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.

Sex differences in bone mineral content and bone geometry accrual: a review of the Paediatric Bone Mineral Accural Study (1991-2017).

CONTEXT: Girls' and boys' growth patterns differ in timing and tempo, and they have different lifestyles with regards to diet and physical activity. These factors have all been linked with bone mineral accrual. OBJECTIVE: To identify the associations of boys' and girls' growth, maturation, and lifestyle choices relating to parameters of bone geometry and mineral accrual. METHODS: Between 1991 and 1993, 251 children aged 8-15 years were recruited into a mixed-longitudinal cohort study (The Paediatric Bone Mineral Accrual Study (PBMAS)) and followed repeatedly over 26 years. RESULTS: It was found that girls matured approximately two years earlier than boys (11.8 vs. 13.4 years) but on average were shorter, had less lean mass and had greater fat mass (p < 0.05). There was a dissociation between the growth of bone and its mineralisation in both sexes. Boys had greater bone mass and bone geometry (p < 0.05). Both a healthy childhood diet and high levels of physical activity were associated with improved bone parameters. CONCLUSIONS: Most, but not all, of the sex differences observed, were explained by height and lean mass differences. The importance of diet and physical activity on obtaining optimal bone mass during adolescence in both sexes was also paramount.

Exploring the relationship between adolescent biological maturation, physical activity, and sedentary behaviour: a systematic review and narrative synthesis.

CONTEXT: Across adolescence, there is a notable decline in physical activity in boys and girls. Maturational timing may be a risk factor for disengagement from physical activity and increased sedentary behaviours during adolescence. OBJECTIVE: This systematic review aimed to summarise literature that examined the relationship between maturational timing, physical activity and sedentary behaviour in adolescents. METHODS: Six electronic databases were searched for articles that assessed biological maturation and physical activity (including sports participation and active transportation) or sedentary behaviours in adolescents. Two reviewers conducted title, abstract, and full-text screening, reference and forward citation searches. Included articles were evaluated for quality using a standardised tool. A narrative synthesis was used to analyse the findings due to the heterogeneity of the studies. RESULTS: Searches yielded 78 articles (64 unique studies) that met the inclusion criteria, representing 242,316 participants (153,179 unique). Studies ranged from 30.0% (low) to 91.7% (high) in quality. An inverse relationship between maturational timing and physical activity (in 50 and 60% of studies in boys and girls, respectively) and a positive relationship between maturational timing and sedentary behaviour (in 100% and 53% of studies in boys and girls, respectively) was most commonly reported. Evidence supporting an association between maturational timing, sports participation, and active transportation was inconsistent. CONCLUSIONS: While this review demonstrates some evidence for early maturational timing as a risk factor for disengagement from physical activity and increase in sedentary behaviours, the reviewed literature also demonstrates that this relationship is complex. Future research that tracks maturity-related variations in physical activity and sedentary behaviours over adolescence is warranted.

Structural Strength Benefits Observed at the Hip of Premenarcheal Gymnasts Are Maintained Into Young Adulthood 10 Years After Retirement From the Sport.

PURPOSE: Premenarcheal female gymnasts have been consistently found to have greater bone mass and structural advantages. However, little is known about whether these structural advantages are maintained after the loading stimulus is removed. Therefore, the purpose of this study was to investigate the structural properties at the hip after long-term retirement from gymnastics. METHODS: Structural properties were derived from dual-energy X-ray absorptiometry scans using the hip structural analysis program for the same 24 gymnasts and 21 nongymnasts both in adolescence (8-15 y) and adulthood (22-30 y). Structural measures were obtained at the narrow neck, intertrochanter, and femoral shaft and included cross-sectional area, section modulus, and buckling ratio. Multivariate analysis of covariance was used to assess differences between groups in bone measures while controlling for size, age, maturity, and physical activity. RESULTS: Gymnasts were found to have structural advantages at the narrow neck in adolescence (16% greater cross-sectional area, 17% greater section modulus, and 25% lower buckling ratio) and 14 years later (13% greater cross-sectional area and 26% lower buckling ratio). Benefits were also found at the intertrochanter and femoral shaft sites in adolescence and adulthood. CONCLUSION: Ten years after retirement from gymnastics, former gymnasts' maintained significantly better hip bone structure than females who did not participate in gymnastics during growth.

