Genetic determinants of heel bone properties: Genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n 5 14 260), velocity of sound (VOS; n 5 15 514) and BMD (n 5 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n 5 11 452) and new genotyping in 15 cohorts (de novo n 5 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 3 108) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 3 1014). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 3 106 also had the expected direction of association with any fracture (P < 0.05), including threeSNPswithP < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, thisGWAstudy reveals the effect of several genescommon to central DXA-derivedBMDand heel ultrasound/DXAmeasures and points to anewgenetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10−4, Bonferroni corrected), of which six reached P < 5 × 10−8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Child-centered teaching, redemption, and educational identities: A history of the present

Child-centeredness runs a familiar route in educational narratives. From Rousseau to Pestalozzi to Froebel to present day systems of childcare and schooling, childcenteredness is thought to have shifted the treatment of children into closer harmony with their true nature and hence into more sensitive and civilized forms of rearing. The celebratory air surrounding its deployment in education has been pervasive and difficult to contest partly because of the emotive alliances that have been drawn between child-centeredness and progressivism. That is, child-centeredness has been positioned as superseding a harsh, medieval ignorance of children while preventing present-day authoritarian strategies of domination. Child-centeredness is thus presently constituted as a soft space, as a deeply sensitive middle ground, between ignoring children and dominating them completely.

In Perpetual Motion: Theories of Power, Educational History, and the Child

"In Perpetual Motion is an "historical choreography" of power, pedagogy, and the child from the 1600s to the early 1900s. It breaks new ground by historicizing the analytics of power and motion that have interpenetrated renditions of the young. Through a detailed examination of the works of John Locke, Jean-Jacques Rousseau, Johann Herbart, and G. Stanley Hall, this book maps the discursive shifts through which the child was given a unique nature, inscribed in relation to reason, imbued with an effectible interiority, and subjected to theories of power and motion. The book illustrates how developmentalist visions took hold in U.S. public school debates. It documents how particular theories of power became submerged and taken for granted as essences inside the human subject. In Perpetual Motion studiously challenges views of power as in or of the gaze, tracing how different analytics of power have been used to theorize what gazing could notice."--BOOK JACKET.

Overfitting Bayesian mixture models with an unknown number of components

This paper proposes solutions to three issues pertaining to the estimation of finite mixture models with an unknown number of components: the non-identifiability induced by overfitting the number of components, the mixing limitations of standard Markov Chain Monte Carlo (MCMC) sampling techniques, and the related label switching problem. An overfitting approach is used to estimate the number of components in a finite mixture model via a Zmix algorithm. Zmix provides a bridge between multidimensional samplers and test based estimation methods, whereby priors are chosen to encourage extra groups to have weights approaching zero. MCMC sampling is made possible by the implementation of prior parallel tempering, an extension of parallel tempering. Zmix can accurately estimate the number of components, posterior parameter estimates and allocation probabilities given a sufficiently large sample size. The results will reflect uncertainty in the final model and will report the range of possible candidate models and their respective estimated probabilities from a single run. Label switching is resolved with a computationally light-weight method, Zswitch, developed for overfitted mixtures by exploiting the intuitiveness of allocation-based relabelling algorithms and the precision of label-invariant loss functions. Four simulation studies are included to illustrate Zmix and Zswitch, as well as three case studies from the literature. All methods are available as part of the R package Zmix, which can currently be applied to univariate Gaussian mixture models.

A lifespan perspective on leadership

In this chapter, we present a lifespan model of leadership that outlines how leader and follower age as well as age-related changes in leader traits and characteristics, leader behaviors, and follower attribution and identification processes may influence leadership effectiveness. First, we describe how leader traits and characteristics change with age and how these developmental changes may impact on leader behaviors and, subsequently, leadership effectiveness. Specifically, we discuss age-related changes in leaders’ task competence, interpersonal attributes, and motivation to lead. We particularly focus on how generativity – a set of interconnected motives pertaining to establishing and guiding future generations – may emerge as an important concern among older leaders. Second, we review theoretical approaches that help explain how and why leader age and age-related traits and characteristics, follower age, as well as leader-follower age differences may influence follower attribution and identification processes. Third, we outline a number of boundary conditions of the effects proposed by our lifespan model of leadership, including leader-follower relationship duration, situational characteristics, as well as the cultural, social, and historical context. We conclude the chapter by discussing our model’s implications for future research and organizational practice.

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF