Hip structural analysis (HSA) of proximal femur scans by dual energy X-ray absorptiometry estimates hip geometry and structural strength, but little is known about how these parameters change during peak bone mass development. We describe age-related changes, precision and long-term stability, and sex and race/ethnic identity differences in hip geometry measures by HSA, and test whether HSA measures predict childhood fractures in healthy children. We used data from the Bone Mineral Density in Childhood Study, a multi-center, longitudinal cohort study of 2,014 healthy U.S. children, ages 5-23y, with up to 7 annual visits. HSA measures included cortical thickness, cross-sectional area, cross-sectional moment of inertia, section modulus, buckling ratio, and bone width at the narrow neck and femoral shaft, and hip axis length. Additional measures included self-identified race and ethnicity, Z-scores for height, BMIZ, appendicular lean soft tissue mass index and fat mass index, and self-reported physical activity, calcium intake, Tanner stage and fractures. Results indicated age-related trends and sex differences in hip geometry. Reference ranges were generated and HSA Z-scores were adjusted for height-for-age Z-score. Femoral shaft measures showed better precision (CV: 1.1 to 3.7%) than narrow neck measures (CV: 2.2 to 7.4%); buckling ratio (both sites) was the least precise. HSA Z-scores tracked well over one year (0.77 to 0.94). Narrow neck buckling ratio (HR 1.16 [95% CI: 1.02, 1.31]) and hip axis length Z-scores (HR 1.20 [95% CI: 1.00, 1.44]) associated with fracture risk. When adjusted for covariates (BMD Z-score, BMIZ, Tanner stage, sex), narrow neck cross-sectional area, cross-sectional moment of inertia, section modulus and bone width, and femoral shaft cross-sectional area and section modulus Z-scores positively associated with fractures (e.g., section modulus Z-score associated with 44% increased fracture risk). These findings provide the foundation for evaluating hip geometry as an indicator of bone strength in children.

The polygenic risk score genetic quantitative ultrasound speed of sound (gSOS) was developed using machine learning algorithms in adults of European ancestry and associates with reduced odds of fracture in adults. We aimed to determine if gSOS was associated with bone health in children. Two observational studies of children were evaluated: (1) children enrolled in the Bone Mineral Density in Childhood Study (BMDCS) with genetic data (N = 1727) and (2) children with genetic data for research at the Children's Hospital of Philadelphia (CHOP; N = 10 301). Genetic variants were used to calculate gSOS and genetic ancestry. For the BMDCS, puberty stage, dietary calcium, physical activity, and fracture accumulation (none or ≥1 fracture) were self-reported, height and weight were measured and BMI calculated. Areal BMD (aBMD) of the lumbar spine, hip, radius, and whole body were assessed by DXA and expressed as Z-scores. The CHOP study paired genetic data with documentation of fracture in the electronic health record (EHR). Genetic quantitative ultrasound speed of sound associated with higher aBMD Z-scores across 7 skeletal sites [eg, a 1 SD increase in gSOS associated with 0.17 (95% CI: 0.10-0.24) higher LS aBMD Z-score]. These associations were consistent for males and females, age, puberty stage, and lifestyle factors, and most consistent among children of European genetic ancestry. A 1 SD increase in gSOS associated with 24% reduced likelihood of self-reported fracture in the BMDCS (OR = 0.76, 95% CI: 0.66, 0.88) and a 12% reduced likelihood of a recorded fracture in the CHOP EHR (OR = 0.88; 95% CI: 0.82, 0.95). No sex or genetic ancestry differences were found. A higher gSOS score associated with higher aBMD at multiple skeletal sites and reduced odds of fracture in two independent pediatric samples. This genetic tool may have clinical utility to help enhance bone health in early life and protect against fracture across the lifespan.

