Pubertal growth in height, sitting height and leg length in achondroplasia.

Background: Children with achondroplasia (ACH) appear to lack a pubertal growth spurt in height.Aim To explore the growth spurt in height and its segments sitting height and leg length, in a large sample of ACH cases using growth curve modelling.Subjects and methods: Height and sitting height were measured longitudinally in ACH children, and the data were analysed using the SITAR (SuperImposition by Translation and Rotation) growth model, which estimates a mean growth curve and random effects for individuals defining differences in size, pubertal timing and intensity.Results: Out of 402 ACH children, 85 boys and 75 girls aged 7-20 years had respectively 529 and 454 measurements of height and sitting height, with leg length calculated by difference. SITAR analysis identified peaks in mean height velocity at 13.3 and 11.3 years in boys and girls, with peak velocities of 4.3 and 4.4 cm/year. Mean peak velocity for sitting height was 3.0 cm/year, but leg length showed no peak. The SITAR models explained 92% to 99% of the cross-sectional variance.Conclusion: ACH children do experience a growth spurt in puberty, but only half that of control children. The spurt is due entirely to sitting height, with no leg length spurt.

Tanner's tempo of growth in adolescence: recent SITAR insights with the Harpenden Growth Study and ALSPAC.

Background: James Tanner emphasised the "tempo" of growth, i.e. the adolescent spurt as summarised by its timing (age at peak velocity or APV) and intensity (peak velocity, PV).Aim: The paper applies the SITAR growth curve model to pubertal growth data with the aim of clarifying the growth pattern across multiple measurements and the spectrum of APV and PV.Subjects and methods: Data for 7-20 years on ten anthropometric measurements in 619 children from the Harpenden Growth Study, and on height in 10410 children from the ALSPAC study, were analysed using SITAR (SuperImposition by Translation And Rotation). SITAR models pubertal growth as a mean curve with APV and PV fitted as subject-specific random effects, and a random measurement intercept.Results: Mean APV for Harpenden girls and boys averaged 12.0 and 13.9 years across the ten measurements. PV expressed as percent per year lay in the narrow range 4-8%. Splitting the ALSPAC subjects into 9 by 5 APV and PV groups and fitting separate SITAR models to each group confirmed SITAR's good fit while highlighting the spectrum of growth patterns.Conclusion: SITAR works well to summarise pubertal growth. The disappointment is that Tanner did not live to see it in action.

Commentary: Methods for calculating growth trajectories and constructing growth centiles.

This commentary rounds off a collection of papers focusing on statistical methods for analysing growth data. In two papers, Anderson and colleagues discuss growth trajectory models in early life, using data on height and weight from the HBGDki initiative, while two papers from Ohuma and Altman review methods for centile construction, with data from the INTERGROWTH-21st project used to provide worked examples of centiles for birthweight and fetal head circumference. Anderson et al focus on four growth trajectory models: quadratic Laird-Ware, SITAR, brokenstick, and FACE, where the latter two fit better than the former two applied to length data in individuals. On this basis, they recommend brokenstick and FACE for future work. However, they do not discuss the timescale on which the growth models assess growth faltering nor the relevance of this timescale to later health outcome. Models that best detect short-term fluctuations in growth (brokenstick and FACE) may not necessarily be best at predicting later outcome. It is premature to exclude the quadratic Laird-Ware or SITAR models, which give a parsimonious summary of growth in individuals over a longer timescale. Ohuma and Altman highlight the poor quality of reporting in fetal centile studies, and they provide recommendations for good practice. Their birthweight centiles example illustrates both the power of the GAMLSS software and its capacity for misuse. The longitudinal fetal head circumference centiles are biased such that 5% of infants are below the 3rd centile and 5% above the 97th .

Fifty years of child height and weight in Japan and South Korea: Contrasting secular trend patterns analyzed by SITAR.

