basic body geometry. Temperature adaptation predicts a gradient of decreased size along the limbs reflecting decreasing tissue temperature/blood flow. We examined these questions by comparing the size of body segments among Peruvian children born and raised in differentially stressful environments. In a cross-sectional sample of children aged 6 months to 14 years (n = 447) we measured head circumference, head-trunk height, total upper and lower limb lengths, and zeugopod (ulna and tibia) and autopod (hand and foot) lengths.
Results
Highland children (exposed to greater stress) had significantly shorter limbs and zeugopod and autopod elements than lowland children, while differences in head-trunk height were smaller. Zeugopod elements appeared most sensitive to environmental conditions, as they were relatively shorter among highland children than their respective autopod elements.
Discussion
The results suggest that functional traits (hand, foot, and head) may be partially protected at the expense of the tibia and ulna. The results do not fit the predictions of the distal blood flow and temperature adaptation models as explanations for relative limb segment growth under stress conditions. Rather, our data support the extension of the thrifty phenotype hypothesis to limb growth, and suggest that certain elements of limb growth may be sacrificed under tough conditions to buffer more functional traits.
doi:10.1371/journal.pone.0051795
PMCID: PMC3521697  PMID: 23272169
20.  Assessing the efficacy of the healthy eating and lifestyle programme (HELP) compared with enhanced standard care of the obese adolescent in the community: study protocol for a randomized controlled trial 
Trials  2011;12:242.
Background
The childhood obesity epidemic is one of the foremost UK health priorities. Childhood obesity tracks into adult life and places individuals at considerable risk for diabetes, cardiovascular disease, liver disease and other morbidities. There is widespread need for paediatric lifestyle programmes as change may be easier to accomplish in childhood than later in life.
Study Design/Method
The study will evaluate the management of adolescent obesity by conducting a Medical Research Council complex intervention phase III efficacy randomised clinical trial of the Healthy Eating Lifestyle Programme within primary care. The study tests a community delivered multi-component intervention designed for adolescents developed from best practice as identified by National Institute for Health and Clinical Excellence. The hospital based pilot reduced body mass index and improved health-related quality of life.
Subjects will be individually randomised to receiving either the Healthy Eating Lifestyle Programme (12 fortnightly family sessions) or enhanced standard care. Baseline and follow up assessments will be undertaken blind to allocation status. A health economic evaluation is also being conducted.
200 obese young people (13-17 years, body mass index > 98th centile for age and sex) will be recruited from primary care within the greater London area.
The primary hypothesis is that a motivational and solution-focused family-based weight management programme delivered over 6 months is more efficacious in reducing body mass index in obese adolescents identified in the community than enhanced standard care.
The primary outcome will be body mass index at the end of the intervention, adjusted for baseline body mass index, age and sex.
The secondary hypothesis is that the Healthy Eating Lifestyle Programme is more efficacious in improving quality of life and psychological function and reducing waist circumference and cardiovascular risk factors in obese adolescents than enhanced standard care assessed at 6 and 12 months post baseline assessment.
Improvement in quality of life predicts on-going lifestyle change and maximises the chances of long-term weight reduction. We will explore whether improvement in QOL may be intermediate on the pathway between the intervention and body mass index change.
Trial registration
ISRCTN: ISRCTN99840111
doi:10.1186/1745-6215-12-242
PMCID: PMC3267689  PMID: 22088133
21.  Genetic and Environmental Influences on Infant Growth: Prospective Analysis of the Gemini Twin Birth Cohort 
PLoS ONE  2011;6(5):e19918.
Objective
Infancy is a critical period during which rapid growth potentially programs future disease risk. Identifying the modifiable determinants of growth is therefore important. To capture the complexity of infant growth, we modeled growth trajectories from birth to six months in order to compare the genetic and environmental influences on growth trajectory parameters with single time-point measures at birth, three and six months of age.
Methods
Data were from Gemini, a population sample of 2402 UK families with twins. An average 10 weight measurements per child made by health professionals were available over the first six months. Weights at birth, three and six months were identified. Longitudinal growth trajectories were modeled using SITAR utilizing all available weight measures for each child. SITAR generates three parameters: size (characterizing mean weight throughout infancy), tempo (indicating age at peak weight velocity (PWV)), and velocity (reflecting the size of PWV). Genetic and environmental influences were estimated using quantitative genetic analysis.
