A Haplotype-Based Permutation Approach in Gene-Based Testing

The soaring cost of health care is the biggest public health issue facing our country today. Development of strategies that improve the delivery of health care by identifying high risk individuals for a disease is a major approach to better utilize limited medical resources. Incorporating genomic data into risk stratification models is an essential component for creating these diagnostic and treatment strategies. Although initially applied to just small subsets of disease, advances in technology are making it economically feasible to utilize a patient's genomic data in a wider range of medical disorders. Current genetic association studies are crucial for identifying which loci to include in these models. Genome Wide Association Studies (GWAS) are a valuable tool for identifying genetic variants associated with disease. Commonly, each SNP is initially independently tested in a GWAS with a univariate analysis. By combining the effects of multiple alleles, multivariate analysis of GWAS may increase power to detect associations and, thus, identify additional risk loci. We employ a haplotype block analysis within genes boundaries for a newly developed gene-based method, “GeneBlock”. GeneBlock is compared in a power analysis with two previously published permutation algorithms (GWiS and Fisher) and a simulation method (Vegas). All methods are tested in an Alzheimer Disease GWAS consisting of 1334 cases and 1475 controls. Results from the Alzheimer’s analysis were subsequently compared with haplotype and univariate analysis. Power analyses shows both GeneBlock and GWiS as more powerful methods than Vegas and Fisher. A combinational approach involving the selection of the lowest p-value from Vegas, GWiS, and Geneblock has higher power than any individual method even when controlling for the additional multiple comparisons. Fisher and Vegas identify no significant genes in the Alzheimer’s GWAS, while GWiS and Geneblock identified four (PRDM16, ARHGEF16, HLA-DRA, TRAF1) and three (C17orf51, MGC29506, SLC23A1) respectively. The combination method is also most powerful in the real GWAS data; it identified all seven of the above significant genes. Comparing single, haplotype, and gene level analyses revealed that only about 1/3 of the top 100 genes are shared, indicating a large variance in results between methods

Galactic interstellar 18O/17O ratios - a radial gradient?

(Abridged) Our aim is to determine 18O/17O abundance ratios across the entire Galaxy. These provide a measure of the amount of enrichment by high-mass versus intermediate-mass stars. Such ratios, derived from the C18O and C17O J=1-0 lines alone, may be affected by systematic errors. Therefore, the C18O and C17O (1-0), (2-1), and (3-2), as well as the 13CO (1-0) and (2-1) lines, were observed towards 18 prominent galactic targets (a total of 25 positions). The combined dataset was analysed with an LVG model, accounting for optical depth effects. The data cover galactocentric radii R between 0.1 and 16.9 kpc (solar circle at 8.5 kpc). Near the centre of the Galaxy, 18O/17O = 2.88 +/- 0.11. For the galactic disc out to an R of ca. 10 kpc, 18O/17O = 4.16 +/- 0.09. At ca. R = 16.5 kpc, 18O/17O = 5.03 +/- 0.46. Assuming that 18O is synthesised predominantly in high-mass stars (M > 8 Msun), while C17O is mainly a product of lower-mass stars, the ratio from the inner Galaxy indicates a dominance of CNO-hydrogen burning products that is also apparent in the C- and N-isotope ratios. The high 18O/17O value of the solar system (5.5) relative to that of the ambient ISM suggests contamination by nearby high-mass stars during its formation. High values in the metal-poor environment of the outer Galaxy are not matched by the low values observed towards the even more metal-poor LMC. Apparently, the outer Galaxy cannot be considered as an intermediate environment between the solar neighbourhood and the ISM of small metal-poor galaxies. The apparent 18O/17O gradient along the galactic disc and the discrepancy between outer disc and LMC isotope ratios may be explained by different ages of the respective stellar populations.Comment: Accepted by Astron. & Astroph.; 10 pages + 4 pages on-line material (figs

The interstellar C18O/C17O ratio in the solar neighbourhood: The rho Oph cloud

Observations of up to ten carbon monoxide (CO and isotopomers) transitions are presented to study the interstellar C18O/C17O ratio towards 21 positions in the nearby (d~140pc) low-mass star forming cloud rho Oph. A map of the C18O J=1-0 distribution of parts of the cloud is also shown. An average 12C18O/12C17O isotopomeric ratio of 4.11 +/- 0.14, reflecting the 18O/17O isotope ratio, is derived from Large Velocity Gradient (LVG) calculations. From LTE column densities we derive a ratio of 4.17 +/-0.26. These calculations also show that the kinetic temperature decreases from about 30 K in the cloud envelope to about 10 K in the cloud cores. This decrease is accompanied by an increase of the average molecular hydrogen density from 10^4 cm-3 to >10^5 cm-3. Towards some lines of sight C18O optical depths reach values of order unity.Comment: 13 pages, 9 figures; accepted for publication in A&

A Precise Proper Motion for the Crab Pulsar, and the Difficulty of Testing Spin-Kick Alignment for Young Neutron Stars

We present a detailed measurement of the proper motion of the Crab pulsar, with the primary goal of comparing the direction of its proper motion with the projected axis of its pulsar wind nebula (the projected spin axis of the pulsar). We demonstrate that our measurement is robust and has an uncertainty of only +/-0.4 mas/yr on each component of the proper motion. We find mu_alpha = -11.7+/-0.4+/-0.5 mas/yr and mu_delta = +4.2+/-0.4+/-0.5 mas/yr relative to the pulsar's standard of rest, where the two uncertainties are from the measurement and the ncertainties in correcting the proper motion reference frame, respectively. Comparing this proper motion to the symmetry axis of the pulsar wind nebula, we must also consider the unknown velocity of the pulsar's progenitor (assumed to be ~10 km/s), and hence add an additional uncertainty of +/-2 mas/yr to each component of the proper motion, although this could be significantly larger. This implies a projected misalignment with the nebular axis of 14+/-2+/-9 degrees. We conclude that the precision of individual measurements which compare the direction of motion of a neutron star to a fixed axis will often be limited by fundamental uncertainties regarding reference frames and progenitor properties. The question of spin-kick (mis)alignment, and its implications for asymmetries and other processes during supernova core-collapse, is best approached by considering a statistical ensemble of such measurements, rather than detailed studies of individual sources. [abriged]Comment: 15 pages, 6 figures. Accepted for publication in ApJ. Figure 3 fixed, included at low resolutio

Grain boundary pinning and glassy dynamics in stripe phases

We study numerically and analytically the coarsening of stripe phases in two spatial dimensions, and show that transient configurations do not achieve long ranged orientational order but rather evolve into glassy configurations with very slow dynamics. In the absence of thermal fluctuations, defects such as grain boundaries become pinned in an effective periodic potential that is induced by the underlying periodicity of the stripe pattern itself. Pinning arises without quenched disorder from the non-adiabatic coupling between the slowly varying envelope of the order parameter around a defect, and its fast variation over the stripe wavelength. The characteristic size of ordered domains asymptotes to a finite value $R_g \sim \lambda_0\ \epsilon^{-1/2}\exp(|a|/\sqrt{\epsilon})$, where$\epsilon\ll 1$is the dimensionless distance away from threshold,$\lambda_0$the stripe wavelength, and$a$ a constant of order unity. Random fluctuations allow defect motion to resume until a new characteristic scale is reached, function of the intensity of the fluctuations. We finally discuss the relationship between defect pinning and the coarsening laws obtained in the intermediate time regime.Comment: 17 pages, 8 figures. Corrected version with one new figur

Non-isothermal model for the direct isotropic/smectic-A liquid crystalline transition

An extension to a high-order model for the direct isotropic/smectic-A liquid crystalline phase transition was derived to take into account thermal effects including anisotropic thermal diffusion and latent heat of phase-ordering. Multi-scale multi-transport simulations of the non-isothermal model were compared to isothermal simulation, showing that the presented model extension corrects the standard Landau-de Gennes prediction from constant growth to diffusion-limited growth, under shallow quench/undercooling conditions. Non-isothermal simulations, where meta-stable nematic pre-ordering precedes smectic-A growth, were also conducted and novel non-monotonic phase-transformation kinetics observed.Comment: First revision: 20 pages, 7 figure

No straight lines – young women’s perceptions of their mental health and wellbeing during and after pregnancy: a systematic review and meta-ethnography

Background: Young mothers face mental health challenges during and after pregnancy including increased rates of depression compared to older mothers. While the prevention of teenage pregnancy in countries such as the United States and the United Kingdom has been a focus for policy and research in recent decades, the need to understand young women’s own experiences has been highlighted. The aim of this meta-ethnography was to examine young women’s perceptions of their mental health and wellbeing during and after pregnancy to provide new understandings of those experiences. Methods: A systematic review and meta-ethnographic synthesis of qualitative research was conducted. Seven databases were systematically searched and forward and backward searching conducted. Papers were included if they were from Organisation for Economic Co-operation and Development countries and explored mental health and wellbeing experiences of young mothers (age under 20 in pregnancy; under 25 at time of research) as a primary research question – or where evidence about mental health and wellbeing from participants was foregrounded. Nineteen papers were identified and the Critical Appraisal Skills Programme checklist for qualitative research used to appraise the evidence. Following the seven-step process of meta-ethnography, key constructs were examined within each study and then translated into one another. Results: Seven translated themes were identified forming a new line of argument wherein mental health and wellbeing was analysed as relating to individual bodily experiences; tied into past and present relationships; underpinned by economic insecurity and entangled with feelings of societal surveillance. There were ‘no straight lines’ in young women’s experiences, which were more complex than dominant narratives around overcoming adversity suggest. Conclusions: The synthesis concludes that health and social care professionals need to reflect on the operation of power and stigma in young women’s lives and its impact on wellbeing. It adds to understanding of young women’s mental health and wellbeing during and after pregnancy as located in physical and structural factors rather than individual capacities alone

Performance of the LHCb vertex locator

The Vertex Locator (VELO) is a silicon microstrip detector that surrounds the proton-proton interaction region in the LHCb experiment. The performance of the detector during the first years of its physics operation is reviewed. The system is operated in vacuum, uses a bi-phase CO2 cooling system, and the sensors are moved to 7 mm from the LHC beam for physics data taking. The performance and stability of these characteristic features of the detector are described, and details of the material budget are given. The calibration of the timing and the data processing algorithms that are implemented in FPGAs are described. The system performance is fully characterised. The sensors have a signal to noise ratio of approximately 20 and a best hit resolution of 4 μm is achieved at the optimal track angle. The typical detector occupancy for minimum bias events in standard operating conditions in 2011 is around 0.5%, and the detector has less than 1% of faulty strips. The proximity of the detector to the beam means that the inner regions of the n+-on-n sensors have undergone space-charge sign inversion due to radiation damage. The VELO performance parameters that drive the experiment's physics sensitivity are also given. The track finding efficiency of the VELO is typically above 98% and the modules have been aligned to a precision of 1 μm for translations in the plane transverse to the beam. A primary vertex resolution of 13 μm in the transverse plane and 71 μm along the beam axis is achieved for vertices with 25 tracks. An impact parameter resolution of less than 35 μm is achieved for particles with transverse momentum greater than 1 GeV/c