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Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes.
Bradfield, JP, Kember, RL, Ulrich, A, Balkiyarova, Z, Alyass, A, Aris, IM, Bell, JA, Broadaway, KA, Chen, Z, Chai, JF, et al
Genome biology. 2024;(1):22
Abstract
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.
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Smartphone prediction of skeletal muscle mass: model development and validation in adults.
McCarthy, C, Tinsley, GM, Yang, S, Irving, BA, Wong, MC, Bennett, JP, Shepherd, JA, Heymsfield, SB
The American journal of clinical nutrition. 2023;(4):794-801
Abstract
BACKGROUND Skeletal muscle is a large and clinically relevant body component that has been difficult and impractical to quantify outside of specialized facilities. Advances in smartphone technology now provide the opportunity to quantify multiple body surface dimensions such as circumferences, lengths, surface areas, and volumes. OBJECTIVES This study aimed to test the hypothesis that anthropometric body measurements acquired with a smartphone application can be used to accurately estimate an adult's level of muscularity. METHODS Appendicular lean mass (ALM) measured by DXA served as the reference for muscularity in a sample of 322 adults. Participants also had digital anthropometric dimensions (circumferences, lengths, and regional and total body surface areas and volumes) quantified with a 20-camera 3D imaging system. Least absolute shrinkage and selection operator (LASSO) regression procedures were used to develop the ALM prediction equations in a portion of the sample, and these models were tested in the remainder of the sample. Then, the accuracy of the prediction models was cross-validated in a second independent sample of 53 adults who underwent ALM estimation by DXA and the same digital anthropometric estimates acquired with a smartphone application. RESULTS LASSO models included multiple significant demographic and 3D digital anthropometric predictor variables. Evaluation of the models in the testing sample indicated respective RMSEs in women and men of 1.56 kg and 1.53 kg and R2's of 0.74 and 0.90, respectively. Cross-validation of the LASSO models in the smartphone application group yielded RMSEs in women and men of 1.78 kg and 1.50 kg and R2's of 0.79 and 0.95; no significant differences or bias between measured and predicted ALM values were observed. CONCLUSIONS Smartphone image capture capabilities combined with device software applications can now provide accurate renditions of the adult muscularity phenotype outside of specialized laboratory facilities. Am J Clin Nutr 2023;x:xx. This trial was registered at clinicaltrials.gov as NCT03637855 (https://clinicaltrials.gov/ct2/show/NCT03637855), NCT05217524 (https://clinicaltrials.gov/ct2/show/NCT05217524), and NCT03771417 (https://clinicaltrials.gov/ct2/show/NCT03771417).
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Reference ranges for body composition indices by dual energy X-ray absorptiometry from the Bone Mineral Density in Childhood Study Cohort.
Zemel, BS, Shepherd, JA, Grant, SFA, Lappe, JM, Oberfield, SE, Mitchell, JA, Winer, KK, Kelly, A, Kalkwarf, HJ
The American journal of clinical nutrition. 2023;(4):792-803
Abstract
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 percentiles, 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.
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What Is a 2021 Reference Body?
Müller, MJ, Bosy-Westphal, A, Braun, W, Wong, MC, Shepherd, JA, Heymsfield, SB
Nutrients. 2022;(7)
Abstract
The historical 1975 Reference Man is a ‘model’ that had been used as a basis for the calculation of radiation doses, metabolism, pharmacokinetics, sizes for organ transplantation and ergonomic optimizations in the industry, e.g., to plan dimensions of seats and other formats. The 1975 Reference Man was not an average individual of a population; it was based on the multiple characteristics of body compositions that at that time were available, i.e., mainly from autopsy data. Faced with recent technological advances, new mathematical models and socio-demographic changes within populations characterized by an increase in elderly and overweight subjects a timely ‘state-of-the-art’ 2021 Reference Body are needed. To perform this, in vivo human body composition data bases in Kiel, Baton Rouge, San Francisco and Honolulu were analyzed and detailed 2021 Reference Bodies, and they were built for both sexes and two age groups (≤40 yrs and >40 yrs) at BMIs of 20, 25, 30 and 40 kg/m2. We have taken an integrative approach to address ‘structure−structure’ and ‘structure−function’ relationships at the whole-body level using in depth body composition analyses as assessed by gold standard methods, i.e., whole body Magnetic Resonance Imaging (MRI) and the 4-compartment (4C-) model (based on deuterium dilution, dual-energy X-ray absorptiometry and body densitometry). In addition, data obtained by a three-dimensional optical scanner were used to assess body shape. The future applications of the 2021 Reference Body relate to mathematical modeling to address complex metabolic processes and pharmacokinetics using a multi-level/multi-scale approach defining health within the contexts of neurohumoral and metabolic control.