Objectives Japanese and South Koreans have traditionally been shorter than Europeans, but have recently become appreciably taller. The aim was to quantify the secular trend patterns in height and weight growth in the two countries over 50 years using the SITAR growth curve model. Methods Data on mean height and weight by sex in 1-year age groups from 1 to 20 years were obtained by decade in South Korea (1965-2005) and Japan (1950-2010). The data were analyzed using SITAR (SuperImposition by Translation And Rotation), which estimates a mean curve and three adjustments-size, timing and intensity-reflecting how the individual surveys differ from the mean. A sensitivity analysis compared results for the Japanese data based on cohort as well as period. Results Growth patterns in the two countries changed dramatically over the study period, affecting not only height and weight but also developmental age, in that the growth period advanced in timing and shrank in duration. SITAR fitted the data well. The trends were larger in South Korea than Japan, and puberty timing in Japan stabilized by 1970. Most of the height increment seen in adults had already accrued by age 1.5 years, whereas the adult weight increment accrued throughout childhood. Conclusions The secular height trend in these countries represents increased growth in the long bones during infancy, so it can be viewed as the inverse of stunting. There are striking country differences in growth pattern, but they are not easily explained by differences in national income, diet or lifestyle.

The effect of galsulfase enzyme replacement therapy on the growth of patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome).

Mucopolysaccharidosis (MPS) VI is an autosomal recessive lysosomal storage disorder arising from deficient activity of N-acetylgalactosamine-4-sulfatase (arylsulfatase B) and subsequent intracellular accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin-4-sulfate. Manifestations are multi-systemic and include skeletal abnormalities such as dysostosis multiplex and short stature. Reference height-for-age growth charts for treatment-naïve MPS VI patients have been published for both the slowly and rapidly progressing populations. Categorization of disease progression for these charts was based on urinary GAG (uGAG) level; high (>200µg/mg creatinine) levels identified subjects as rapidly progressing. Height data for 141 patients who began galsulfase treatment by the age of 18years were collected and stratified by baseline uGAG level and age at ERT initiation in 3-year increments. The reference MPS VI growth charts were used to calculate change in Z-score from pre-treatment baseline to last follow-up. Among patients with high baseline uGAG levels, galsulfase ERT was associated with an increase in Z-score for those beginning treatment at 0-3, >3-6, >6-9, >9-12, and >12-15years of age (p<0.05). Increases in Z-score were not detected for patients who began treatment between 15 and 18years of age, nor for patients with low (≤200µg/mg creatinine) baseline uGAG levels, regardless of age at treatment initiation. The largest positive deviation from untreated reference populations was seen in the high uGAG excretion groups who began treatment by 6years of age, suggesting an age- and severity-dependent impact of galsulfase ERT on growth.

The relationship between Insulin-like Growth Factor 1, sex steroids and timing of the pubertal growth spurt.

OBJECTIVE: Progress through puberty involves a complex hormonal cascade, but the individual contributions of hormones, particularly IGF-1, are unknown. We reanalysed Chard growth study data to explore the tempo of puberty based on changes in both height and hormone levels, using a novel method of growth curve analysis. DESIGN AND SUBJECTS: Schoolboys (n = 54) and girls (n = 70) from Chard, Somerset, England, recruited in 1981 at age 8/9 and followed to age 16. MEASUREMENTS: Every 6 months, height and Tanner stages (genitalia, breast, pubic hair) were recorded, and in a subsample (24 boys, 27 girls), blood samples were taken. Serum IGF-1, testosterone (boys) and oestradiol (girls) were measured by radioimmunoassay. Individual growth curves for each outcome were analysed using variants of the super-imposition by translation and rotation (SITAR) method, which estimates a mean curve and subject-specific random effects corresponding to size, and age and magnitude of peak velocity. RESULTS: The SITAR models fitted the data well, explaining 99%, 65%, 86% and 47% of variance for height, IGF-1, testosterone and oestradiol, respectively, and 69-88% for the Tanner stages. During puberty, the variables all increased steeply in value in individuals, the ages at peak velocity for the different variables being highly correlated, particularly for IGF-1 vs height (r = 0·74 for girls, 0·92 for boys). CONCLUSIONS: IGF-1, like height, the sex steroids and Tanner stages, rises steeply in individuals during puberty, with the timings of the rises tightly synchronized within individuals. This suggests that IGF-1 may play an important role in determining the timing of puberty.

The evidential value of developmental age imaging for assessing age of majority.

AIM: To consider the evidential value of developmental age images for identifying age of majority. METHODS: The published literature on hand-wrist X-rays, MRI scans of the distal radius and orthopantomograms of the lower left third molar is considered in terms of the mean age of attainment of the adult appearance and the diagnostic test performance of the adult appearance to predict adult status, either administratively (under-17 football) or forensically. RESULTS: The mean age of attainment of a mature hand-wrist X-ray is under 18 years and most individuals are mature before age 18. For the MRI wrist scan and the third molar the age of attainment is over 19 years and the adult appearance is an indicator of adulthood, while the immature appearance is uninformative about likely age. So MRI and third molars have high specificity, but low sensitivity. CONCLUSIONS: Bone age assessed by hand-wrist X-ray is uninformative and should not be used. The adult appearance of MRI wrist scans and third molars provide evidence of being over-age, although there remains a small risk of minors being misclassified as adult. The immature appearance is uninformative about likely age and, overall, more than one third of assessments are wrong.

Height, adiposity and hormonal cardiovascular risk markers in childhood: how to partition the associations?

OBJECTIVE: Obesity is associated with rapid growth during childhood. There is uncertainty over how to adjust for body size, when using adiposity as a proxy for cardiovascular risk. We studied associations of height, body composition (by dual-energy X-ray absorptiometry) and cardiovascular risk markers (insulin resistance (IR), leptin) in children. METHODS: Using partial correlations in 172 children aged 7-12 years, we investigated associations of (a) fat mass with IR or leptin, adjusting for height or lean mass, and (b) height or lean mass with IR or leptin, adjusting for fat mass. Analyses were conducted both cross-sectionally at each age, and for changes between 7 and 12 years. RESULTS: Height, fat mass, lean mass, IR and leptin were all inter-correlated at all ages. Although fat mass was strongly associated with IR and leptin, height was independently negatively associated with leptin (whole sample, adjusting for age: boys r=-0.12, girls r=-0.13; P<0.001). Independent of adiposity, height was also associated with insulin IR (whole sample, adjusting for age: boys r=0.11, girls r=0.20; P<0.001). When analysed by year of age, these associations tended to remain significant at older ages. Change in height from 7 to 12 years was also associated with change in IR (boys: r=0.18, P<0.05; girls: r=0.34, P<0.01), independently of change in adiposity, with similar findings for lean mass. CONCLUSIONS: During childhood, markers of cardiovascular risk have a complex profile, associated with growth as well as fat accumulation. Taller and faster-growing children have elevated risk markers, independently of their adiposity. These findings have implications for the interpretation of pediatric indices of adiposity that aim to adjust for body size. Adiposity indices that perform best at summarizing metabolic risk may not be those that perform best at understanding the developmental aetiology of risk.

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 programme 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 (interquartile range=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 (s.d.=2.2, range=4-20). Growth trajectories were modelled using SuperImposition by Translation And Rotation (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% (s.e.=1.3%) and delayed growth tempo by 1.0 (s.e.=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% (s.e.=1.1%) and smaller size by 102 g (s.e.=25 g). 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.

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=9563 with complete data from 1788 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) 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 m(-2) (s.e.=0.021, P<0.0001), zBMI reduced by mean 0.18 (s.e.=0.0038, P<0.0001), self-esteem score increased by 3.53 U (s.e.=0.13, P<0.0001) and psychological distress score decreased by 2.65 U (s.e.=0.31, P<0.0001). Change in outcomes varied by participant, family, neighbourhood and programme factors. Generally, outcomes improved less among children from less advantaged backgrounds and in Asian compared with 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.

A mixed effects model to estimate timing and intensity of pubertal growth from height and secondary sexual characteristics.

AIM: To estimate and compare pubertal growth timing and intensity in height, Tanner stage markers and testis volume. SUBJECTS AND METHODS: Data on height, genital stage, breast stage and pubic hair stage, testis volume and menarche in 103 boys and 74 girls from the Edinburgh Longitudinal Growth Study were analysed. The SITAR model for height and a novel mixed effects logistic model for Tanner stage and testis volume provided estimates of peak velocity (PV, intensity) and age at peak velocity (APV, timing), both overall (from fixed effects) and for individuals (random effects). RESULTS: Based on the six markers, mean APV was 13.0-14.0 years in boys and 12.0-13.1 years in girls, with between-subject standard deviations of ~1 year. PV for height was 8-9 cm/year by sex and for testis volume 6 ml/year, while Tanner stage increased by 1.2-1.8 stages per year at its peak. The correlations across markers for APV were 0.6-0.8 for boys and 0.8-0.92 for girls, very significantly higher for girls (p = 0.005). Correlations for PV were lower, -0.2-0.6. CONCLUSIONS: The mixed effects models perform well in estimating timing and intensity in individuals across several puberty markers. Age at peak velocity correlates highly across markers, but peak velocity less so.

Childhood psychological function and obesity risk across the lifecourse: findings from the 1970 British Cohort Study.

BACKGROUND: Psychological comorbidities of obesity are well recognised. However, the role of childhood psychological problems in the aetiology of later obesity has been little studied. DESIGN: Secondary analyses of a national birth cohort (1970 British Cohort Study). ANALYSIS: Logistic regression models to predict obesity risk at 26, 30 and 34 years related to hypothesised predictors: maternal and teacher reported child psychological function at 5 and 10 years (general behavioural, conduct, emotional or attentional/hyperactivity problems) and maternal psychological function. RESULTS: General behavioural problems at age 5 years increased the risk of obesity at 30 and 34 years. Persistence of these problems through childhood further increased the obesity risk. Inattention/hyperactivity at 10 years similarly increased risk of obesity at 30 years (adjusted odds ratios (AOR) 1.3). Chronic conduct problems at 5 and 10 years also increased the obesity risk at 30 years (AOR 1.6 (1.1, 2.4) P<0.05). Childhood emotional disorders and maternal psychological function were not associated with adult obesity. CONCLUSION: Children with early and persistent behavioural problems, particularly conduct problems, hyperactivity and inattention in early and mid-childhood are at an increased risk of obesity in adult life. The promotion of child and adolescent mental health and well-being may form an important part of future obesity prevention strategies. The promotion of healthy eating and activity should form part of secondary prevention and management strategies for children with disruptive behaviour disorders.

Medical, statistical, ethical and human rights considerations in the assessment of age in children and young people subject to immigration control.

BACKGROUND: Unprecedented changes in both the scale and the complexity of international migration have led to international concern and controversy over the assessment of age in children and young people subject to immigration control or seeking asylum who say they are children yet have no documents to prove their stated age. SOURCES OF DATA: The article reviews the existing evidence on the reliability of medical and non-medical techniques for the assessment of chronological age. AREAS OF AGREEMENT: There is evidence that radiography (X-rays) of bones and teeth, which is increasingly relied upon by immigration authorities, is imprecise, unethical and potentially unlawful, and should not be used for age assessment. AREAS OF CONTROVERSY: Medical techniques including X-rays continue to be relied upon in the absence of an alternative approach resulting in legal challenges and uncertainty for children and young people. AREAS TIMELY FOR DEVELOPING RESEARCH: Further work is needed to establish a process for age assessment based on a 'holistic' multi-disciplinary approach which focuses not on chronological age exclusively but rather on the needs of children and young people subject to immigration control.

The development of growth references and growth charts.