Influence of nutrition provision during the first two weeks of life in premature infants on adolescent body composition and blood pressure.

OBJECTIVE: Adequate nutrition is paramount for premature infants. Longitudinal information is scant on the effects of early nutrition and later growth. The purpose of this study was to determine the influence of early energy and protein provision in premature infants on adolescent body composition and blood pressure. METHODS: In 2007-2008 we obtained data from 36 male (12.3±1.7 years) and 25 female (11.5±1.8 years) adolescents born preterm at <34 weeks gestation (range 23-34 weeks) between October 1st 1989 and December 31st 1995 (birth weight <1850 g). The adolescents were divided into groups depending on infant intake mode (enteral vs parenteral), energy provision (<70 kcal/kg/d and ≥70 kcal/kg/d) and protein provision (>2.5 g/kg/d for ≥5 days and >2.5 g/kg/d for <5 days) during the first 14 days of life. RESULTS: After controlling for birth weight and biological maturity, adolescents who received ≥70 kcal/kg/d during infancy were significantly taller (163±11 cm vs. 156±11 cm) and heavier (58±16 kg vs. 49±16 kg) than adolescents who received <70 kcal/kg/d. There were no significant differences in systolic and diastolic BP and total percent body fat between the two groups. CONCLUSIONS: Our data suggests that higher infant energy provision appears to be related to adolescent size, it does not appear to contribute to adverse risk factors such as higher systolic BP or increased body fat.

Preterm birth and adolescent bone mineral content.

The purpose of this study was to determine the influence of preterm low birth weight on bone mineral content in adolescence. In 2007 to 2008, data on adolescents were obtained for study, including 16 females and 25 males who were born preterm (≤37 weeks' gestation) between October 1, 1989, and December 31, 1995, with a birth weight of less than 1850 g. Preterm low-birth-weight individuals were age- and sex-matched to full-term (>37 weeks) normal-birth-weight (>2500 g) controls. Total body, hip, and spine bone mineral content (BMC) was assessed using dual energy X-ray absorptiometry. Male preterm individuals had less BMC at the proximal femur in adolescence compared with controls ( p < 0.05). However, once adjusted for age, maturity, height, weight, physical activity, and diet, there were no differences between groups ( p < 0.05) in any bone parameters. These findings suggest that preterm birth and low birth weight did not influence bone accrual in these individuals at adolescence.

The associations of exposure to combined hormonal contraceptive use on bone mineral content and areal bone mineral density accrual from adolescence to young adulthood: A longitudinal study.

BACKGROUND: The association of long term combined hormone based contraceptives (CHC) use on bone mineral content (BMC) and areal bone mineral density (aBMD) development remains controversial, as it appears that the relationship may be age-dependent. The purpose of this study was to investigate the long-term associations of CHC exposure on the accrual of bone parameters from adolescence into young-adulthood. METHODS: 110 women (67 exposed to CHC) were drawn from the Pediatric Bone Mineral Accrual Study (PBMAS). Serial measures of total body (TB), lumbar spine (LS) and femoral neck (FN) BMC and aBMD were assessed by DXA (a total of 950 scans) and aligned by biological age (BA, years from peak height velocity [PHV]). Multilevel random effects models were constructed to assess the time dependent associations between annual CHC exposure and the development of bone parameters. RESULTS: After BA, height, lean tissue mass, fat mass, calcium and vitamin D intake, and physical activity were controlled, it was observed that those individuals exposed to CHC 6-years post PHV developed significantly less (-0.00986 ± 0.00422 g/cm2) TB aBMD than their non CHC exposed peers. Additionally, there were significant BA by CHC exposure interactions, where CHC exposure 6-years or more post PHV resulted in developing less TB BMC (-4.94 ± 2.41 g), LS BMC (-0.29 ± 0.11 g) and LS aBMD (-0.00307 ± 0.00109 g/cm2). One year after the attainment of PHV, CHC users were predicted to have 1.2% more TB BMC, 3.8% more LS BMC and 1.7% more LS aBMD than non-users. At 9-years post PHV the predicted differences showed that CHC users had 0.9% less TB BMC and 2.7% less LS BMC and 1.6% less LS BMD than those not exposed to CHC. CONCLUSIONS: CHC may not hinder the development of BMC or aBMD during adolescence; however, exposure 6-years or more after PHV may be detrimental.

