Growth reference charts for children with hypochondroplasia.

Hypochondroplasia (HCH) is a rare skeletal dysplasia causing mild short stature. There is a paucity of growth reference charts for this population. Anthropometric data were collected to generate height, weight, and head circumference (HC) growth reference charts for children with a diagnosis of HCH. Mixed longitudinal anthropometric data and genetic analysis results were collected from 14 European specialized skeletal dysplasia centers. Growth charts were generated using Generalized Additive Models for Location, Scale, and Shape. Measurements for height (983), weight (896), and HC (389) were collected from 188 (79 female) children with a diagnosis of HCH aged 0-18 years. Of the 84 children who underwent genetic testing, a pathogenic variant in FGFR3 was identified in 92% (77). The data were used to generate growth references for height, weight, and HC, plotted as charts with seven centiles from 2nd to 98th, for ages 0-4 and 0-16 years. HCH-specific growth charts are important in the clinical care of these children. They help to identify if other comorbidities are present that affect growth and development and serve as an important benchmark for any prospective interventional research studies and trials.

Post-malnutrition growth and its associations with child survival and non-communicable disease risk: a secondary analysis of the Malawi 'ChroSAM' cohort.

OBJECTIVE: To explore patterns of post-malnutrition growth (PMGr) during and after treatment for severe malnutrition and describe associations with survival and non-communicable disease (NCD) risk 7 years post-treatment. DESIGN: Six indicators of PMGr were derived based on a variety of timepoints, weight, weight-for-age z-score and height-for-age z-score (HAZ). Three categorisation methods included no categorisation, quintiles and latent class analysis (LCA). Associations with mortality risk and seven NCD indicators were analysed. SETTING: Secondary data from Blantyre, Malawi between 2006 and 2014. PARTICIPANTS: A cohort of 1024 children treated for severe malnutrition (weight-for-length z-score < 70 % median and/or MUAC (mid-upper arm circumference) < 110 mm and/or bilateral oedema) at ages 5-168 months. RESULTS: Faster weight gain during treatment (g/d) and after treatment (g/kg/day) was associated with lower risk of death (adjusted OR 0·99, 95 % CI 0·99, 1·00; and adjusted OR 0·91, 95 % CI 0·87, 0·94, respectively). In survivors (mean age 9 years), it was associated with greater hand grip strength (0·02, 95 % CI 0·00, 0·03) and larger HAZ (6·62, 95 % CI 1·31, 11·9), both indicators of better health. However, faster weight gain was also associated with increased waist:hip ratio (0·02, 95 % CI 0·01, 0·03), an indicator of later-life NCD risk. The clearest patterns of association were seen when defining PMGr based on weight gain in g/d during treatment and using the LCA method to describe growth patterns. Weight deficit at admission was a major confounder. CONCLUSIONS: A complex pattern of benefits and risks is associated with faster PMGr. Both initial weight deficit and rate of weight gain have important implications for future health.

Preterm birth and subsequent timing of pubertal growth, menarche, and voice break.

BACKGROUND: We evaluated pubertal growth and pubertal timing of participants born preterm compared to those born at term. METHODS: In the ESTER Preterm Birth Study, we collected growth data and measured final height of men/women born very or moderately preterm (<34 gestational weeks, n = 52/55), late preterm (34-<37 weeks, 94/106), and term (≥37 weeks, 131/151), resulting in median 9 measurements at ≥6 years. Timing of menarche or voice break was self-reported. Peak height velocity (PHV, cm/year) and age at PHV (years) were compared with SuperImposition by Translation And Rotation (SITAR) model (sexes separately). RESULTS: Age at PHV (years) and PHV (cm/year) were similar in all gestational age groups. Compared to term controls, insignificant differences in age at PHV were 0.1 (95% CI: -0.2 to 0.4) years/0.2 (-0.1 to 0.4) for very or moderately/late preterm born men and -0.0 (-0.3 to 0.3)/-0.0 (-0.3 to 0.2) for women, respectively. Being born small for gestational age was not associated with pubertal growth. Age at menarche or voice break was similar in all the gestational age groups. CONCLUSIONS: Timing of pubertal growth and age at menarche or voice break were similar in participants born preterm and at term. IMPACT: Pubertal growth and pubertal timing were similar in preterm and term participants in a relatively large cohort with a wide range of gestational ages. Previous literature indicates that small for gestational age is a risk for early puberty in term born children. This was not shown in preterm children. While our study had limited power for children born very preterm, all children born preterm were not at increased risk for early puberty.

