Methodological Issues in Multistage Genome-Wide Association Studies

Because of the high cost of commercial genotyping chip technologies, many investigations have used a two-stage design for genome-wide association studies, using part of the sample for an initial discovery of ``promising'' SNPs at a less stringent significance level and the remainder in a joint analysis of just these SNPs using custom genotyping. Typical cost savings of about 50% are possible with this design to obtain comparable levels of overall type I error and power by using about half the sample for stage I and carrying about 0.1% of SNPs forward to the second stage, the optimal design depending primarily upon the ratio of costs per genotype for stages I and II. However, with the rapidly declining costs of the commercial panels, the generally low observed ORs of current studies, and many studies aiming to test multiple hypotheses and multiple endpoints, many investigators are abandoning the two-stage design in favor of simply genotyping all available subjects using a standard high-density panel. Concern is sometimes raised about the absence of a ``replication'' panel in this approach, as required by some high-profile journals, but it must be appreciated that the two-stage design is not a discovery/replication design but simply a more efficient design for discovery using a joint analysis of the data from both stages. Once a subset of highly-significant associations has been discovered, a truly independent ``exact replication'' study is needed in a similar population of the same promising SNPs using similar methods.Comment: Published in at http://dx.doi.org/10.1214/09-STS288 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Crash Safety Assurances Strategies for Future Plastic and Composite Intensive Vehicles (PCIVs)

This report addresses outstanding safety issues and research needs for Plastics and Composite Intensive Vehicles (PCIVs) to facilitate their safe deployment by 2020. PCIVs have the potential to revolutionize the automotive sector; however, the use of plastics and composite materials in automotive structures requires an in-depth knowledge of their unique performance characteristics in the crash and safety environment. Included in this report is a proposed definition of the PCIV, a review of potential safety benefits, lessons-learned, and progress to date towards crashworthiness of PCIVs as well as proposed safety performance specifications and research needs

Tedera: From a Promising Novel Species to a Commercial Pasture Option for Mediterranean Southern Australia

Tedera (Bituminaria bituminosa var. albomarginata and var. crassiuscula) is a traditional forage species used for centuries in the Canary Islands (Méndez and Fernández 1990), that has increasingly attracted interest from researchers in regions with Mediterranean-type climates from Spain, Italy, Israel, Greece, Portugal, Morocco, Turkey and Australia. In 2000, Australian pasture researchers started a large and systematic screening process that evaluated about 720 species of exotic and native legumes, grasses and herbs for adaptation and productivity in Mediterranean and temperate environments (Real et al. 2011). Tedera was one of the few novel perennial legumes to show potential for domestication (Real et al. 2008; Real et al. 2011). Now an international multidisciplinary team has come together to take tedera forward towards commercial adoption by farmers in Mediterranean-type environments. This paper provides a technical update and discussion on all research aspects conducted by the tedera research team up to February 2013

Efficient Dynamic Importance Sampling of Rare Events in One Dimension

Exploiting stochastic path integral theory, we obtain \emph{by simulation} substantial gains in efficiency for the computation of reaction rates in one-dimensional, bistable, overdamped stochastic systems. Using a well-defined measure of efficiency, we compare implementations of ``Dynamic Importance Sampling'' (DIMS) methods to unbiased simulation. The best DIMS algorithms are shown to increase efficiency by factors of approximately 20 for a $5 k_B T$ barrier height and 300 for $9 k_B T$, compared to unbiased simulation. The gains result from close emulation of natural (unbiased), instanton-like crossing events with artificially decreased waiting times between events that are corrected for in rate calculations. The artificial crossing events are generated using the closed-form solution to the most probable crossing event described by the Onsager-Machlup action. While the best biasing methods require the second derivative of the potential (resulting from the ``Jacobian'' term in the action, which is discussed at length), algorithms employing solely the first derivative do nearly as well. We discuss the importance of one-dimensional models to larger systems, and suggest extensions to higher-dimensional systems.Comment: version to be published in Phys. Rev.