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Changes in Bone Mineral Density Following Conventional Oral Phosphonate Treatment of Hypophosphatemic Osteomalacia: A Non-Randomized Controlled Study.
Guo, Y, Zhou, YH, Wu, XP, Tang, CY, Wang, M, Mo, ZH, Shepherd, JA, Ng, BK, Fan, B, Zhou, HD
International journal of general medicine. 2021;:7925-7931
Abstract
PURPOSE There are limited clinical studies aimed at solving the problem of the efficiency of conventional treatment with oral phosphate and calcitriol in adults with hypophosphatemic osteomalacia (HO). In addition, there still had no good non-hazardous markers to evaluate the severity of bone loss of osteomalacia before and after treatment. Therefore, the purpose of this study was to assess the efficacy of conventional treatment with a self-blended phosphate supplementation and calcitriol on patients with HO and whether bone mineral density (BMD) can be helpful for monitoring the efficacy. PATIENTS AND METHODS A total of 21 HO patients and 105 healthy controls were enrolled. All patients were tested for serum biomarkers and BMD of the lumbar spine (L1-L4), femoral neck, and total left hip. After three years of treatment, 11 of 21 HO patients were recalled for BMD measurement. According to the administration of drugs, HO patients with calcium and calcitriol were divided into three phosphate treatment groups: patients in group A (n = 3) received continuous phosphate supplementation, patients in group B (n = 5) received intermittent phosphate supplementation and patients in group C (n = 3) received no phosphate supplementation. RESULTS The diagnoses of 21 HO patients were 5 cases of hereditary hypophosphatemic rickets, 4 cases of Fanconi syndrome with the features of renal tubular acidosis and vitamin D deficiency, and 12 cases of hereditary vitamin D abnormality. The average initial serum phosphorus level of the patient group was approximately 50% lower than that of the control group. Lower BMD was significantly observed in the HO group than the control group at the lumbar spine and total hip. Continuous treatment with the phosphate supplement could increase BMD in the lumbar spine and total hip by 33.4-52.3% and in the femoral neck increased by 43.2-79.3% compared with baseline, and the effect appears to be continued once treatment is discontinued. CONCLUSION These findings suggest that conventional therapy can improve bone mineral defects in patients with HO, especially in the femoral neck. Detection of BMD in HO patients is a good tool to assess the extent of bone defects and the therapeutic effect. TRIAL REGISTRATION Chinese Clinical Trial Registry, ChiCTR-OOC-16010095. Registered 7 December 2016. Retrospectively registered.
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Body Composition Measurements from Birth through 5 Years: Challenges, Gaps, and Existing & Emerging Technologies-A National Institutes of Health workshop.
Gallagher, D, Andres, A, Fields, DA, Evans, WJ, Kuczmarski, R, Lowe, WL, Lumeng, JC, Oken, E, Shepherd, JA, Sun, S, et al
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2020;(8):e13033
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Abstract
Body composition estimates are widely used in clinical research and field studies as measures of energy-nutrient balance, functionality and health. Despite their broad relevance and multiple applications, important gaps remain in techniques available for accurately and precisely quantifying body composition in infants and children from birth through 5 years. Identifying these gaps and highlighting research needs in this age group were the topics of a National Institutes of Health workshop held in Bethesda, MD, USA, 30-31 May 2019. Experts reviewed available methods (multicompartment models, air-displacement plethysmography, dual-energy X-ray absorptiometry, weight-length and height indices, bioimpedance analysis, anthropometry-skinfold techniques, quantitative magnetic resonance, optical imaging, omics and D3-creatine dilution), their limitations in this age range and high priority research needs. A summary of their individual and collective workshop deliberations is provided in this report.
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Effects of Time-Restricted Eating on Weight Loss and Other Metabolic Parameters in Women and Men With Overweight and Obesity: The TREAT Randomized Clinical Trial.
