Computing power of quantitative trait locus association mapping for haploid loci

<p>Abstract</p> <p>Background</p> <p>Statistical power calculations are a critical part of any study design for gene mapping. Most calculations assume that the locus of interest is biallelic. However, there are common situations in human genetics such as X-linked loci in males where the locus is haploid. The purpose of this work is to mathematically derive the biometric model for haploid loci, and to compute power for QTL mapping when the loci are haploid.</p> <p>Results</p> <p>We have derived the biometric model for power calculations for haploid loci and have developed software to perform these calculations. We have verified our calculations with independent mathematical methods.</p> <p>Conclusion</p> <p>Our results fill a need in power calculations for QTL mapping studies. Furthermore, failure to appropriately model haploid loci may cause underestimation of power.</p

Nicorandil, gastrointestinal adverse drug reactions and ulcerations: a systematic review.

Nicorandil is a popular anti-anginal drug in Europe and Japan. Apart from some common adverse drug reactions (ADR), its safety is satisfactory. Several reports have suggested a link between nicorandil, gastrointestinal (GI) ulceration and fistulas. This review aims to critically appraise, synthesize and present the available evidence of all known GI ADR per anatomical location. The study complied with the PRISMA statement. Literature and pharmacovigilance databases were used to provide rate and/or calculate parameters (median age, median dose, history of symptoms, length of therapy and healing time after withdrawal of the drug). Differences in distribution of quantitative variables were analyzed via Mann-Whitney test. Correlation between quantitative variables was assessed with a Spearman's correlation coefficient. A p value < 0.05 was significant. The study found that oral ulcerations occur in 0.2% of the subjects, anal ulcerations are present between 0.07% and 0.37% of patients. Oral and distal GI involvements are the most common ADR (28-29% and 27-31% of all GI ADR, respectively). The hepatobiliary system, the pancreas and salivary glands are not affected by nicorandil exposure. The time to develop oral ulcerations is 74 weeks among people on < 30 mg/day, compared to only 7.5 weeks in individuals on higher regimens (p = 0.47). There is a significant correlation between dose and ulcer healing time (Spearman's 0.525, p < 0.001). In conclusion, ulcerative disease is a very commonly reported GI ADR. A delayed ulcerative tendency supports the hypothesis of an ulcerogenic metabolite. Nicorandil seems to act as a cause of the ulcerations, but appears to also work in synergy with other promoting factors. Whether the action of the metabolites relies on a specific mechanism or a simple chemical ulceration is still to be established

Kepler-16: A Transiting Circumbinary Planet

We report the detection of a planet whose orbit surrounds a pair of low-mass stars. Data from the Kepler spacecraft reveal transits of the planet across both stars, in addition to the mutual eclipses of the stars, giving precise constraints on the absolute dimensions of all three bodies. The planet is comparable to Saturn in mass and size, and is on a nearly circular 229-day orbit around its two parent stars. The eclipsing stars are 20% and 69% as massive as the sun, and have an eccentric 41-day orbit. The motions of all three bodies are confined to within 0.5 degree of a single plane, suggesting that the planet formed within a circumbinary disk.Comment: Science, in press; for supplemental material see http://www.sciencemag.org/content/suppl/2011/09/14/333.6049.1602.DC1/1210923.Doyle.SOM.pd

An ammonia spectral map of the L1495-B218 filaments in the Taurus molecular cloud. I. Physical properties of filaments and dense cores

We present deep NH3 observations of the L1495-B218 filaments in the Taurus molecular cloud covering over a 3° angular range using the K-band focal plane array on the 100 m Green Bank Telescope. The L1495-B218 filaments form an interconnected, nearby, large complex extending over 8 pc. We observed NH3 (1, 1) and (2, 2) with a spectral resolution of 0.038 km s−1 and a spatial resolution of 31''. Most of the ammonia peaks coincide with intensity peaks in dust continuum maps at 350 and 500 μm. We deduced physical properties by fitting a model to the observed spectra. We find gas kinetic temperatures of 8–15 K, velocity dispersions of 0.05–0.25 km s−1, and NH3 column densities of 5 × 1012 to 1 × 1014 cm−2. The CSAR algorithm, which is a hybrid of seeded-watershed and binary dendrogram algorithms, identifies a total of 55 NH3 structures, including 39 leaves and 16 branches. The masses of the NH3 sources range from 0.05 to 9.5 ${{M}_{\odot }}$. The masses of NH3 leaves are mostly smaller than their corresponding virial mass estimated from their internal and gravitational energies, which suggests that these leaves are gravitationally unbound structures. Nine out of 39 NH3 leaves are gravitationally bound, and seven out of nine gravitationally bound NH3 leaves are associated with star formation. We also found that 12 out of 30 gravitationally unbound leaves are pressure confined. Our data suggest that a dense core may form as a pressure-confined structure, evolve to a gravitationally bound core, and undergo collapse to form a protostar

The Nitric Oxide Donor DETA-NONOate Decreases Matrix Metalloproteinase-9 Expression and Activity in Rat Aortic Smooth Muscle and Abdominal Aortic Explants

