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.

The type II integral ER membrane protein VAP-B homolog in C. elegans is cleaved to release the N-terminal MSP domain to signal non-cell-autonomously.

VAMP/synaptobrevin-associated protein B (VAP-B) is a type II ER membrane protein, but its N-terminal MSP domain (MSPd) can be cleaved and secreted. Mutations preventing the cleavage and secretion of MSPd have been implicated in cases of human neurodegenerative diseases. The site of VAP cleavage and the tissues capable in releasing the processed MSPd are not understood. In this study, we analyze the C. elegans VAP-B homolog, VPR-1, for its processing and secretion from the intestine. We show that intestine-specific expression of an N-terminally FLAG-tagged VPR-1 rescues underdeveloped gonad and sterility defects in vpr-1 null hermaphrodites. Immunofluorescence studies reveal that the tagged intestinal expressed VPR-1 is present at the distal gonad. Mass spectrometry analysis of a smaller product of the N-terminally tagged VPR-1 identifies a specific cleavage site at Leu156. Mutation of the leucine results in loss of gonadal MSPd signal and reduced activity of the mutant VPR-1. Thus, we report for the first time the cleavage site of VPR-1 and provide direct evidence that intestinally expressed VPR-1 can be released and signal in the distal gonad. These results establish the foundation for further exploration of VAP cleavage, MSPd secretion, and non-cell-autonomous signaling in development and diseases.

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.

Microfluidic flow cytometry for blood-based biomarker analysis.

Flow cytometry has proven its capability for rapid and quantitative analysis of individual cells and the separation of targeted biological samples from others. The emerging microfluidics technology makes it possible to develop portable microfluidic diagnostic devices for point-of-care testing (POCT) applications. Microfluidic flow cytometry (MFCM), where flow cytometry and microfluidics are combined to achieve similar or even superior functionalities on microfluidic chips, provides a powerful single-cell characterisation and sorting tool for various biological samples. In recent years, researchers have made great progress in the development of the MFCM including focusing, detecting, and sorting subsystems, and its unique capabilities have been demonstrated in various biological applications. Moreover, liquid biopsy using blood can provide various physiological and pathological information. Thus, biomarkers from blood are regarded as meaningful circulating transporters of signal molecules or particles and have great potential to be used as non (or minimally)-invasive diagnostic tools. In this review, we summarise the recent progress of the key subsystems for MFCM and its achievements in blood-based biomarker analysis. Finally, foresight is offered to highlight the research challenges faced by MFCM in expanding into blood-based POCT applications, potentially yielding commercialisation opportunities.

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.

The secreted MSP domain of C. elegans VAPB homolog VPR-1 patterns the adult striated muscle mitochondrial reticulum via SMN-1.

The major sperm protein domain (MSPd) has an extracellular signaling function implicated in amyotrophic lateral sclerosis. Secreted MSPds derived from the C. elegans VAPB homolog VPR-1 promote mitochondrial localization to actin-rich I-bands in body wall muscle. Here we show that the nervous system and germ line are key MSPd secretion tissues. MSPd signals are transduced through the CLR-1 Lar-like tyrosine phosphatase receptor. We show that CLR-1 is expressed throughout the muscle plasma membrane, where it is accessible to MSPd within the pseudocoelomic fluid. MSPd signaling is sufficient to remodel the muscle mitochondrial reticulum during adulthood. An RNAi suppressor screen identified survival of motor neuron 1 (SMN-1) as a downstream effector. SMN-1 acts in muscle, where it colocalizes at myofilaments with ARX-2, a component of the Arp2/3 actin-nucleation complex. Genetic studies suggest that SMN-1 promotes Arp2/3 activity important for localizing mitochondria to I-bands. Our results support the model that VAPB homologs are circulating hormones that pattern the striated muscle mitochondrial reticulum. This function is crucial in adults and requires SMN-1 in muscle, likely independent of its role in pre-mRNA splicing.

The C. elegans VAPB homolog VPR-1 is a permissive signal for gonad development.

VAMP/synaptobrevin-associated proteins (VAPs) contain an N-terminal major sperm protein domain (MSPd) that is associated with amyotrophic lateral sclerosis. VAPs have an intracellular housekeeping function, as well as an extracellular signaling function mediated by the secreted MSPd. Here we show that the C. elegans VAP homolog VPR-1 is essential for gonad development. vpr-1 null mutants are maternal effect sterile due to arrested gonadogenesis following embryo hatching. Somatic gonadal precursor cells and germ cells fail to proliferate fully and complete their respective differentiation programs. Maternal or zygotic vpr-1 expression is sufficient to induce gonadogenesis and fertility. Genetic mosaic and cell type-specific expression studies indicate that vpr-1 activity is important in the nervous system, germ line and intestine. VPR-1 acts in parallel to Notch signaling, a key regulator of germline stem cell proliferation and differentiation. Neuronal vpr-1 expression is sufficient for gonadogenesis induction during a limited time period shortly after hatching. These results support the model that the secreted VPR-1 MSPd acts at least in part on gonadal sheath cell precursors in L1 to early L2 stage hermaphrodites to permit gonadogenesis.