Using linear and natural cubic splines, SITAR, and latent trajectory models to characterise nonlinear longitudinal growth trajectories in cohort studies.

BACKGROUND: Longitudinal data analysis can improve our understanding of the influences on health trajectories across the life-course. There are a variety of statistical models which can be used, and their fitting and interpretation can be complex, particularly where there is a nonlinear trajectory. Our aim was to provide an accessible guide along with applied examples to using four sophisticated modelling procedures for describing nonlinear growth trajectories. METHODS: This expository paper provides an illustrative guide to summarising nonlinear growth trajectories for repeatedly measured continuous outcomes using (i) linear spline and (ii) natural cubic spline linear mixed-effects (LME) models, (iii) Super Imposition by Translation and Rotation (SITAR) nonlinear mixed effects models, and (iv) latent trajectory models. The underlying model for each approach, their similarities and differences, and their advantages and disadvantages are described. Their application and correct interpretation of their results is illustrated by analysing repeated bone mass measures to characterise bone growth patterns and their sex differences in three cohort studies from the UK, USA, and Canada comprising 8500 individuals and 37,000 measurements from ages 5-40 years. Recommendations for choosing a modelling approach are provided along with a discussion and signposting on further modelling extensions for analysing trajectory exposures and outcomes, and multiple cohorts. RESULTS: Linear and natural cubic spline LME models and SITAR provided similar summary of the mean bone growth trajectory and growth velocity, and the sex differences in growth patterns. Growth velocity (in grams/year) peaked during adolescence, and peaked earlier in females than males e.g., mean age at peak bone mineral content accrual from multicohort SITAR models was 12.2 years in females and 13.9 years in males. Latent trajectory models (with trajectory shapes estimated using a natural cubic spline) identified up to four subgroups of individuals with distinct trajectories throughout adolescence. CONCLUSIONS: LME models with linear and natural cubic splines, SITAR, and latent trajectory models are useful for describing nonlinear growth trajectories, and these methods can be adapted for other complex traits. Choice of method depends on the research aims, complexity of the trajectory, and available data. Scripts and synthetic datasets are provided for readers to replicate trajectory modelling and visualisation using the R statistical computing software.

Assessment of height growth in Indian children using growth centiles and growth curves.

BACKGROUND: Growth centiles and growth curves are two ways to present child anthropometry; however, they differ in the type of data used, the method of analysis, the biological parameters fitted and the form of interpretation. AIM: To fit and compare height growth centiles and curves in Indian children. SUBJECTS AND METHODS: 1468 children (796 boys) from Pune India aged 6-18 years with longitudinal data on age and height (n = 7781) were analysed using GAMLSS (Generalised Additive Models for Location Scale and Shape) for growth centiles, and SITAR (SuperImposition by Rotation and Translation) for growth curves. RESULTS: SITAR explained 98.7% and 98.8% of the height variance in boys and girls, with mean age at peak height velocity 13.1 and 11.0 years, and mean peak velocity 9.0 and 8.0 cm/year, respectively. GAMLSS (Box-Cox Cole Green model) also captured the pubertal growth spurt but the centiles were shallower than the SITAR mean curve. Boys showed a mid-growth spurt at age 8 years. CONCLUSION: GAMLSS displays the distribution of height in the population by age and sex, while SITAR effectively and parsimoniously summarises the pattern of height growth in individual children. The two approaches provide distinct, useful information about child growth.

Craniofacial growth and SITAR growth curve analysis.

BACKGROUND: SITAR (SuperImposition by Translation And Rotation) is a shape invariant growth curve model that effectively summarizes somatic growth in puberty. AIM: To apply the SITAR model to longitudinal mandibular growth data to clarify its suitability to facial growth analysis. SUBJECTS AND METHODS: 2D-cephalometric data on two mandibular measurements (AP: articulare-pogonion; CP: condylion-pogonion) were selected from the Denver Growth Study, consisting of longitudinal records (age range: 7.9-19.0 years) of females (sample size N: 21; number of radiographs n: 154) and males (N: 18; n: 137). The SITAR mixed effects model estimated, for each measurement and gender separately, a mean growth curve versus chronological age, along with mean age at peak velocity (APV) and peak velocity (PV), plus subject-specific random effects for PV and mean size. The models were also fitted versus Greulich-Pyle bone age. RESULTS: In males, mean APV occurred at 14.6 years (AP) and 14.4 years (CP), with mean PV 3.1 mm/year (AP) and 3.3 mm/year (CP). In females, APV occurred at 11.6 years (AP and CP), with mean PV 2.3 mm/year (AP) and 2.4 mm/year (CP). The models explained 95-96 per cent of the cross-sectional variance for males and 92-93 per cent for females. The random effects demonstrated standard deviations (SDs) in size of 5.6 mm for males and 3.9 mm for females, and SDs for PV between 0.3 and 0.5 mm/year. The bone age results were similar. CONCLUSION: The SITAR model is a useful tool to analyse epidemiological craniofacial growth based on cephalometric data and provides an array of information on pubertal mandibular growth and its variance in a concise manner.

Duration of obesity exposure between ages 10 and 40 years and its relationship with cardiometabolic disease risk factors: A cohort study.

BACKGROUND: Individuals with obesity do not represent a homogeneous group in terms of cardiometabolic risk. Using 3 nationally representative British birth cohorts, we investigated whether the duration of obesity was related to heterogeneity in cardiometabolic risk. METHODS AND FINDINGS: We used harmonised body mass index (BMI) and cardiometabolic disease risk factor data from 20,746 participants (49.1% male and 97.2% white British) enrolled in 3 British birth cohort studies: the 1946 National Survey of Health and Development (NSHD), the 1958 National Child Development Study (NCDS), and the 1970 British Cohort Study (BCS70). Within each cohort, individual life course BMI trajectories were created between 10 and 40 years of age, and from these, age of obesity onset, duration spent obese (range 0 to 30 years), and cumulative obesity severity were derived. Obesity duration was examined in relation to a number of cardiometabolic disease risk factors collected in mid-adulthood: systolic (SBP) and diastolic blood pressure (DBP), high-density-lipoprotein cholesterol (HDL-C), and glycated haemoglobin (HbA1c). A greater obesity duration was associated with worse values for all cardiometabolic disease risk factors. The strongest association with obesity duration was for HbA1c: HbA1c levels in those with obesity for <5 years were relatively higher by 5% (95% CI: 4, 6), compared with never obese, increasing to 20% (95% CI: 17, 23) higher in those with obesity for 20 to 30 years. When adjustment was made for obesity severity, the association with obesity duration was largely attenuated for SBP, DBP, and HDL-C. For HbA1c, however, the association with obesity duration persisted, independent of obesity severity. Due to pooling of 3 cohorts and thus the availability of only a limited number harmonised variables across cohorts, our models included adjustment for only a small number of potential confounding variables, meaning there is a possibility of residual confounding. CONCLUSIONS: Given that the obesity epidemic is characterised by a much earlier onset of obesity and consequently a greater lifetime exposure, our findings suggest that health policy recommendations aimed at preventing early obesity onset, and therefore reducing lifetime exposure, may help reduce the risk of diabetes, independently of obesity severity. However, to test the robustness of our observed associations, triangulation of evidence from different epidemiological approaches (e.g., mendelian randomization and negative control studies) should be obtained.

Distance and percentage distance from median BMI as alternatives to BMI z score.