Our objective was to examine the role of an exogenous nitric oxide (NO) donor, DETA-NONOate (DETA), on matrix metalloproteinase (MMP)-9, MMP-2, and tissue inhibitor of matrix metalloproteinases (TIMP)-1 expression and activity in interleukin (IL)-1β-induced rat aortic smooth muscle cells (RA-SMCs) and rat aortic explants (RAEs). RA-SMCs were incubated with IL-1β (2 ng/ml), an inflammatory cytokine known to induce MMP-9 expression, and increasing concentrations of DETA (0, 1.0, 10, 100 μM; n = 3/group) for 48 hr. RAEs were incubated with IL-1β (2 ng/mL) and increasing concentrations of DETA (0, 5.0, 50, 100, and 500 μM; n = 3/group) for 48 hr. Media were collected and assayed for NO x by the Griess reaction and MMP-9 activity by zymography. Messenger RNA (mRNA) was extracted from cells and analyzed for MMP-9, MMP-2, and TIMP-1 expression levels by quantitative real-time reverse-transcriptase polymerase chain reaction. All statistical analyses were performed by analysis of variance. In RA-SMCs and RAEs, DETA administration resulted in a dose-dependent increase in media NO x concentration (RA-SCM p < 0.01, RAE p < 0.01) and a concurrent decrease in both MMP-9 expression (RASMC p = 0.01, RAE p = 0.01) and activity (RASMC p = 0.04, RAE p = 0.006). There were no significant differences seen in MMP-2 and TIMP-1 expression or activity in response to DETA exposure. DETA decreased IL-1β-induced MMP-9 expression and activity in both RA-SMCs and RAEs in a dose-dependent fashion. In addition, DETA administration had no effect on MMP-2 or TIMP-1 expression or activity in vitro. These data suggest that NO donors may be beneficial in decreasing MMP-9 levels and might serve to inhibit MMP-9-dependent vessel wall remodeling seen during abdominal aortic aneurysm formation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41371/1/10016_2005_Article_9429.pd

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial

Background Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the eff ect of early detection by screening on ovarian cancer mortality. Methods In this randomised controlled trial, we recruited postmenopausal women aged 50–74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computergenerated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. Findings Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202 638 women: 50 640 (25·0%) to MMS, 50 639 (25·0%) to USS, and 101 359 (50·0%) to no screening. 202 546 (>99·9%) women were eligible for analysis: 50 624 (>99·9%) women in the MMS group, 50 623 (>99·9%) in the USS group, and 101 299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345 570 MMS and 327 775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0–12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0–14 of 15% (95% CI –3 to 30; p=0·10) with MMS and 11% (–7 to 27; p=0·21) with USS. The Royston-Parmar fl exible parametric model showed that in the MMS group, this mortality eff ect was made up of 8% (–20 to 31) in years 0–7 and 23% (1–46) in years 7–14, and in the USS group, of 2% (–27 to 26) in years 0–7 and 21% (–2 to 42) in years 7–14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly diff erent death rates (p=0·021), with an overall average mortality reduction of 20% (–2 to 40) and a reduction of 8% (–27 to 43) in years 0–7 and 28% (–3 to 49) in years 7–14 in favour of MMS. Interpretation Although the mortality reduction was not signifi cant in the primary analysis, we noted a signifi cant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7–14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-eff ectiveness of ovarian cancer screening

The Flat Transmission Spectrum of the Super-Earth GJ1214b from Wide Field Camera 3 on the Hubble Space Telescope

Capitalizing on the observational advantage offered by its tiny M dwarf host, we present HST/WFC3 grism measurements of the transmission spectrum of the super-Earth exoplanet GJ1214b. These are the first published WFC3 observations of a transiting exoplanet atmosphere. After correcting for a ramp-like instrumental systematic, we achieve nearly photon-limited precision in these observations, finding the transmission spectrum of GJ1214b to be flat between 1.1 and 1.7 microns. Inconsistent with a cloud-free solar composition atmosphere at 8.2 sigma, the measured achromatic transit depth most likely implies a large mean molecular weight for GJ1214b's outer envelope. A dense atmosphere rules out bulk compositions for GJ1214b that explain its large radius by the presence of a very low density gas layer surrounding the planet. High-altitude clouds can alternatively explain the flat transmission spectrum, but they would need to be optically thick up to 10 mbar or consist of particles with a range of sizes approaching 1 micron in diameter.Comment: 17 pages, 12 figures, accepted for publication in Ap

Early Emergence of Ethnic Differences in Type 2 Diabetes Precursors in the UK: The Child Heart and Health Study in England (CHASE Study)

Peter Whincup and colleagues carry out a cross-sectional study examining ethnic differences in precursors of of type 2 diabetes among children aged 9–10 living in three UK cities

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Kepler Planet-Detection Mission: Introduction and First Results

The Kepler mission was designed to determine the frequency of Earth-sized planets in and near the habitable zone of Sun-like stars. The habitable zone is the region where planetary temperatures are suitable for water to exist on a planet’s surface. During the first 6 weeks of observations, Kepler monitored 156,000 stars, and five new exoplanets with sizes between 0.37 and 1.6 Jupiter radii and orbital periods from 3.2 to 4.9 days were discovered. The density of the Neptune-sized Kepler-4b is similar to that of Neptune and GJ 436b, even though the irradiation level is 800,000 times higher. Kepler-7b is one of the lowest-density planets (~0.17 gram per cubic centimeter) yet detected. Kepler-5b, -6b, and -8b confirm the existence of planets with densities lower than those predicted for gas giant planets