Faculty Bibliography

Later puberty associates with lower areal bone mineral density (aBMD), and both are risk factors for osteoporosis. However, the association between puberty timing-associated genetic variants and aBMD during development, and the causal relationship between puberty timing and aBMD, remain uncharacterized. We constructed sex-specific polygenic risk scores (GRS) consisting of 333 genetic variants associated with later puberty in European-descent children in the Bone Mineral Density in Childhood Study (BMDCS), consisting of a longitudinal cohort with up to seven assessments (n = 933) and a cross-sectional cohort (n = 486). These GRS were tested for associations with age- and sex-specific aBMD Z-scores at the lumbar spine (LS), femoral neck (FN), total hip, and distal radius, accounting for clinical covariates using sex-stratified linear mixed models. The causal relationship between puberty timing and aBMD was tested in the BMDCS and in publicly available adult data (GEFOS consortium) using two-sample Mendelian randomization (MR). The puberty-delaying GRS was associated with later puberty and lower LS-aBMD in the BMDCS in both sexes (combined beta ± SE = -0.078 ± 0.024; p = 0.0010). In the MR framework, the puberty-delaying genetic instrument also supported a causal association with lower LS-aBMD and FN-aBMD in adults of both sexes. Our results suggest that pubertal timing is causal for diminished aBMD in a skeletal site- and sex-specific manner that tracks throughout life, potentially impacting later risk for osteoporosis, which should be tested in future studies. © 2017 American Society for Bone and Mineral Research.

Osteoporosis is a complex disease with developmental origins. It is therefore important to understand the genetic contribution to pediatric areal bone mineral density (aBMD). Individual skeletal site phenotyping has been primarily used to identify pediatric aBMD loci. However, this approach is limited because there is a degree of aBMD discordance across skeletal sites. We therefore applied a novel multidimensional phenotyping approach to further understand the genetic regulation of pediatric aBMD. Our sample comprised a prospective, longitudinal cohort of 1293 children of European ancestry (52% female; up to seven annual measurements). Principal components analysis was applied to dual-energy X-ray absorptiometry-derived aBMD Z-scores for total hip, femoral neck, spine, and distal radius to generate multidimensional aBMD phenotypes (ie, principal component scores). We tested the association between a genetic score (percentage of bone lowering alleles at 63 loci) and each principal component. We also performed a genomewide association study (GWAS) using the multiethnic baseline data (n = 1885) to identify novel loci associated with these principal components. The first component (PC1) reflected a concordant phenotypic model of the skeleton (eg, higher loading score = higher BMD across all sites). In contrast, PC2 was discordant for distal radius versus spine and hip aBMD, and PC3 was discordant for spine versus distal radius and hip aBMD. The genetic score was associated with PC1 (beta = -0.05, p = 3.9 × 10^-10 ), but was not associated with discordant PC2 or PC3. Our GWAS discovered variation near CPED1 that associated with PC2 (rs67991850, p = 2.5 × 10^-11 ) and near RAB11FIP5 (rs58649746, p = 4.8 × 10^-9 ) that associated with PC3. In conclusion, an established bone fragility genetic summary score was associated with a concordant skeletal phenotype, but not discordant skeletal phenotypes. Novel associations were observed for the discordant multidimensional skeletal phenotypes that provide new biological insights into the developing skeleton. © 2017 American Society for Bone and Mineral Research.

PURPOSE:This study aimed to determine if replacing time spent in high- and low-impact physical activity (PA) predicts changes in pediatric bone mineral density (BMD) and content (BMC). METHODS:We analyzed data from the longitudinal Bone Mineral Density in Childhood Study (N = 2337 with up to seven visits). The participants were age 5-19 yr at baseline, 51.2% were female, and 80.6% were nonblack. Spine, total hip, and femoral neck areal BMD and total body less head (TBLH) BMC Z-scores were calculated. Hours per day spent in high- and low-impact PA were self-reported. Standard covariate-adjusted (partition model) and time allocation-sensitive isotemporal substitution modeling frameworks were applied to linear mixed models. Statistical interactions with sex, self-reported ancestry, age, and bone fragility genetic scores (percentage of areal BMD-lowering alleles carried) were tested. RESULTS:In standard models, high-impact PA was positively associated with bone Z-score at all four skeletal sites (e.g., TBLH-BMC Z-score: beta = 0.05, P = 2.0 × 10), whereas low-impact PA was not associated with any of the bone Z-scores. In isotemporal substitution models, replacing 1 h·d of low- for high-impact PA was associated with higher bone Z-scores (e.g., TBLH-BMC Z-score: beta = 0.06, P = 2.9 × 10). Conversely, replacing 1 h·d of high- for low-impact PA was associated with lower bone Z-scores (e.g., TBLH-BMC Z-score: beta = -0.06, P = 2.9 × 10). The substitution associations were similar for each sex and ancestry group, and for those with higher and lower genetic scores for bone fragility (P-interactions > 0.05), but increased in strength among the older adolescents (P-age interactions < 0.05). CONCLUSIONS:Time-sensitive models suggest that replacing low-impact PA for high-impact PA would be beneficial for the growing skeleton in the majority of children.