INTRODUCTION:Race-specific reference ranges for pediatric areal bone mineral density (BMD) are widely used, but the value of race-based clinical algorithms has been questioned. We developed race-neutral pediatric reference ranges for areal BMD and bone mineral apparent density (BMAD) and compared race-specific vs race-neutral Z-scores in their ability to predict prospective fractures. MATERIAL AND METHODS:This secondary analysis of the Bone Mineral Density in Childhood Study used longitudinal BMD data of the spine, hip, forearm, and total body less head and BMAD from dual-energy x-ray absorptiometry (DXA) scans. Race/ethnicity, dietary calcium, physical activity, and prospective fractures were assessed by questionnaire. Race-neutral reference ranges and height-for-age Z-score adjustment equations were created using the lambda-sigma-mu method. Race-neutral and race-specific Z-scores were compared using linear mixed-effect modeling. Cox proportional hazard modeling was used to test whether race-neutral Z-scores associated with fracture. RESULTS:Race-neutral BMD and BMAD Z-scores were 0.5 to 0.7 SD greater than race-specific Z-scores for Black children but only ∼0.1 SD lower for children from other race/ethnicity groups. Growth and lifestyle factors modified group differences. One SD increase in race-neutral Z-scores was associated with a 12% to 18% reduced risk of fracture. CONCLUSION:We present the first race-neutral pediatric reference ranges for BMD and BMAD that are weighted to be representative of the US population and demonstrate that these Z-scores associate with fracture risk. Adoption of these new reference ranges should be considered, with thoughtful implementation for patients previously monitored with race-specific reference ranges, especially among children who identify as Black.

Background:Obesity disproportionately affects marginalized and low-income populations. Birth parent obesity from the prenatal period and childhood has been associated with child obesity. It is unknown whether prenatal or postnatal birth parent obesity has differential effects on subsequent changes in adiposity and metabolic health in children. Objectives:We evaluated how birth parent obesity 7 y after delivery was associated with child body composition changes and cardiometabolic health in midchildhood and further assessed the influence of the perinatal and postpartum period on associations. Methods:Black and Dominican pregnant individuals were enrolled, and dyads (n = 319) were followed up at child age 7 and 9 y. Measures included, height, weight, waist circumference (WC), and percent body fat (BF%). Multiple linear regression was used to relate postpartum weight status with child outcomes accounting for attrition, and a series of secondary analyses were conducted with additional adjustment for perinatal weight status, gestational weight gain (GWG), and/or long-term weight retention to evaluate how these factors influenced associations. Results:Almost one-quarter (23%) of birth parents and 24.1% children were classified with obesity at child age 7 y, while at 9 y, 30% of children had obesity. Birth parent obesity at child age 7 y was associated with greater changes, from ages 7 to 9 y, in child BMI z-score (β: 0.13; 95% CI: 0.02, 0.24) and BF% (β: 1.15; 95% CI: 0.22, 2.09) but not obesity at age 9 y. All observed associations crossed the null after additional adjustment for prenatal factors. Conclusions:Birth parent obesity at 7-y postpartum is associated with greater gains in child BMI z-score and BF% in midchildhood. These associations diminish after accounting for prenatal size, suggesting a lasting impact of the perinatal environment and that interventions supporting families from the prenatal period through childhood are needed.

OBJECTIVE:The objective of this study was to examine associations between umbilical cord mitochondrial DNA copy number (mtDNAcn) and adiposity across childhood. METHODS:In a prospective birth cohort of Dominican and African American children from New York City, New York (1998-2006), mtDNAcn was measured in cord blood. Children (N = 336) were evaluated for their height, weight, and bioimpedance at age 5, 7, 9, and 11 years. We used linear mixed-effects models to assess associations of mtDNAcn tertiles in cord blood with child BMI, BMI z scores, fat mass index, and body fat percentage. Latent class growth models and interactions between mtDNAcn and child age or child age2 were used to assess associations between age and adiposity trajectories. RESULTS:BMI was, on average, 1.5 kg/m2 higher (95% CI: 0.58, 2.5) in individuals with mtDNAcn in the low- compared with the middle-mtDNAcn tertile. Results were similar for BMI z score, fat mass index, and body fat percentage. Moreover, children in the low-mtDNAcn group had increased odds of being in an "increasing" or "high-stable" adiposity class. CONCLUSIONS:Lower mtDNAcn at birth may predict greater childhood adiposity, highlighting the potential key role of perinatal mitochondrial function in adiposity during development.