Chandra Detection of a TypeII Quasar at z=3.288

We report on observations of a TypeII quasar at redshift z=3.288, identified as a hard X-ray source in a 185 ks observation with the Chandra X-ray Observatory and as a high-redshift photometric candidate from deep, multiband optical imaging. CXOJ084837.9+445352 (hereinafter CXO52) shows an unusually hard X-ray spectrum from which we infer an absorbing column density N(H) = (4.8+/-2.1)e23 / cm2 (90% confidence) and an implied unabsorbed 2-10 keV rest-frame luminosity of L(2-10) = 3.3e44 ergs/s, well within the quasar regime. Hubble Space Telescope imaging shows CXO52 to be elongated with slight morphological differences between the WFPC2 F814W and NICMOS F160W bands. Optical and near-infrared spectroscopy of CXO52 show high-ionization emission lines with velocity widths ~1000 km/s and flux ratios similar to a Seyfert2 galaxy or radio galaxy. The latter are the only class of high-redshift TypeII luminous AGN which have been extensively studied to date. Unlike radio galaxies, however, CXO52 is radio quiet, remaining undetected at radio wavelengths to fairly deep limits, f(4.8GHz) < 40 microJy. High-redshift TypeII quasars, expected from unification models of active galaxies and long-thought necessary to explain the X-ray background, are poorly constrained observationally with few such systems known. We discuss recent observations of similar TypeII quasars and detail search techniques for such systems: namely (1) X-ray selection, (2) radio selection, (3) multi-color imaging selection, and (4) narrow-band imaging selection. Such studies are likely to begin identifying luminous, high-redshift TypeII systems in large numbers. We discuss the prospects for these studies and their implications to our understanding of the X-ray background.Comment: 28 pages, 5 figures; to appear in The Astrophysical Journa

In Vivo Time- Resolved Microtomography Reveals the Mechanics of the Blowfly Flight Motor

Dipteran flies are amongst the smallest and most agile of flying animals. Their wings are driven indirectly by large power muscles, which cause cyclical deformations of the thorax that are amplified through the intricate wing hinge. Asymmetric flight manoeuvres are controlled by 13 pairs of steering muscles acting directly on the wing articulations. Collectively the steering muscles account for <3% of total flight muscle mass, raising the question of how they can modulate the vastly greater output of the power muscles during manoeuvres. Here we present the results of a synchrotron-based study performing micrometre-resolution, time-resolved microtomography on the 145 Hz wingbeat of blowflies. These data represent the first four-dimensional visualizations of an organism's internal movements on sub-millisecond and micrometre scales. This technique allows us to visualize and measure the three-dimensional movements of five of the largest steering muscles, and to place these in the context of the deforming thoracic mechanism that the muscles actuate. Our visualizations show that the steering muscles operate through a diverse range of nonlinear mechanisms, revealing several unexpected features that could not have been identified using any other technique. The tendons of some steering muscles buckle on every wingbeat to accommodate high amplitude movements of the wing hinge. Other steering muscles absorb kinetic energy from an oscillating control linkage, which rotates at low wingbeat amplitude but translates at high wingbeat amplitude. Kinetic energy is distributed differently in these two modes of oscillation, which may play a role in asymmetric power management during flight control. Structural flexibility is known to be important to the aerodynamic efficiency of insect wings, and to the function of their indirect power muscles. We show that it is integral also to the operation of the steering muscles, and so to the functional flexibility of the insect flight motor

Characterization of rare spontaneous Human Immunodeficiency Virus viral controllers attending a national United Kingdom clinical service using a combination of serology and molecular diagnostic assays

Background We report outcomes and novel characterization of a unique cohort of 42 individuals with persistently indeterminate human immunodeficiency virus (HIV) status, the majority of whom are HIV viral controllers. Methods Eligible individuals had indeterminate or positive HIV serology, but persistently undetectable HIV ribonucleic acid (RNA) by commercial assays and were not taking antiretroviral therapy (ART). Routine investigations included HIV Western blot, HIV viral load, qualitative HIV-1 deoxyribonucleic acid (DNA), coinfection screen, and T-cell quantification. Research assays included T-cell activation, ART measurement, single-copy assays detecting HIV-1 RNA and DNA, and plasma cytokine quantification. Human immunodeficiency virus seropositivity was defined as ≥3 bands on Western blot; molecular positivity was defined as detection of HIV RNA or DNA. Results Human immunodeficiency virus infection was excluded in 10 of 42 referrals, remained unconfirmed in 2 of 42, and was confirmed in 30 of 42, who were identified as HIV elite controllers (ECs), normal CD4 T-cell counts (median 820/mL, range 805–1336), and normal CD4/CD8 ratio (median 1.8, range 1.2–1.9). Elite controllers had a median duration of elite control of 6 years (interquartile range = 4–14). Antiretroviral therapy was undetected in all 23 subjects tested. Two distinct categories of ECs were identified: molecular positive (n = 20) and molecular negative (n = 10). Conclusions Human immunodeficiency virus status was resolved for 95% of referrals with the majority diagnosed as EC. The clinical significance of the 2 molecular categories among ECs requires further investigation