BMI z (BMIz) score based on the Centers for Disease Control and Prevention growth charts is widely used, but it is inaccurate above the 97th percentile. We explored the performance of alternative metrics based on the absolute distance or % distance of a child's BMI from the median BMI for sex and age. We used longitudinal data from 5628 children who were first examined <12 years to compare the tracking of three BMI metrics: distance from median, % distance from median and % distance from median on a log scale. We also explored the effects of adjusting these metrics for age differences in the distribution of BMI. The intraclass correlation coefficient (ICC) was used to compare tracking of the metrics. Metrics based on % distance (whether on the original or log scale) yielded higher ICCs compared with distance from median. The ICCs of the age-adjusted metrics were higher than that of the unadjusted metrics, particularly among children who were (1) overweight or had obesity, (2) younger and (3) followed for >3 years. The ICCs of the age-adjusted metrics were also higher compared with that of BMIz among children who were overweight or obese. Unlike BMIz, these alternative metrics do not have an upper limit and can be used for assessing BMI in all children, even those with very high BMIs. The age-adjusted % from median (on a log or linear scale) works well for all ages, while unadjusted % from median is better limited to older children or short follow-up periods.

Developmental origins of variability in pelvic dimensions: Evidence from nulliparous South Asian women in the United Kingdom.

OBJECTIVES: Pelvic growth may be sensitive to early-life nutrition, with implications for maternal risk of obstructed labor. However, the "developmental origins" of adult pelvic variability require further investigation. We tested whether adult pelvic dimensions are associated with two components of height, indexing different periods of linear growth: tibia length, a proxy for early postnatal growth, and height-residual (height regressed on tibia length), a proxy for later growth. We also tested whether adult pelvic dimensions are associated with birth weight, a marker of nutritional investment in utero. METHODS: In this cross-sectional study, data were obtained on 68 nulliparous young women of South Asian ancestry. Pelvic dimensions (bi-iliac and bi-acetabular breadth, anteroposterior pelvic inlet and outlet, interspinous and intertuberous diameter) were measured using magnetic resonance imaging. Height and tibia length were measured manually. Birth weight and gestational age were obtained by recall. Multivariable regression models were fitted with a given pelvic dimension regressed on height-residual, tibia, and birth weight, with the latter adjusted for gestational age. RESULTS: Controlling for birth weight, height-residual was predictive of bi-acetabular breadth, bi-iliac breadth, and the pelvic inlet, while tibia length significantly predicted all dimensions except interspinous diameter. Controlling for the linear growth variables, birth weight was predictive of bi-iliac breadth only. CONCLUSIONS: Markers of linear growth during both early and later development were associated with adult pelvic dimensions, whereas size at birth was poorly predictive. Efforts to reduce stunting in early life may facilitate the attainment of maximum potential growth for both height and the pelvis.

Four decades of socio-economic inequality and secular change in the physical growth of Guatemalans.

OBJECTIVE: To investigate changes in socio-economic inequalities in growth in height, weight, BMI and grip strength in children born during 1955-1993 in Guatemala, a period of marked socio-economic-political change. DESIGN: We modelled longitudinal data on height, weight, BMI and hand grip strength using Super-Imposition by Translation and Rotation (SITAR). Internal Z-scores summarising growth size, timing and intensity (peak growth velocity, e.g. cm/year) were created to investigate inequalities by socio-economic position (SEP; measured by school attended). Interactions of SEP with date of birth were investigated to capture secular changes in inequalities. SETTING: Urban and peri-urban schools in the region of Guatemala City, Guatemala. PARTICIPANTS: Participants were 40 484 children and adolescents aged 3-19 years of Ladino and Maya ancestry (nobservations 157 067). RESULTS: The difference in height (SITAR size) between lowest and highest SEP decreased from -2·0 (95 % CI -2·2, -1·9) sd to -1·4 (95 % CI -1·5, -1·3) sd in males, and from -2·0 (95 % CI -2·1, -1·9) sd to -1·2 (95 % CI -1·3, -1·2) sd in females over the study period. Inequalities also reduced for weight, BMI and grip strength, due to greater secular increases in lowest-SEP groups. The puberty period was earlier and shorter in higher-SEP individuals (earlier SITAR timing and higher SITAR intensity). All SEP groups showed increases in BMI intensity over time. CONCLUSIONS: Inequality narrowed between the 1960s and 1990s. The lowest-SEP groups were still >1 sd shorter than the highest. Risks remain for reduced human capital and poorer population health for urban Guatemalans.