CONTEXT: De Montbeillard produced the first growth chart in the late 18(th) century. Since then, growth assessment has developed to become an essential component of child health practice. OBJECTIVE: To provide a brief history of (i) anthropometry, i.e. growth measurements; (ii) growth references, the statistical summary of anthropometry and (iii) growth charts, the visual representation of growth references for clinical use. METHODS: The major contributors in the three categories over the past 200 years were identified and their historical contributions put in context with more recent developments. RESULTS: Anthropometry was originally collected for administrative or public health purposes, its medical role emerging at the end of the 19(th) century. Growth reference data were collected in earnest from the 19(th) century, during which time the familiar statistical summary statistics-mean, SD, centiles-were developed. More advanced statistical methods emerged much later. Growth charts first appeared in the late 19(th) century and Tanner and Whitehouse later popularized the concepts of velocity and conditional references for growth in puberty. An important recent reference is the WHO growth standard, which documents optimal growth and has been adopted by many countries including the UK. Arising from it, the UK-WHO charts have pioneered many design features to improve usability and accuracy. CONCLUSION: Growth charts have developed considerably in 200 years and they represent an impressive synthesis of anthropometry, statistical summary and chart design.

Influence of secular trends and sample size on reference equations for lung function tests.

The aim of our study was to determine the contribution of secular trends and sample size to lung function reference equations, and establish the number of local subjects required to validate published reference values. 30 spirometry datasets collected between 1978 and 2009 provided data on healthy, white subjects: 19,291 males and 23,741 females aged 2.5-95 yrs. The best fit for forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) and FEV(1)/FVC as functions of age, height and sex were derived from the entire dataset using GAMLSS. Mean z-scores were calculated for individual datasets to determine inter-centre differences. This was repeated by subdividing one large dataset (3,683 males and 4,759 females) into 36 smaller subsets (comprising 18-227 individuals) to preclude differences due to population/technique. No secular trends were observed and differences between datasets comprising >1,000 subjects were small (maximum difference in FEV(1) and FVC from overall mean: 0.30- -0.22 z-scores). Subdividing one large dataset into smaller subsets reproduced the above sample size-related differences and revealed that at least 150 males and 150 females would be necessary to validate reference values to avoid spurious differences due to sampling error. Use of local controls to validate reference equations will rarely be practical due to the numbers required. Reference equations derived from large or collated datasets are recommended.

New aids for the non-invasive prenatal diagnosis of achondroplasia: dysmorphic features, charts of fetal size and molecular confirmation using cell-free fetal DNA in maternal plasma.

OBJECTIVES: To improve the prenatal diagnosis of achondroplasia by constructing charts of fetal size, defining frequency of sonographic features and exploring the role of non-invasive molecular diagnosis based on cell-free fetal deoxyribonucleic acid (DNA) in maternal plasma. METHODS: Data on fetuses with a confirmed diagnosis of achondroplasia were obtained from our databases, records reviewed, sonographic features and measurements determined and charts of fetal size constructed using the LMS (lambda-mu-sigma) method and compared with charts used in normal pregnancies. Cases referred to our regional genetics laboratory for molecular diagnosis using cell-free fetal DNA were identified and results reviewed. RESULTS: Twenty-six cases were scanned in our unit. Fetal size charts showed that femur length was usually on or below the 3(rd) centile by 25 weeks' gestation, and always below the 3(rd) by 30 weeks. Head circumference was above the 50(th) centile, increasing to above the 95(th) when compared with normal for the majority of fetuses. The abdominal circumference was also increased but to a lesser extent. Commonly reported sonographic features were bowing of the femora, frontal bossing, short fingers, a small chest and polyhydramnios. Analysis of cell-free fetal DNA in six pregnancies confirmed the presence of the c.1138G > A mutation in the FGRF3 gene in four cases with achondroplasia, but not the two subsequently found to be growth restricted. CONCLUSIONS: These data should improve the accuracy of diagnosis of achondroplasia based on sonographic findings, and have implications for targeted molecular confirmation that can reliably and safely be carried out using cell-free fetal DNA.