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.

Differences in the relationship of weight to height, and thus the meaning of BMI, according to age, sex, and birth year cohort.

Background: Weight can be adjusted for height using the Benn parameter (kg/mB), where B is the power that minimises the correlation with height.Aim: To investigate how the Benn parameter changes across age (10-65 years) and time (1956-2015) and differs between sexes.Subjects and methods: The sample comprised 49,717 individuals born in 1946, 1958, 1970 or 2001. Cross-sectional estimates of the Benn parameter were produced and cohort differences at ages 10/11 and 42/43 years were examined using linear regression. Multilevel modelling was used to develop trajectories showing how the Benn parameter changed over age from childhood to mid-adulthood in the three older cohorts.Results: The Benn parameter was closest to 2 in childhood but consistently lower across adulthood, particularly in females and the most recent cohort. At ages 10/11 years, the Benn parameter was greater than 3 in both sexes in the 2001 cohort but between 2.2 and 2.7 in the three older cohorts. This difference was estimated to be +0.67 (0.53, 0.81) in males and +0.53 (0.38, 0.68) in females, compared to the 1946 cohort, and was driven by a much higher weight SD in the 2001 cohort. Conversely, at ages 42/43 years, the Benn parameter was lowest in the 1970 cohort due to a slightly lower weight-height correlation. This difference was estimated to be -0.12 (-0.34, 0.10) in males and -0.15 (-0.42, 0.13) in females, compared to the 1946 cohort.Conclusions: Changes over time in the obesogenic environment appear to have firstly reduced the Benn parameter due to a lowering of the weight-height correlation but secondly and more drastically increased the Benn parameter due to increasing weight variation.

Steady Growth in Early Infancy Is Associated with Greater Anthropometry in Indian Children Born Low Birth Weight at Term.

BACKGROUND: Patterns of early growth are associated with later body composition and risk of adult noncommunicable disease but information from low-income countries is limited. OBJECTIVES: The aim of this study was to investigate early growth trajectories and later anthropometric and bone density outcomes among children born term low birth weight (LBW: 1.8-2.5 kg). METHODS: We used data from 902 children from the Delhi Infant Vitamin D Supplementation study of LBW term infants (which collected monthly anthropometry from birth to 6 mo) and who had height, weight, midupper arm circumference (MUAC), midupper arm muscle circumference (MUAMC), subscapular and triceps skinfold thicknesses, tibia and radius bone density measured at age 4-6 y. We investigated how growth in the first 6 mo of life, modeled using the SuperImposition by Translation and Rotation (SITAR) growth curve model, was related to these outcomes. SITAR summarizes each infant's weight and length trajectory in terms of a population mean curve and child-specific growth parameters: size, timing, and intensity. These were included as explanatory variables in linear regression models for the childhood outcomes. RESULTS: Considering the infant weight and length SITAR parameters jointly, childhood weight was strongly associated with infant length timing [estimated regression coefficient ß = 0.25 (95% CI: 0.10, 0.39)] and with weight size, timing, and intensity [ß = 9.01 (6.75, 11.27), ß = -0.25 (-0.43, -0.07), ß = 5.03 (3.22, 6.84), respectively]. Childhood height was associated only with the length parameters [ß = 0.97 (0.71, 1.23), ß = -0.43 (-0.77, -0.09), ß = 11.68 (8.60, 14.75), respectively]; childhood MUAC, MUAMC, and skinfolds with all parameters; and bone density with none. Overall, delayed and sustained growth in infant weight and length resulted in higher values of all outcomes except bone density, with the period up to 15 wk of age appearing critical for setting childhood anthropometry in this population. CONCLUSIONS: The explanation for the effects of delayed growth and length of the period in which trajectories are set is unclear; however, sustained and delayed growth in early infancy appears to be beneficial for these LBW children at least in the short-term. The trial was registered at clinicaltrials.gov as BT/PR7489/PID/20/285/2006.

Life course associations of height, weight, fatness, grip strength, and all-cause mortality for high socioeconomic status Guatemalans.