Results
In line with previous studies, heritability of weight at birth and three months was low (38%), but it was higher at six months (62%). Heritability of the growth trajectory parameters was high for size (69%) and velocity (57%), but low (35%) for tempo. Common environmental influences predominated for tempo (42%).
Conclusion
Modeled growth parameters using SITAR indicated that size and velocity were primarily under genetic influence but tempo was predominantly environmentally determined. These results emphasize the importance of identifying specific modifiable environmental determinants of the timing of peak infant growth.
doi:10.1371/journal.pone.0019918
PMCID: PMC3103521  PMID: 21637764
22.  Effect of oxandrolone and timing of pubertal induction on final height in Turner’s syndrome: randomised, double blind, placebo controlled trial 
Objective To examine the effect of oxandrolone and the timing of pubertal induction on final height in girls with Turner’s syndrome receiving a standard dose of growth hormone.
Design Randomised, double blind, placebo controlled trial.
Setting 36 paediatric endocrinology departments in UK hospitals.
Participants Girls with Turner’s syndrome aged 7-13 years at recruitment, receiving recombinant growth hormone therapy (10 mg/m2/week).
Interventions Participants were randomised to oxandrolone (0.05 mg/kg/day, maximum 2.5 mg/day) or placebo from 9 years of age. Those with evidence of ovarian failure at 12 years were further randomised to oral ethinylestradiol (year 1, 2 µg daily; year 2, 4 μg daily; year 3, 4 months each of 6, 8, and 10 μg daily) or placebo; participants who received placebo and those recruited after the age of 12.25 years started ethinylestradiol at age 14.
Main outcome measure Final height.
Results 106 participants were recruited, of whom 14 withdrew and 82/92 reached final height. Both oxandrolone and late pubertal induction increased final height: by 4.6 (95% confidence interval 1.9 to 7.2) cm (P=0.001, n=82) for oxandrolone and 3.8 (0.0 to 7.5) cm (P=0.05, n=48) for late pubertal induction with ethinylestradiol. In the 48 children who were randomised twice, the effects on final height (compared with placebo and early induction of puberty) of oxandrolone alone, late induction alone, and oxandrolone plus late induction were similar, averaging 7.1 (3.4 to 10.8) cm (P<0.001). No cases of virilisation were reported.
Conclusion Oxandrolone had a positive effect on final height in girls with Turner’s syndrome treated with growth hormone, as did late pubertal induction with ethinylestradiol at age 14 years. However, these effects were not additive, so using both had no advantage. Oxandrolone could, therefore, be offered as an alternative to late pubertal induction for increasing final height in Turner’s syndrome.
Trial registration Current Controlled Trials ISRCTN50343149.
doi:10.1136/bmj.d1980
PMCID: PMC3076731  PMID: 21493672
23.  Association between Common Variation at the FTO Locus and Changes in Body Mass Index from Infancy to Late Childhood: The Complex Nature of Genetic Association through Growth and Development 
PLoS Genetics  2011;7(2):e1001307.
An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta-analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, p = 10−20) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10−23). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (−0.40% (95% CI: −0.74, −0.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (−4.72% (−5.81, −3.63), p = 10−17), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk.
Author Summary
Variation at the FTO locus is reliably associated with BMI and adiposity-related traits, but little is still known about the effects of variation at this gene, particularly in children. We have examined a large collection of samples for which both genotypes at rs9939609 and multiple measurements of BMI are available. We observe a positive association between the minor allele (A) at rs9939609 and BMI emerging in childhood that has the characteristics of a shift in the age scale leading simultaneously to lower BMI during infancy and higher BMI in childhood. Assessed in cross section and longitudinally, we find evidence of variation at rs9939609 being associated with the timing of AR and the concert of events expected with such a change to the BMI curve. Importantly, the apparently negative association between the minor allele (A) and BMI in early life, which is then followed by an earlier AR and greater BMI in childhood, is a pattern known to be associated with both the risk of adult BMI and metabolic disorders such as type 2 diabetes (T2D). These findings are important in our understanding of the contribution of FTO to adiposity, but also in light of efforts to appreciate genetic effects in a lifecourse context.
