BackgroundBody mass index (BMI) is criticized for not distinguishing fat from lean mass and ignoring fat distribution, leaving its ability to detect health effects unclear.ObjectivesThe aim of this study was to compare BMI with total and regional fat indexes from dual-energy x-ray absorptiometry in their associations with cardiometabolic traits. Duration of exposure to and change in each index across adolescence were examined in relation to detailed traits in young adulthood.MethodsBMI was examined alongside total, trunk, arm, and leg fat indexes (each in kilograms per square meter) from dual-energy x-ray absorptiometry at ages 10 and 18 years in relation to 230 traits from targeted metabolomics at age 18 years in 2,840 offspring from the Avon Longitudinal Study of Parents and Children.ResultsHigher total fat mass index and BMI at age 10 years were similarly associated with cardiometabolic traits at age 18 years, including higher systolic and diastolic blood pressure, higher very low-density lipoprotein and low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, higher triglycerides, and higher insulin and glycoprotein acetyls. Associations were stronger for both indexes measured at age 18 years and for gains in each index from age 10 to 18 years (e.g., 0.45 SDs [95% confidence interval: 0.38 to 0.53] in glycoprotein acetyls per SD unit gain in fat mass index vs. 0.38 SDs [95% confidence interval: 0.27 to 0.48] per SD unit gain in BMI). Associations resembled those for trunk fat index. Higher lean mass index was weakly associated with traits and was not protective against higher fat mass index.ConclusionsThe results of this study support abdominal fatness as a primary driver of cardiometabolic dysfunction and BMI as a useful tool for detecting its effects.

IMPORTANCE Bone health in early life is thought to influence the risk of osteoporosis in later life. OBJECTIVE To examine whether puberty timing is associated with bone mineral density accrual up to adulthood. DESIGN, SETTING, AND PARTICIPANTS This cohort study used data from the Avon Longitudinal Study of Parents and Children, a prospective population-based birth cohort initiated in 1991 to 1992 in southwest England. The participants were 6389 healthy British people who underwent regular follow-up, including up to 6 repeated bone density scans from ages 10 to 25 years. Data analysis was performed from June 2018 to June 2019. EXPOSURES Age at puberty from estimated age at peak height velocity (years). MAIN OUTCOMES AND MEASURES Gains per year in whole-body bone mineral density (grams per square centimeter), assessed by dual-energy x-ray absorptiometry at ages 10, 12, 14, 16, 18, and 25 years and modeled using linear splines. RESULTS A total of 6389 participants (3196 [50.0%] female) were included. The mean (SD) age at peak height velocity was 13.5 (0.9) years for male participants and 11.6 (0.8) years for female participants. Male participants gained bone mineral density at faster rates than did female participants, with the greatest gains in both male participants (0.139 g/cm 2 /y; 95% CI, 0.127-0.151 g/cm 2 /y) and female participants (0.106 g/cm 2 /y; 95% CI, 0.098-0.114 g/cm 2 /y) observed between the year before and 2 years after peak height velocity. When aligned by chronological age, per 1-year older age at puberty was associated with faster subsequent gains in bone mineral density; the magnitudes of faster gains were greatest between ages 14 and 16 years in both male participants (0.013 g/cm 2 /y; 95% CI, 0.011-0.015 g/cm 2 /y) and female participants (0.014 g/cm 2 /y; 95% CI, 0.014-0.015 g/cm 2 /y), were greater in male participants (0.011 g/cm 2 /y; 95% CI, 0.010-0.013 g/cm 2 /y) than in female participants (0.003 g/cm 2 /y; 95% CI, 0.003-0.004 g/cm 2 /y) between ages 16 and 18 years, and were least in both male participants (0.002 g/cm 2 /y; 95% CI, 0.001-0.003 g/cm 2 /y) and female participants (0.000 g/cm 2 /y; 95% CI, −0.001 to 0.000 g/cm 2 /y) between ages 18 and 25 years. Despite faster gains, older age at puberty was associated with persistently lower bone mineral density, changing from 0.050 g/cm 2 (95% CI, −0.056 to −0.045 g/cm 2) lower at age 14 years to 0.047 g/cm 2 (95% CI, −0.051 to −0.043 g/cm 2) lower at age 25 years in male participants and from 0.044 g/cm 2 (95% CI, −0.046 to −0.041 g/cm 2) to 0.034 g/cm 2 (95% CI, −0.036 to −0.032 g/cm 2) lower at the same ages in female participants. (continued) Key Points Question Is puberty timing associated with growth-related bone accrual up to adulthood? Findings In this cohort study of 6389 participants who underwent repeated bone density scans from ages 10 to 25 years, later puberty was associated with persistently lower bone mineral density, despite some catch-up during puberty. Meaning People with older pubertal age should be advised on how t...