OBJECTIVES: The objective of this study was to investigate the association between physical growth in preadult life with five outcomes at ages 64 to 76: weight, body mass index (BMI), estimated body fat percentage, hand grip strength, and mortality. METHODS: Super-imposition by translation and rotation (SITAR) growth curves of 40 484 Guatemalan individuals aged 3 to 19 years were modeled for the parameters of size, timing and intensity (peak growth velocity, eg, cm/year) of height, weight, BMI, and grip strength. Associations between the SITAR parameters and old age outcomes were tested using linear and binary logistic regression for a follow-up sample of high socioeconomic status (SES) Guatemalans, of whom 50 were aged 64 to 76 years at re-measurement and 45 died prior to the year 2017. RESULTS: SITAR models explained 69% to 98% of the variance in each outcome, with height the most precise. Individuals in the follow-up sample who had a higher BMI before the age of 20 years had higher estimated body fat (B = 1.4 CI -0.02-2.8) and BMI (B = 1.2, CI 0.2-2.2) at the ages of 64 to 76 years. Those who grew slower in height but faster in weight and BMI before the age of 20 years had higher BMI and body fat later in life. CONCLUSIONS: These findings highlight the importance of a life course perspective on health and mortality risk. Childhood exposures leading to variation in preadult growth may be key to better understanding health and mortality risks in old age.

A discussion of statistical methods to characterise early growth and its impact on bone mineral content later in childhood.

BACKGROUND: Many statistical methods are available to model longitudinal growth data and relate derived summary measures to later outcomes. AIM: To apply and compare commonly used methods to a realistic scenario including pre- and postnatal data, missing data, and confounders. SUBJECTS AND METHODS: Data were collected from 753 offspring in the Southampton Women's Survey with measurements of bone mineral content (BMC) at age 6 years. Ultrasound measures included crown-rump length (11 weeks' gestation) and femur length (19 and 34 weeks' gestation); postnatally, infant length (birth, 6 and 12 months) and height (2 and 3 years) were measured. A residual growth model, two-stage multilevel linear spline model, joint multilevel linear spline model, SITAR and a growth mixture model were used to relate growth to 6-year BMC. RESULTS: Results from the residual growth, two-stage and joint multilevel linear spline models were most comparable: an increase in length at all ages was positively associated with BMC, the strongest association being with later growth. Both SITAR and the growth mixture model demonstrated that length was positively associated with BMC. CONCLUSIONS: Similarities and differences in results from a variety of analytic strategies need to be understood in the context of each statistical methodology.

Relationship between body mass, lean mass, fat mass, and limb bone cross-sectional geometry: Implications for estimating body mass and physique from the skeleton.

OBJECTIVES: Estimating body mass from skeletal dimensions is widely practiced, but methods for estimating its components (lean and fat mass) are poorly developed. The ability to estimate these characteristics would offer new insights into the evolution of body composition and its variation relative to past and present health. This study investigates the potential of long bone cross-sectional properties as predictors of body, lean, and fat mass. MATERIALS AND METHODS: Humerus, femur and tibia midshaft cross-sectional properties were measured by peripheral quantitative computed tomography in sample of young adult women (n = 105) characterized by a range of activity levels. Body composition was estimated from bioimpedance analysis. RESULTS: Lean mass correlated most strongly with both upper and lower limb bone properties (r values up to 0.74), while fat mass showed weak correlations (r ≤ 0.29). Estimation equations generated from tibial midshaft properties indicated that lean mass could be estimated relatively reliably, with some improvement using logged data and including bone length in the models (minimum standard error of estimate = 8.9%). Body mass prediction was less reliable and fat mass only poorly predicted (standard errors of estimate ≥11.9% and >33%, respectively). DISCUSSION: Lean mass can be predicted more reliably than body mass from limb bone cross-sectional properties. The results highlight the potential for studying evolutionary trends in lean mass from skeletal remains, and have implications for understanding the relationship between bone morphology and body mass or composition.

Optimal design for longitudinal studies to estimate pubertal height growth in individuals.

BACKGROUND: The SITAR model expresses individual pubertal height growth in terms of mean size, peak height velocity (PHV) and age at PHV. AIM: To use SITAR to identify the optimal time interval between measurements to summarise individual pubertal height growth. SUBJECTS AND METHODS: Heights in 3172 boys aged 9-19 years from Christ's Hospital School measured on 128 679 occasions (a median of 42 heights per boy) were analysed using the SITAR (SuperImposition by Translation And Rotation) mixed effects growth curve model, which estimates a mean curve and three subject-specific random effects. Separate models were fitted to sub-sets of the data with measurement intervals of 2, 3, 4, 6, 12 and 24 months, and the different models were compared. RESULTS: The models for intervals 2-12 months gave effectively identical results for the residual standard deviation (0.8 cm), mean spline curve (6 degrees of freedom) and random effects (correlations >0.9), showing there is no benefit in measuring height more often than annually. The model for 2-year intervals fitted slightly less well, but needed just four-to-five measurements per individual. CONCLUSIONS: Height during puberty needs to be measured only annually and, with slightly lower precision, just four biennial measurements can be sufficient.