Oxidation levels of North American over-the-counter n-3 (omega-3) supplements and the influence of supplement formulation and delivery form on evaluating oxidative safety.

The aim of the present study was to evaluate the oxidation status of North American n-3 (omega-3) PUFA nutritional supplements commercially available in Canada and evaluate the influence of product formulation and delivery form on oxidative safety. A total of 171 North American over-the-counter n-3 PUFA nutritional supplements were analysed for oxidation safety. Primary and secondary oxidation and total oxidation (TOTOX) were determined using the American Oil Chemists' Society (AOCS) procedures. Comparisons between supplements' final forms, oil source and n-3 PUFA concentration quartiles, as measures of product formulations and delivery forms, were compared using ANOVA. Of the products successfully tested, 50 % exceeded the voluntary recommended levels for markers of oxidation. Another 18 % of products were approaching the limits with 1-3 years before expiration. Encapsulated products without flavour additives had significantly lower secondary and TOTOX levels than bulk oils and flavoured products (P < 0·05). Children's products had significantly higher primary, secondary and TOTOX levels compared with all other products (P < 0·05). Markers of oxidation did not differ between oil sources (P > 0·05), with the exception of krill oil products having higher secondary oxidation levels than plant-based products (P > 0·05). Markers of oxidation did not differ between n-3 PUFA supplement concentration quartiles. Consumers may be at risk of exposure to higher levels of oxidative products. New regulatory mandates need to be introduced to ensure that all n-3 PUFA products, used as nutritional supplements, regardless of their formulation or delivery form, can be tested for oxidative safety and compliance.

Adolescent physical activity and bone strength at the proximal femur in adulthood.

INTRODUCTION: Physical activity (PA) enhances bone structural strength at the proximal femur in adolescence, but whether these benefits are maintained into early adulthood remains unknown. The purpose of this study was to investigate whether males and females, described as active, average, and inactive during adolescence, display differences in structural strength at the proximal femur in early adulthood (20-30 yr). METHODS: One hundred four participants (55 males and 49 females) from the Pediatric Bone Mineral Accrual Study (PBMAS) were categorized into adolescent PA groupings (inactive, average, and active) using the Physical Activity Questionnaire for Adolescents. Cross-sectional area and section modulus (Z) at the narrow neck, intertrochanter, and femoral shaft (S) sites of the proximal femur were assessed using hip structural analysis in young adulthood from femoral neck dual-energy x-ray absorptiometry scans. Group differences were assessed using ANCOVA, controlling for adult height (Ht), adult weight (Wt), adolescent bone geometry, sex, percentage adult total body lean tissue (LTM%), and adult PA levels. RESULTS: Active adolescents had significantly greater adjusted bone geometric measures at all sites than their inactive classified peers during adolescence (P < 0.05). In adulthood, when adjusted for Ht, Wt, adolescent bone geometry, sex, LTM%, and adult PA levels, adolescent participants categorized as active had significantly greater adjusted adult bone geometric measures at the proximal femur than adult participants who were classified as inactive during adolescence (P < 0.05). CONCLUSIONS: Skeletal advantages associated with adolescence activity appear to confer greater geometric bone structural strength at the proximal femur in young adulthood.

Structural strength development at the proximal femur in 4- to 10-year-old precompetitive gymnasts: a 4-year longitudinal hip structural analysis study.