Lowe, DA, Wu, N, Rohdin-Bibby, L, Moore, AH, Kelly, N, Liu, YE, Philip, E, Vittinghoff, E, Heymsfield, SB, Olgin, JE, et al
JAMA internal medicine. 2020;(11):1491-1499
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IMPORTANCE The efficacy and safety of time-restricted eating have not been explored in large randomized clinical trials. OBJECTIVE To determine the effect of 16:8-hour time-restricted eating on weight loss and metabolic risk markers. INTERVENTIONS Participants were randomized such that the consistent meal timing (CMT) group was instructed to eat 3 structured meals per day, and the time-restricted eating (TRE) group was instructed to eat ad libitum from 12:00 pm until 8:00 pm and completely abstain from caloric intake from 8:00 pm until 12:00 pm the following day. DESIGN, SETTING, AND PARTICIPANTS This 12-week randomized clinical trial including men and women aged 18 to 64 years with a body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) of 27 to 43 was conducted on a custom mobile study application. Participants received a Bluetooth scale. Participants lived anywhere in the United States, with a subset of 50 participants living near San Francisco, California, who underwent in-person testing. MAIN OUTCOMES AND MEASURES The primary outcome was weight loss. Secondary outcomes from the in-person cohort included changes in weight, fat mass, lean mass, fasting insulin, fasting glucose, hemoglobin A1c levels, estimated energy intake, total energy expenditure, and resting energy expenditure. RESULTS Overall, 116 participants (mean [SD] age, 46.5 [10.5] years; 70 [60.3%] men) were included in the study. There was a significant decrease in weight in the TRE (-0.94 kg; 95% CI, -1.68 to -0.20; P = .01), but no significant change in the CMT group (-0.68 kg; 95% CI, -1.41 to 0.05, P = .07) or between groups (-0.26 kg; 95% CI, -1.30 to 0.78; P = .63). In the in-person cohort (n = 25 TRE, n = 25 CMT), there was a significant within-group decrease in weight in the TRE group (-1.70 kg; 95% CI, -2.56 to -0.83; P < .001). There was also a significant difference in appendicular lean mass index between groups (-0.16 kg/m2; 95% CI, -0.27 to -0.05; P = .005). There were no significant changes in any of the other secondary outcomes within or between groups. There were no differences in estimated energy intake between groups. CONCLUSIONS AND RELEVANCE Time-restricted eating, in the absence of other interventions, is not more effective in weight loss than eating throughout the day. TRIAL REGISTRATION ClinicalTrials.gov Identifiers: NCT03393195 and NCT03637855.
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Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging.
Correa-de-Araujo, R, Addison, O, Miljkovic, I, Goodpaster, BH, Bergman, BC, Clark, RV, Elena, JW, Esser, KA, Ferrucci, L, Harris-Love, MO, et al
Frontiers in physiology. 2020;:963
Abstract
Skeletal muscle fat infiltration (known as myosteatosis) is an ectopic fat depot that increases with aging and is recognized to negatively correlate with muscle mass, strength, and mobility and disrupt metabolism (insulin resistance, diabetes). An interdisciplinary workshop convened by the National Institute on Aging Division of Geriatrics and Clinical Gerontology on September 2018, discussed myosteatosis in the context of skeletal muscle function deficit (SMFD). Its purpose was to gain a better understanding of the roles of myosteatosis in aging muscles and metabolic disease, particularly its potential determinants and clinical consequences, and ways of properly assessing it. Special attention was given to functional status and standardization of measures of body composition (including the value of D3-creatine dilution method) and imaging approaches [including ways to better use dual-energy X-ray absorptiometry (DXA) through the shape and appearance modeling] to assess lean mass, sarcopenia, and myosteatosis. The workshop convened innovative new areas of scientific relevance to light such as the effect of circadian rhythms and clock disruption in skeletal muscle structure, function, metabolism, and potential contribution to increased myosteatosis. A muscle-bone interaction perspective compared mechanisms associated with myosteatosis and bone marrow adiposity. Potential preventive and therapeutic approaches highlighted ongoing work on physical activity, myostatin treatment, and calorie restriction. Myosteatosis' impact on cancer survivors raised new possibilities to identify its role and to engage in cross-disciplinary collaboration. A wide range of research opportunities and challenges in planning for the most appropriate study design, interpretation, and translation of findings into clinical practice were discussed and are presented here.