Puberty is a time of substantial biological and psychological changes. One of the hallmarks of puberty is a rapid growth spurt, however its timing varies between individuals. The impact of pubertal timing on later health outcomes has been of interest in life course epidemiology, however its measurement can be challenging. Age at peak height velocity (aPHV) offers an objective measure of pubertal timing without having to rely on physical examination or self-report. We describe the derivation of aPHV estimates in Avon Longitudinal Study of Parents and Children (ALSPAC) offspring, using Superimposition by Translation And Rotation (SITAR) mixed effects growth curve analysis. ALSPAC is a rich source of phenotypic and genotypic data and given the importance of pubertal timing for later health outcomes, these data offer an opportunity to explore the determinants and consequences of aPHV.

Objective Conventional scoring methods for radiographic hip osteoarthritis (rHOA) are subjective and show inconsistent relationships with clinical outcomes. To provide a more objective rHOA scoring method, we aimed to develop a semi-automated classifier based on dual-energy X-ray absorptiometry (DXA) images, and confirm its relationships with clinical outcomes. Methods Hip DXAs in UK Biobank (UKB) were marked up for osteophyte area from which acetabular, superior and inferior femoral head osteophyte grades were derived. Joint space narrowing (JSN) grade was obtained automatically from minimum joint space width (mJSW) measures. Clinical outcomes related to rHOA comprised hip pain, hospital diagnosed OA (HES OA) and total hip replacement (THR). Logistic regression and Cox proportional hazard modelling were used to examine associations between overall rHOA grade (0–4; derived from combining osteophyte and JSN grades), and the clinical outcomes. Results 40 340 individuals were included in the study (mean age 63.7), of whom 81.2% had no evidence of rHOA, while 18.8% had grade ≥1 rHOA. Grade ≥1 osteophytes at each location and JSN were associated with hip pain, HES OA and THR. Associations with all three clinical outcomes increased progressively according to rHOA grade, with grade 4 rHOA and THR showing the strongest association [57.70 (38.08–87.44)]. Conclusions Our novel semi-automated tool provides a useful means for classifying rHOA on hip DXAs, given its strong and progressive relationships with clinical outcomes. These findings suggest DXA scanning can be used to classify rHOA in large DXA-based cohort studies supporting further research, with the future potential for population-based screening.

STUDY QUESTION Is earlier puberty more likely a result of adiposity gain in childhood than a cause of adiposity gain in adulthood? SUMMARY ANSWER Pre-pubertal fat mass is associated with earlier puberty timing but puberty timing is not associated with post-pubertal fat mass change. WHAT IS KNOWN ALREADY Age at puberty onset has decreased substantially in the last several decades. Whether reducing childhood adiposity prevents earlier puberty and if early puberty prevention itself also has additional independent benefits for prevention of adult adiposity is not well understood. STUDY DESIGN, SIZE, DURATION Prospective birth cohort study of 4176 participants born in 1991/1992 with 18 232 repeated measures of fat mass from age 9 to 18 years. PARTICIPANTS/MATERIALS, SETTING, METHODS We used repeated measures of height from 5 to 20 years to identify puberty timing (age at peak height velocity, aPHV) and repeated measures of directly measured fat mass from age 9 to 18 years, from a contemporary UK birth cohort study to model fat mass trajectories by chronological age and by time before and after puberty onset. We then examined associations of these trajectories with puberty timing separately in females and males. MAIN RESULTS AND THE ROLE OF CHANCE In models by chronological age, a 1-year later aPHV was associated with 20.5% (95% confidence interval (CI): 18.6–22.4%) and 23.4% (95% (CI): 21.3–25.5%) lower fat mass in females and males, respectively, at 9 years. These differences were smaller at age 18 years: 7.8% (95% (CI): 5.9–9.6%) and 12.4% (95% (CI): 9.6–15.2%) lower fat mass in females and males per year later aPHV. Trajectories of fat mass by time before and after puberty provided strong evidence for an association of pre-pubertal fat mass with puberty timing, and little evidence of an association of puberty timing with post-pubertal fat mass change. The role of chance is likely to be small in this study given the large sample sizes available. LIMITATIONS, REASONS FOR CAUTION Participants included in our analyses were more socially advantaged than those excluded. The findings of this work may not apply to non-White populations and further work examining associations of puberty timing and fat mass in other ethnicities is required. WIDER IMPLICATIONS OF THE FINDINGS Previous research has relied on self-reported measures of puberty timing such as age of voice breaking in males, has lacked data on pre-and post-pubertal adiposity together and relied predominantly on indirect measures of adiposity such as BMI. This has led to conflicting results on the nature and direction of the association between puberty timing and adiposity in females and males. Our work provides important clarity on this, suggesting that prevention of adiposity in childhood is key for prevention of early puberty, adult adiposity and associated cardiovascular risk. In contrast, our findings suggest that prevention of early puberty without prevention of childhood adiposity would have little impact on prevention of adult adiposity. STUDY FUNDING/COMPETING INTEREST(S) The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for Avon Longitudinal Study of Parents and Children (ALSPAC). L.M.O.K. is supported by a UK Medical Research Council Population Health Scientist fellowship (MR/M014509/1) and a Health Research Board (HRB) of Ireland Emerging Investigator Award (EIA-FA-2019-007 SCaRLeT). J.A.B. is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). L.D.H. and A.F. are supported by Career Development Awards from the UK Medical Research Council (grants MR/M020894/1 and MR/M009351/1, respectively). All authors work in a unit that receives funds from the UK Medical Research Council (grant MC_UU_00011/3, MC_UU_00011/6). No competing interests to declare. TRIAL REGISTRATION NUMBER N/A.