Gymnastics, a high-impact weight-bearing physical activity, has been shown to be highly osteogenic. Previously in this cohort, bone mass development (bone mineral content accrual [BMC]) was shown to be positively associated with low-level (recreational) gymnastics exposure (1 to 2 hours per week); however, BMC is only one single component of bone strength. Bone strength is influenced not only by bone mineralization but also bone geometry, bone architecture, and the imposing loads on the bone. The aim of this study was to investigate whether low-level gymnastics training influenced the estimated structural geometry development at the proximal femur. A total of 165 children (92 gymnasts and 73 non-gymnasts) between the ages of 4 and 6 years were recruited into this study and assessed annually for 4 years. During the 4 years, 64 gymnasts withdrew from the sport and were reclassified as ex-gymnasts. A dual-energy X-ray absorptiometry (DXA) image of each child's hip was obtained. Values of cross-sectional area (CSA), section modulus (Z), and cortical thickness (CT) at the narrow neck (NN), intertrochanter (IT), and shaft (S) were estimated using the hip structural analysis (HSA) program. Multilevel random-effects models were constructed and used to develop bone structural strength development trajectories (estimate ± SEE). Once the confounders of body size and lifestyle were controlled, it was found that gymnasts had 6% greater NN CSA than non-gymnasts controls (0.09 ± 0.03 cm(2) , p < 0.05), 7% greater NN Z (0.04 ± 0.01 cm(3) , p < 0.05), 5% greater IT CSA (0.11 ± 0.04 cm(3) , p < 0.05), 6% greater IT Z (0.07 ± 0.03 cm(3) , p < 0.05), and 3% greater S CSA (0.06 ± 0.03 cm(3) , p < 0.05). These results suggest that early exposure to low-level gymnastics participation confers benefits related to geometric and bone architecture properties during childhood and, if maintained, may improve bone health in adolescence and adulthood.

The timing of BMD and geometric adaptation at the proximal femur from childhood to early adulthood in males and females: a longitudinal study.

During adolescence, the peak velocity in bone mass accretion preceded the peak velocity of estimated geometry at the hip. Whether this pattern continues into adulthood when maximum values are achieved remains unknown. The purpose of this study was (1) to identify the ages at which peak values of areal BMD (aBMD), cross-sectional area (CSA), and section modulus (Z) occur, (2) to determine the percent of adult peak attained during adolescence, and (3) to determine the relationship between body composition and the timing of the adult peak values. One-hundred and sixty-five (92 females) individuals' aBMD, CSA, and Z values were assessed serially at the narrow neck (NN), intertrochanter (IT), and shaft (S) using hip structural analysis (HSA). Peak bone values and the ages of attainment were assessed using factorial MANOVA. In males, aBMDp (NN 19.4 ± 2.7 years, IT 20 ± 3.4 years, and S 21.8 ± 2.8 years) occurred significantly earlier than CSAp at all sites (NN 21.6 ± 3.2 years, IT 21.1 ± 3.4 years, and S 22.3 ± 3.1 years) and earlier than Zp at the NN (22 ± 3.2 years) and IT (21.3 ± 2.9 years). In females, aBMDp (NN 17.9 ± 2.7 years, IT 18.7 ± 3.5 years, and S 19.7 ± 3.3 years) occurred significantly earlier than CSAp at all sites (NN 20.6 ± 3.6 years, IT 19.4 ± 3.9 years, and S 21.0 ± 3.3 years) and earlier than Zp at the NN (20.7 ± 3.4 years) and S (20.6 ± 3.5 years). The changes in bone mass precede changes in geometric CSA, and this timing may be integral for the development and maintenance of bone strength.

Maturational timing does not predict HSA estimated adult bone geometry at the proximal femur.