OBJECTIVES:To examine the global prevalence of polycystic ovary syndrome (PCOS) among adolescents across world regions, comparing the 2003 Rotterdam consensus criteria with the current International Evidence-based PCOS Guideline criteria which omits polycystic ovarian morphology (PCOM). DESIGN:Systematic review and meta-analysis, Prospero CRD42022372029. METHODS:OVID MEDLINE, All EBM, PsycInfo, EMBASE, and CINAHL were searched from 1990 to November 2023 for studies assessing the prevalence of PCOS in unselected adolescent populations. RESULTS:Overall, 15 708 articles were identified. After removal of duplicates, 11 868 titles and abstracts and 445 full texts were assessed. Of these, 24 articles reporting on 23 studies from five world regions were included. In meta-analysis of 20 studies (n = 14 010 adolescents), global prevalence was 9.8% (95% CI 7.2, 12.3) according to original Rotterdam criteria, and 6.3% (95% CI 3.9, 8.8) according to International Evidence-based Guideline criteria. Global PCOS prevalence based on self-report was 9.8% (95% CI 5.5, 14.1). Grouped by WHO region, prevalence ranged from 2.9% (95% CI 2.0, 3.9) in the Western Pacific region to 11.4% (95% CI 7.1, 15.7) in the South-East Asia region according to guideline criteria. CONCLUSION:This paramount global meta-analysis on adolescent PCOS diagnosis directly informed the 2023 International PCOS Guideline. Guideline criteria generated a global PCOS prevalence of 6.3%, compared with 9.8% on Rotterdam criteria (including PCOM). Excluding PCOM, which overlaps with normal pubertal transition, is expected to deter over-diagnosis. To avoid under-diagnosis, the Guideline recommends identifying those with either irregular cycles or hyperandrogenism as being "at risk"; this group should undergo longitudinal serial evaluations until adulthood.

Background: Little is known about the relationship between metabolic factors and weight loss success in adolescents undergoing bariatric surgery. Methods: The objective of this study was to assess if baseline metabolic characteristics associate with weight loss in adolescents undergoing laparoscopic sleeve gastrectomy. A retrospective study was conducted in a comprehensive adolescent bariatric surgery center of 151 subjects (34 male, 117 female). Anthropometric measurements and metabolic factors including blood pressure, fasting glucose, HbA1c, Metabolic Syndrome (MeS), liver function, triglycerides, and waist circumference were collected at one pre-surgical visit, and at 6 and/or 12 months post-laparoscopic sleeve gastrectomy. Weight loss was compared between subjects with normal or abnormal baseline metabolic factors. Absolute BMI change was used to measure successful weight loss. Results: Higher baseline systolic blood pressure (SBP) was associated with greater weight loss as measured by body mass index (BMI) change and BMI standard deviation score (BMI-SDS) change at 6 and 12 months. Those patients in the 6-month follow up group with an abnormal hemoglobin A1C (HbA1c) at baseline had significantly more weight loss as measured by BMI-SDS. None of the other parameters, including fasting glucose, Metabolic Syndrome (MeS), liver function, triglycerides and waist circumference showed a predictive relationship. Discussion/Conclusion: Elevated SBP and HbA1c in adolescents with morbid obesity may reflect a population more likely to achieve successful weight loss, and thus, may be a good target for bariatric surgery, specifically laparoscopic sleeve gastrectomy, as an intervention for severe obesity. An assessment of behavioral differences in patients with and without elevated BP and HbA1c might explain the mechanism for the improved weight loss.

Background Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. Conclusion We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern.