Context:Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry. Objective:The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries. Design:Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL). Patients or Other Participants:In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study. Main Outcome Measures:Blood concentrations of 25(OH)D were measured for all participants. Results:Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively. Conclusions:Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.

Current tools for objectively measuring young children's observed behaviors are expensive, time-consuming, and require extensive training and professional administration. The lack of scalable, reliable, and validated tools impacts access to evidence-based knowledge and limits our capacity to collect population-level data in non-clinical settings. To address this gap, we developed mobile technology to collect videos of young children while they watched movies designed to elicit autism-related behaviors and then used automatic behavioral coding of these videos to quantify children's emotions and behaviors. We present results from our iPhone study Autism & Beyond, built on ResearchKit's open-source platform. The entire study-from an e-Consent process to stimuli presentation and data collection-was conducted within an iPhone-based app available in the Apple Store. Over 1 year, 1756 families with children aged 12-72 months old participated in the study, completing 5618 caregiver-reported surveys and uploading 4441 videos recorded in the child's natural settings. Usable data were collected on 87.6% of the uploaded videos. Automatic coding identified significant differences in emotion and attention by age, sex, and autism risk status. This study demonstrates the acceptability of an app-based tool to caregivers, their willingness to upload videos of their children, the feasibility of caregiver-collected data in the home, and the application of automatic behavioral encoding to quantify emotions and attention variables that are clinically meaningful and may be refined to screen children for autism and developmental disorders outside of clinical settings. This technology has the potential to transform how we screen and monitor children's development.

Publications on the prevalence of unicompartmental knee arthroplasty in the United States using a single database may have underestimated the "true" number of cases performed, given that several unicondylar knee arthroplasty (UKA) patients are <65 years and have private insurance. The prevalence of UKA in elderly (≥65 years) and younger (<65 years) populations was evaluated using the 2002 to 2011 5% sample of the Medicare data (Part B) and the 2004 to June 2012 MarketScan Commercial and Medicare Supplemental databases, respectively. The prevalence of UKA was stratified by age, gender, census region, Charlson comorbidity index, Medicare buy-in status, and diagnosis. The annual rate of change in the UKA rate was examined using Poisson regression to evaluate temporal changes considering year as a covariate. A total of 5235 and 23,310 UKA procedures were identified from the 5% Medicare and MarketScan databases, respectively. The rates of UKA generally increased until 2008, after which there was a decline. In both cohorts, gender and year of operation were found to be significantly associated with UKA rate. Analysis of data obtained over the past few years revealed that males 55 to 64 years, 65 to 69 years, and 70 to 74 years were the only age-gender groups whose UKA rates appeared to be trending upward. From 2002 to 2011, the rate of UKAs performed in the United States has increased, and a significant proportion of the surgeries were performed in younger (<65 years) patients.

Future orientation (FO) has received increasing attention for its positive effects on adolescent well-being and successful transition to adulthood. Although numerous measures of FO exist, most are not developmentally appropriate for diverse populations of adolescents, do not assess all theoretical components of FO, and/or were not developed for administration in schools. Additionally, the invariance of existing measures across racial/ethnic groups has not been examined using appropriately rigorous procedures. Using data from 2575 students in grades 6-9, this study examined the psychometric quality and measurement invariance of the FO scale on the School Success Profile (SSP) across African American (34.8%), Latino (27.0%), and European American (38.1%) subsamples. A one-factor model fit the data well in all three groups. Analyses identified only a small number of noninvariant parameters, supporting the conclusion that the scale has partial measurement invariance across the three groups. On average, African Americans had significantly higher levels of FO than the other two groups; mean scores for Latinos and European Americans were lower and statistically equivalent to each other. Construct validity of the SSP FO scale was also supported by findings of medium-sized relationships of FO scores to scores on five other constructs: low grades, school engagement, parent educational support, psychological distress, and school behavior. Multiple group tests of the magnitude and direction of the validity relationships indicated statistical equivalence across the three groups. Results support the use of the SSP FO scale by school psychologists to assess FO and to evaluate the effects of interventions targeting FO as a promoter of well-being and school success.

This study examined how experiences of service denial and discrimination in three health care settings-doctors' offices, emergency rooms, and mental health clinics-might contribute to attempted suicide among transgender adults. Mechanisms of this relationship were examined, including treatment receipt and the use of substances to cope with mistreatment. Perceived emotional social support was also tested as a potential protective factor against the deleterious effects of service denial and discrimination on treatment receipt, substance use, and attempted suicide. The analysis included 4190 respondents from the National Transgender Discrimination Survey. Structural equation modeling was employed to test hypothesized relationships. Being denied a greater number of services and discriminated against in more settings were associated with lower levels of treatment receipt. Service denial was also correlated with increased rates of coping-motivated substance use and elevated rates of attempted suicide. Treatment receipt mediated the relationships between service denial/discrimination and substance use. Substance use mediated the relationship between treatment receipt and attempted suicide. Higher levels of support were protective to treatment receipt when denied services in one setting, but no longer retained protective effects when denied in two or three settings. Results have critical implications for service access and delivery and policies that protect transgender help-seekers in the health care system.