Late maturational timing is documented to be detrimental to bone strength primarily at the distal radius. Studies at the proximal femur have focused on bone mass and the results remain controversial. The purpose of this study was to examine the long term relationship between the onset of maturation and the development of estimated cross sectional area (CSA) and section modulus (Z) at the proximal femur. Two hundred and twenty six individuals (108 males and 118 females) from the Saskatchewan Pediatric Bone Mineral Accrual Study (PBMAS) were classified into maturity groups based on age of attainment of peak height velocity. CSA and Z were serially assessed at the narrow neck (NN), intertrochanter (IT) and proximal shaft (S) sites using hip structural analysis (HSA). Multilevel models were constructed to examine the development of CSA and Z by maturity group. Cross sectional observations indicated that during adolescence, early maturing males had significantly greater CSA and Z than late maturing males at all sites of the proximal femur, while early maturing females had greater Z at the NN and S, and greater CSA at the NN, IT and S sites compared to late maturing females. When age, body size, body composition, physical activity and dietary intake were controlled no significant effects of maturational timing were found at the NN, IT or S regions (p>0.05) in either males or females. In this population of healthy individuals there appears to be no effect of the onset of maturation on estimated CSA and Z development at the proximal femur in both males and females. This may be a result of the proximal femur's loading environment. Future research is required to determine the role of loading on the relationship between maturational timing and bone structure and strength development at the proximal femur.

Effect of maturational timing on bone mineral content accrual from childhood to adulthood: evidence from 15 years of longitudinal data.

A higher bone mass may reduce the risk of osteoporosis and fractures. The role of maturational timing for optimizing bone mass is controversial due to the lack of prospective evidence from childhood to adulthood. The purpose of this study was to examine the long term relationship between the onset of maturation and bone mineral content (BMC) development. Two hundred thirty individuals (109 males and 121 females) from the Saskatchewan Pediatric Bone Mineral Accrual Study (PBMAS) were classified into maturity groups based on age of peak height velocity. BMC was serially assessed using dual energy X-ray absorptiometry (DXA). Multilevel models were constructed to examine the independent development of BMC by maturity group. When age, body size, and body composition were controlled early maturing females had on average 3-4%, 62.2 ± 16.8g (p<0.05), more total body BMC than their average maturing peers by 20 years of age. In contrast, late maturing females had 50.7 ± 15.6g less total body BMC. No maturational effects were found at either the lumbar spine or femoral neck (p>0.05) in females. There were no significant differences in BMC development at any site among male maturational groups (p>0.05). In this group of healthy participants, there appears to be a sex-dependent effect on the relationship between maturational timing and total body BMC development. Early, average and late maturing males displayed similar BMC development. Late maturing females had compromised BMC accrual compared to their early and average maturing peers.

Peak lean tissue mass accrual precedes changes in bone strength indices at the proximal femur during the pubertal growth spurt.

PURPOSE: We examined the timing of the age and the magnitude of peak lean tissue mass accrual (PLTV) relative to the age and magnitude of two variables of bone strength [peak cross sectional area velocity (PCSAV), and peak section modulus velocity, (PZV)] at the proximal femur in males and females during the adolescent growth spurt. We hypothesized that the age of PLTV would precede the ages of PCSAV and PZV and that there is a positive relationship between the magnitude of PLTV and both PCSAV and PZV in both genders. METHODS: 41 males and 42 females aged 8-18 years were selected from the Saskatchewan Pediatric Bone Mineral Accrual Study (1991-2005). Participants' total body lean tissue mass was assessed annually for 6 consecutive years using DXA. Narrow neck and femoral shaft cross sectional areas (CSA) and section modulus (Z) were determined using the hip structural analysis (HSA) program. Participants were aligned by maturational age (years from peak height velocity). Lean tissue mass, CSA, and Z were converted into whole year velocities and the maturational age of peak tissue velocities was determined using a cubic spline curve fitting procedure. A 2 x 3 (gender x tissue) factorial MANOVA with repeated measures was used to test for differences between age of PLTV and the ages of PCSAV and PZV between genders. Multiple regression analyses were used to examine the relationship between PLTV and both PCSAV and PZV. RESULTS: There were no sex differences in the ages at which tissue peaks occurred when aligned by maturational age. There were significant differences between the age of PLTV and both PCSAV and PZV at the narrow neck (p=0.001) and femoral shaft (p=0.03), where the age of PLTV preceded both PCSAV and PZV when pooled by gender. PLTV was a significant predictor of the magnitude of both PCSAV and PZV at all sites (p<0.05). CONCLUSIONS: These findings support the hypothesis that the age of PLTV precedes the age of PCSA and PZV at the proximal femur. Results support the theory that muscle development is an important factor in affecting bone strength.