Background: Body composition assessment aids evaluation of energy stores and the impact of diseases and interventions on child growth. Current United States pediatric reference ranges from the National Health and Nutrition Examination Survey (NHANES) include 20% of children with obesity, body mass index of >= 95th percentile. Objectives: This study aimed to develop dual energy X-ray absorptiometry (DXA) based reference ranges in a diverse cohort with low-obesity prevalence from the Bone Mineral Density in Childhood Study (BMDCS). Methods: This is a secondary analysis of a longitudinal, prospective, observational cohort. Healthy children (height and BMI within 3rd to 97th per-centiles, ages 5-19 y at enrollment), from 5 United States centers were measured annually for <7 visits. Whole body scans were acquired using Hologic scanners. A subsample underwent repeat measurements to determine precision. We generated reference ranges for appendicular and total lean soft tissue mass index (LSTM Index), fat mass index (FMI), and other body composition measures. Resulting curves were compared to NHANES and across subgroups. Sex and age-specific equations were developed to adjust body composition Z-scores for height Z score. Results: We obtained 9846 scans of 2011 participants (51% female, 22% Black, 17% Hispanic, 48% White, 7% Asian/Pacific Islander, and 6% with obesity). Precision (percent coefficient of variation) ranged from 0.7% to 1.96%. Median and-2 standard deviation curves for BMDCS and NHANES were similar, but NHANES +2 standard deviation LSTM Index and FMI curves were distinctly greater than the respective BMDCS curves. Subgroup differences were more extreme for appendicular LSTM Index-Z (mean +/- SD: Asian -0.52 +/- 0.93 compared with Black 0.77 +/- 0.87) than for FMI-Z (Hispanic 0.29 +/- 0.98 compared with Black -0.14 +/- 1.1) and were smaller for Z-scores adjusted for height Z-score. Conclusions: These reference ranges add to sparse normative data regarding body composition in children and adolescents and are based on a cohort with an obesity prevalence similar to current BMI charts. Awareness of subgroup differences aids in interpreting results.

BACKGROUND AND AIM: Mitochondrial DNA copy number (mtDNAcn) is a biomarker representing the average number of mitochondrial genomes in a cell. Significant changes in mtDNAcn may indicate mitochondrial dysfunction and can be used as a measure for mitochondrial toxicity or cellular stress. While alterations in mtDNAcn have been implicated in dysregulated pathways associated with diabetes and obesity, research has mainly focused on adults and not on children. METHOD: The study sample included a cohort of Dominican and African American children from Northern Manhattan and South Bronx, NY recruited from 1998 to 2006. mtDNAcn was measured in cord blood and split into low (33rd percentile), middle (33rd-67th percentile), or high (67th percentile) categories. Children were followed up with measurements for height, weight, and bioimpedance at ages 5, 7, 9, and 11 years. Mixed-effects models with random intercepts for participants were used to assess associations between mtDNAcn in cord blood and child BMI and BMI-z scores. Interactions between mtDNAcn categories and child age or child age squared were used to assess associations between age and adiposity trajectories at different levels of mtDNAcn. RESULTS: Adjusting for relevant covariates (maternal age, ethnicity, BMI, completion of high school, previous birth, environmental tobacco smoke exposure, receipt of public assistance, sex, age, age squared, and DNA input concentration), BMI was on average 1.2 kg/m2 higher (β = 1.2, 95% CI: 0.24, 2.15) and BMIz was on average 0.34 standard deviations higher (β = 0.34, 95% CI: 0.07, 0.62) in individuals with low mtDNAcn compared to individuals in the middle mtDNAcn group. BMI trajectories also differed by mtDNAcn level – children beginning life with lower cord blood mtDNAcn tended to follow a trajectory of higher BMI and BMI z-score. CONCLUSIONS: Results suggest that lower cord blood mtDNAcn is associated with higher childhood adiposity in this cohort of Dominican and African American children.