doi:10.1371/journal.pgen.1001307
PMCID: PMC3040655  PMID: 21379325
24.  SITAR—a useful instrument for growth curve analysis 
Background Growth curve analysis is a statistical issue in life course epidemiology. Height in puberty involves a growth spurt, the timing and intensity of which varies between individuals. Such data can be summarized with individual Preece–Baines (PB) curves, and their five parameters then related to earlier exposures or later outcomes. But it involves fitting many curves.
Methods We present an alternative SuperImposition by Translation And Rotation (SITAR) model, a shape invariant model with a single fitted curve. Curves for individuals are matched to the mean curve by shifting their curve up–down (representing differences in mean size) and left–right (for differences in growth tempo), and the age scale is also shrunk or stretched to indicate how fast time passes in the individual (i.e. velocity). These three parameters per individual are estimated as random effects while fitting the curve. The outcome is a mean curve plus triplets of parameters per individual (size, tempo and velocity) that summarize the individual growth patterns. The data are heights for Christ’s Hospital School (CHS) boys aged 9–19 years (N = 3245, n = 129 508), and girls with Turner syndrome (TS) aged 9–18 years from the UK Turner Study (N = 105, n = 1321).
Results The SITAR model explained 99% of the variance in both datasets [residual standard deviation (RSD) 6–7 mm], matching the fit of individually-fitted PB curves. In CHS, growth tempo was associated with insulin-like growth factor-1 measured 50 years later (P = 0.01, N = 1009). For the girls with TS randomized to receive oxandrolone from 9 years, velocity was substantially increased compared with placebo (P = 10−8).
Conclusions The SITAR growth curve model is a useful epidemiological instrument for the analysis of height in puberty.
doi:10.1093/ije/dyq115
PMCID: PMC2992626  PMID: 20647267
Height; puberty; Turner syndrome; growth curve; random effects
25.  An ecological systems approach to examining risk factors for early childhood overweight: findings from the UK Millennium Cohort Study 
Objective
To use an ecological systems approach to examine individual-, family-, community-, and area-level risk factors for overweight (including obesity) in 3-year-old children.
Design
Prospective nationally representative cohort study
Setting
England, Wales, Scotland, Northern Ireland
Participants
13 188 singleton children age three in the Millennium Cohort Study, born between 2000 and 2002, who had complete height/weight data
Main outcome measure
Childhood overweight (including obesity) defined by the International Obesity TaskForce cut-offs for body mass index
Results
23.0% of 3-year-old children were overweight or obese. In the fully adjusted model, primarily individual- and family-level factors were associated with early childhood overweight: birthweight z-score (adjusted odds ratio, 1.36, 95% CI 1.30 to 1.42), Black ethnicity (1.41, 1.11 to 1.80) (compared to white), introduction to solid foods <4 months (1.12, 1.02 to 1.23), lone motherhood (1.32, 1.15 to 1.51), smoking during pregnancy (1-9 cigarettes daily: 1.34, 1.17 to 1.54; 10-19: 1.49, 1.26 to 1.75; 20+: 1.34, 1.05 to 1.70), parental overweight (both: 1.89, 1.63 to 2.19; father only: 1.45, 1.28 to 1.63; mother only: 1.37, 1.18 to 1.58), prepregnancy overweight (1.28, 1.14 to 1.45), and maternal employment ≥21 hours/week (1.23, 1.10 to 1.37) (compared to never worked). Breastfeeding ≥4 months (0.86, 0.76 to 0.97) (compared to none) and Indian ethnicity (0.63, 0.42 to 0.94) were associated with a decreased risk of early childhood overweight. Children from Wales were also more likely to be overweight than children from England.
Conclusions
Most risk factors for early childhood overweight are modifiable or would allow at-risk groups to be identified. Policies and interventions should focus on parents and providing them with an environment to support healthy behaviours for themselves and their children.
doi:10.1136/jech.2008.077917
PMCID: PMC2678539  PMID: 18801795
obesity; preschool children; parents

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