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Changes in Visceral and Subcutaneous Fat in Youth With Type 2 Diabetes in the TODAY Study.
Dhaliwal, R, Shepherd, JA, El Ghormli, L, Copeland, KC, Geffner, ME, Higgins, J, Levitsky, LL, Nadeau, KJ, Weinstock, RS, White, NH, et al
Diabetes care. 2019;(8):1549-1559
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OBJECTIVE In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, metformin plus rosiglitazone (M + R) maintained glycemic control better than metformin alone (M) or metformin plus lifestyle (M + L) in youth with type 2 diabetes (T2D). We hypothesized that changes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) would explain the differential treatment effects on glycemia. RESEARCH DESIGN AND METHODS In 626 youth ages 11-17 years with T2D duration <2 years, VAT and SAT were estimated by DXA at baseline and at 6 and 24 months. Changes from baseline were analyzed in linear mixed models. RESULTS Baseline mean age was 13.9 years, 66.4% were female, 72.2% were Hispanic/non-Hispanic black, and 20.3% were non-Hispanic white (NHW). Mean BMI was 33.7 kg/m2. VAT increased more in M + R (13.1%) than M + L (3.9%, P = 0.0006) or M (6.5%, P = 0.0146). SAT also increased more in M + R (13.3%) than in M + L (5.4%, P < 0.0001) or M (6.4%, P = 0.0005), indicating no significant fat redistribution in M + R. In NHWs, VAT increased more in M + R than M (P = 0.0192) and M + L (P = 0.0482) but did not explain the race-ethnicity differences in treatment effects on glycemic control among treatment groups. VAT and SAT increases correlated with higher HbA1c, lower insulin sensitivity, and lower oral disposition index (all P < 0.05), but associations did not differ by treatment group. CONCLUSIONS In contrast to the existing reports in adults with T2D, in TODAY, M + R resulted in the most VAT accumulation compared with M + L or M. Differential effects on depot-specific indirect measures of adiposity are unrelated to treatment effects in sustaining glycemic control. Additional studies are needed to understand the clinical markers of metabolic risk profile in youth with T2D on rosiglitazone.
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Lumbar Spine Bone Mineral Apparent Density in Children: Results From the Bone Mineral Density in Childhood Study.
Kindler, JM, Lappe, JM, Gilsanz, V, Oberfield, S, Shepherd, JA, Kelly, A, Winer, KK, Kalkwarf, HJ, Zemel, BS
The Journal of clinical endocrinology and metabolism. 2019;(4):1283-1292
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CONTEXT Dual-energy X-ray absorptiometry (DXA) is a cornerstone of pediatric bone health assessment, yet differences in height-for-age confound the interpretation of areal bone mineral density (aBMD) measures. To reduce the confounding of short stature on spine bone density, use of bone mineral apparent density (BMAD) and height-for-age Z-score (HAZ)‒adjusted aBMD (aBMDHAZ) are recommended. However, spine BMAD reference data are sparse, and the degree to which BMAD and aBMDHAZ account for height-related artifacts in bone density remains unclear. OBJECTIVE We developed age-, sex-, and population ancestry‒specific spine BMAD reference ranges; compared height-adjustment methods in accounting for shorter stature; and assessed the stability of these measures over time. DESIGN Secondary analysis of data from a previous longitudinal study. PARTICIPANTS Children and adolescents aged 5 to 19 years at baseline (n = 2014; 922 males; 22% black) from the Bone Mineral Density in Childhood Study. MAIN OUTCOME MEASURES Lumbar spine BMAD and aBMDHAZ from DXA. RESULTS Spine BMAD increased nonlinearly with age and was greater in blacks and females (all P < 0.001). Age-specific spine BMAD z-score reference curves were constructed for black and non‒black males and females. Overall, both BMAD and aBMDHAZz scores reduced the confounding influence of shorter stature, but neither was consistently unbiased across all age ranges. Both BMAD and aBMDHAZz scores tracked strongly over 6 years (r = 0.70 to 0.80; all P < 0.001). CONCLUSION This study provided robust spine BMAD reference ranges and demonstrated that BMAD and aBMDHAZ partially reduced the confounding influence of shorter stature on bone density.