Abstract Background Polybrominated diphenyl ethers (PBDEs) are flame-retardant compounds widely used in household products until phase out in 2004. PBDEs are endocrine disruptors and are suggested to influence signaling related to weight control. Prenatal exposures to PBDEs may alter childhood adiposity, yet few studies have examined these associations in human populations. Methods Data were collected from a birth cohort of Dominican and African American mother-child pairs from New York City recruited from 1998 to 2006. PBDE congeners BDE-47, − 99, − 100, and − 153 were measured in cord plasma (ng/μL) and dichotomized into low (< 80th percentile) and high (>80th percentile) exposure categories. Height and weight were collected at ages 5, 7, 9, 11, and an ancillary visit from 8 to 14 years (n = 289). Mixed-effects models with random intercepts for participant were used to assess associations between concentrations of individual PBDE congeners or the PBDE sum and child BMI z-scores (BMIz). To assess associations between PBDEs and the change in BMIz over time, models including interactions between PBDE categories and child age and (child age)2 were fit. Quantile g-computation was used to investigate associations between BMIz and the total PBDE mixture. Models were adjusted for baseline maternal covariates: ethnicity, age, education, parity, partnership status, and receipt of public assistance, and child covariates: child sex and cord cholesterol and triglycerides. Results The prevalence of children with obesity at age 5 was 24.2% and increased to 30% at age 11. Neither cord levels of individual PBDEs nor the total PBDE mixture were associated with overall BMIz in childhood. The changes in BMIz across childhood were not different between children with low or high PBDEs. Results were similar when adjusting for postnatal PBDE exposures. Conclusions Prenatal PBDE exposures were not associated with child growth trajectories in a cohort of Dominican and African American children.

Trabecular bone score (TBS) is used for fracture prediction in adults, but its utility in children is limited by absence of appropriate reference values. We aimed to develop reference ranges for TBS by age, sex, and population ancestry for youth ages 5 to 20 years. We also investigated the association between height, body mass index (BMI), and TBS, agreement between TBS and lumbar spine areal bone mineral density (aBMD) and bone mineral apparent density (BMAD) Z-scores, tracking of TBS Z-scores over time, and precision of TBS measurements. We performed secondary analysis of spine dual-energy X-ray absorptiometry (DXA) scans from the Bone Mineral Density in Childhood Study (BMDCS), a mixed longitudinal cohort of healthy children (n = 2014) evaluated at five US centers. TBS was derived using a dedicated TBS algorithm accounting for tissue thickness rather than BMI. TBS increased only during ages corresponding to pubertal development with an earlier increase in females than males. There were no differences in TBS between African Americans and non-African Americans. We provide sex-specific TBS reference ranges and LMS values for calculation of TBS Z-scores by age and means and SD for calculation of Z-scores by pubertal stage. TBS Z-scores were positively associated with height Z-scores at some ages. TBS Z-scores explained only 27% and 17% of the variance of spine aBMD and BMAD Z-scores. Tracking of TBS Z-scores over 6 years was lower (r = 0.47) than for aBMD or BMAD Z-scores (r = 0.74 to 0.79), and precision error of TBS (2.87%) was greater than for aBMD (0.85%) and BMAD (1.22%). In sum, TBS Z-scores provide information distinct from spine aBMD and BMAD Z-scores. Our robust reference ranges for TBS in a well-characterized pediatric cohort and precision error estimates provide essential tools for clinical assessment using TBS and determination of its value in predicting bone fragility in childhood and adolescence. (c) 2022 American Society for Bone and Mineral Research (ASBMR).