The contribution of shape changes to hip osteoarthritis (HOA) remains unclear, as is the extent to which these vary according to HOA severity. In the present study, we used statistical shape modeling (SSM) to evaluate relationships between hip shape and HOA of different severities using UK Biobank DXA images. We performed a cross-sectional study in individuals with left hip dual-energy X-ray absorptiometry (DXA) scans. Statistical shape modeling (SSM) was used to quantify hip shape. Radiographic HOA (rHOA) was classified using osteophyte size and number and joint space narrowing. HOA outcomes ranged in severity from moderate (grade 2) to severe (grade ≥3) rHOA, hospital-diagnosed HOA, and subsequent total hip replacement (THR). Confounder-adjusted logistic regression between the top 10 hip shape modes (HSMs) and OA outcomes was performed. Further models adjusted for alpha angle (AA) and lateral center-edge angle (LCEA), reflecting acetabular dysplasia and cam morphology, respectively. Composite HSM figures were produced combining HSMs associated with separate OA outcomes. A total of 40,311 individuals were included (mean 63.7 years, 47.8% male), of whom 5.7% had grade 2 rHOA, 1.7% grade ≥3 rHOA, 1.3% hospital-diagnosed HOA, and 0.6% underwent THR. Composite HSM figures for grade 2 rHOA revealed femoral neck widening, increased acetabular coverage, and enlarged lesser and greater trochanters. In contrast, grade ≥3 rHOA, hospital-diagnosed HOA, and THR were suggestive of cam morphology and reduced acetabular coverage. Associations between HSMs depicting cam morphology and reduced acetabular coverage and more severe HOA were attenuated by AA and LCEA adjustment, respectively. Relationships between hip shape and HOA differed according to severity. Notably, cam morphology and acetabular dysplasia were features of severe HOA, but unrelated to moderate disease, suggesting possible prognostic utility.

The relationship between circulating total bilirubin and incident non-alcoholic fatty liver disease (NAFLD) is uncertain. We aimed to assess the association of total bilirubin with the risk of new-onset NAFLD and investigate any causal relevance to the association using a Mendelian randomization (MR) study. Plasma total bilirubin levels were measured at baseline in the PREVEND prospective study of 3824 participants (aged 28-75 years) without pre-existing cardiovascular disease or NAFLD. Incident NAFLD was estimated using the biomarker-based algorithms, fatty liver index (FLI) and hepatic steatosis index (HSI). Odds ratios (ORs) (95% confidence intervals) for NAFLD were assessed. The genetic variant rs6742078 located in the UDP-glucuronosyltransferase (UGT1A1) locus was used as an instrumental variable. Participants were followed up for a mean duration of 4.2 years. The multivariable adjusted OR (95% CIs) for NAFLD as estimated by FLI (434 cases) was 0.82 (0.73-0.92; p = 0.001) per 1 standard deviation (SD) change in log e total bilirubin. The corresponding adjusted OR (95% CIs) for NAFLD as estimated by HSI (452 cases) was 0.87 (0.78-0.97; p = 0.012). The rs6742078 variant explained 20% of bilirubin variation. The ORs (95% CIs) for a 1 SD genetically elevated total bilirubin level was 0.98 (0.69-1.38; p = 0.900) for FLI and 1.14 (0.81-1.59; p = 0.451) for HSI. Elevated levels of total bilirubin were not causally associated with decreased risk of NAFLD based on MR analysis. The observational association may be driven by biases such as unmeasured confounding and/or reverse causation. However, due to low statistical power, larger-scale investigations are necessary to draw definitive conclusions.

Puberty is a time of substantial biological and psychological changes. One of the hallmarks of puberty is a rapid growth spurt, however its timing varies between individuals. The impact of pubertal timing on later health outcomes has been of interest in life course epidemiology, however its measurement can be challenging. Age at peak height velocity (aPHV) offers an objective measure of pubertal timing without having to rely on physical examination or self-report. We describe the derivation of aPHV estimates in Avon Longitudinal Study of Parents and Children (ALSPAC) offspring, using Superimposition by Translation And Rotation (SITAR) mixed effects growth curve analysis. ALSPAC is a rich source of phenotypic and genotypic data and given the importance of pubertal timing for later health outcomes, these data offer an opportunity to explore the determinants and consequences of aPHV.