Objective: To use magnetic resonance imaging (MRI) to quantify the follicle number per ovary (FNPO) using biplanar measurements and determine the ovarian volume (OV) using three-dimensional measurements in adolescents and young adults with polycystic ovary syndrome (PCOS) and controls and compare the differences between these groups; to examine the relationships between FNPO and OV and metabolic markers associated with PCOS; to compare OV obtained by use of MRI and ultrasound between young patients with PCOS and controls. Design: Cross-sectional study. Setting: Outpatient within a major medical center in New York City. Patients: Adolescent girls and young women aged 13-25 years with PCOS (n = 16) and body mass index-, age-, and ethnicity- comparable control subjects (n = 15). Interventions: None. Main Outcome Measures: The OV and FNPO by use of MRI, OV by use of transabdominal pelvic ultrasound, anthropometric measurements, and biochemical and hormonal evaluation. Results: The FNPO was higher in participants with PCOS (23.7 +/- 4.6 follicles) than in controls (15.2 +/- 4 follicles) when adjusted for menstrual age. The OV by use of ultrasound was higher in participants with PCOS (11.7 +/- 5.6 mL) than in controls (8.1 +/- 3.4 mL); however, OV by use of MRI did not differ between the groups. The OV by use of MRI and ultrasound correlated in participants with PCOS (r = 0.62) but not in controls. Conclusions: Our results are in line with prior studies showing that FNPO may be a more sensitive measure of polycystic ovary morphology than OV. The results of this study support the use of ovarian k , a promising diagnostic tool for PCOS, in young patients. (Fertil Steril Rep (R) 2022;3:102-9. (c) 2022 by American Society for Reproductive Medicine.)

Abstract Introduction: There is a paucity of data exploring the effect of baseline metabolic factors on weight loss success following laparoscopic sleeve gastrectomy (LSG) in adolescents. This study aimed to identify if there is a relationship between abnormal baseline metabolic characteristics including Metabolic Syndrome (MeS), elevated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), impaired glucose tolerance, and liver function in adolescents presenting for LSG and subsequent weight loss. METHODS: This was a retrospective study at the Center for Adolescent Bariatric Surgery. Subjects were recruited from 2010-2021. Patients with diabetes, identified by fasting blood glucose ≥ 125 mg/dl, 2-hour blood glucose ≥ 200 mg/dl, or HbA1c ≥ 6.5%, were excluded. Anthropometric measurements, fasting triglycerides, HDL, glucose, ALT, HbA1c, and oral glucose tolerance test results were collected pre-surgery and at 6 and/or 12 months post-surgery. Subjects were classified as having childhood MeS using de Ferranti et. al. [1] criteria. Successful weight loss was defined by a change in BMI of at least -11.49 kg/m 2 in the 6-month group and -13. 05 kg/m 2 in the 12-month group. ALT > 22 mg/dl for females and > 26 mg/dl for males, HbA1c ≥ 5.7%, and HOMA-IR > 2.7 were considered abnormal. Chi-squared or Fisher's analyses were performed using RStudio [2], calculating the presence of a relationship between abnormal metabolic factors pre-surgery and subsequent weight loss at 6 and 12 months. A p-value of <0. 05 was considered significant. RESULTS: 143 patients (6-month group: n = 122, 12-month group: n= 78) with a mean baseline age of 16 ± 1.82 years were included. The mean baseline BMI was 46.7 ± 7.9 kg/m 2 . At baseline, 45% of patients had MeS. A greater number of patients with baseline elevated systolic blood pressure (SBP) were in the successful weight loss group compared to the unsuccessful weight loss group at 6 (p = 0. 0163) and 12 (p = 0. 0315) months. Additionally, there were more patients with abnormal baseline HbA1c in the successful weight loss group at 6 months (p = 0. 0239), albeit this was not significant at 12 months. CONCLUSION: Our results suggest that patients with elevated versus normal HbA1c levels may have greater weight loss success after LSG surgery. Performing bariatric surgery in patients with prediabetes may therefore be a key to weight loss success in the adolescent population. Further analyses are needed to elucidate the relationship between glucose metabolism dysregulation and elevated SBP at baseline and weight loss success. REFERENCES: 1. de Ferranti SD, Gauvreau K, Ludwig DS, Neufeld EJ, Newburger JW, Rifai N. Prevalence of the metabolic syndrome in American adolescents: findings from the Third National Health and Nutrition Examination Survey. Circulation. 2004;110(16): 2494-7. 2. Holleran S, Ramakrishnan R (2021). cufunctions, a package to facilitate statistical analyses in R, http: //biomath. net/cufunctions.html"> NOTES: *ACB and ASF are co-first authors. Presentation: No date and time listed