Comparison of multimarker logistic regression models, with application to a genomewide scan of schizophrenia.

BACKGROUND: Genome-wide association studies (GWAS) are a widely used study design for detecting genetic causes of complex diseases. Current studies provide good coverage of common causal SNPs, but not rare ones. A popular method to detect rare causal variants is haplotype testing. A disadvantage of this approach is that many parameters are estimated simultaneously, which can mean a loss of power and slower fitting to large datasets.Haplotype testing effectively tests both the allele frequencies and the linkage disequilibrium (LD) structure of the data. LD has previously been shown to be mostly attributable to LD between adjacent SNPs. We propose a generalised linear model (GLM) which models the effects of each SNP in a region as well as the statistical interactions between adjacent pairs. This is compared to two other commonly used multimarker GLMs: one with a main-effect parameter for each SNP; one with a parameter for each haplotype. RESULTS: We show the haplotype model has higher power for rare untyped causal SNPs, the main-effects model has higher power for common untyped causal SNPs, and the proposed model generally has power in between the two others. We show that the relative power of the three methods is dependent on the number of marker haplotypes the causal allele is present on, which depends on the age of the mutation. Except in the case of a common causal variant in high LD with markers, all three multimarker models are superior in power to single-SNP tests.Including the adjacent statistical interactions results in lower inflation in test statistics when a realistic level of population stratification is present in a dataset.Using the multimarker models, we analyse data from the Molecular Genetics of Schizophrenia study. The multimarker models find potential associations that are not found by single-SNP tests. However, multimarker models also require stricter control of data quality since biases can have a larger inflationary effect on multimarker test statistics than on single-SNP test statistics. CONCLUSIONS: Analysing a GWAS with multimarker models can yield candidate regions which may contain rare untyped causal variants. This is useful for increasing prior odds of association in future whole-genome sequence analyses.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Orbitofrontal cortex volume and brain reward response in obesity.

Background/objectivesWhat drives overconsumption of food is poorly understood. Alterations in brain structure and function could contribute to increased food seeking. Recently, brain orbitofrontal cortex (OFC) volume has been implicated in dysregulated eating but little is known how brain structure relates to function.Subjects/methodsWe examined obese (n=18, age=28.7±8.3 years) and healthy control women (n=24, age=27.4±6.3 years) using a multimodal brain imaging approach. We applied magnetic resonance and diffusion tensor imaging to study brain gray and white matter volume as well as white matter (WM) integrity, and tested whether orbitofrontal cortex volume predicts brain reward circuitry activation in a taste reinforcement-learning paradigm that has been associated with dopamine function.ResultsObese individuals displayed lower gray and associated white matter volumes (P<0.05 family-wise error (FWE)- small volume corrected) compared with controls in the orbitofrontal cortex, striatum and insula. White matter integrity was reduced in obese individuals in fiber tracts including the external capsule, corona radiata, sagittal stratum, and the uncinate, inferior fronto-occipital, and inferior longitudinal fasciculi. Gray matter volume of the gyrus rectus at the medial edge of the orbitofrontal cortex predicted functional taste reward-learning response in frontal cortex, insula, basal ganglia, amygdala, hypothalamus and anterior cingulate cortex in control but not obese individuals.ConclusionsThis study indicates a strong association between medial orbitofrontal cortex volume and taste reinforcement-learning activation in the brain in control but not in obese women. Lower brain volumes in the orbitofrontal cortex and other brain regions associated with taste reward function as well as lower integrity of connecting pathways in obesity (OB) may support a more widespread disruption of reward pathways. The medial orbitofrontal cortex is an important structure in the termination of food intake and disturbances in this and related structures could contribute to overconsumption of food in obesity

A 125 GeV SM-like Higgs in the MSSM and the γγ\gamma \gamma rate

We consider the possibility of a Standard Model (SM)-like Higgs in the context of the Minimal Supersymmetric Standard Model (MSSM), with a mass of about 125 GeV and with a production times decay rate into two photons which is similar or somewhat larger than the SM one. The relatively large value of the SM-like Higgs mass demands stops in the several hundred GeV mass range with somewhat large mixing, or a large hierarchy between the two stop masses in the case that one of the two stops is light. We find that, in general, if the heaviest stop mass is smaller than a few TeV, the rate of gluon fusion production of Higgs bosons decaying into two photons tends to be somewhat suppressed with respect to the SM one in this region of parameters. However, we show that an enhancement of the photon decay rate may be obtained for light third generation sleptons with large mixing, which can be naturally obtained for large values of $\tan\beta$ and sizable values of the Higgsino mass parameter.Comment: 14 pages, 4 figures. Corrected small typos and added reference

Graphical approaches for the control of generalised error rates

When simultaneously testing multiple hypotheses, the usual approach in the context of confirmatory clinical trials is to control the familywise error rate (FWER), which bounds the probability of making at least one false rejection. In many trial settings, these hypotheses will additionally have a hierarchical structure that reflects the relative importance and links between different clinical objectives. The graphical approach of Bretz et al. (2009) is a flexible and easily communicable way of controlling the FWER while respecting complex trial objectives and multiple structured hypotheses. However, the FWER can be a very stringent criterion that leads to procedures with low power, and may not be appropriate in exploratory trial settings. This motivates controlling generalised error rates, particularly when the number of hypotheses tested is no longer small. We consider the generalised familywise error rate (k-FWER), which is the probability of making k or more false rejections, as well as the tail probability of the false discovery proportion (FDP), which is the probability that the proportion of false rejections is greater than some threshold. We also consider asymptotic control of the false discovery rate (FDR), which is the expectation of the FDP. In this paper, we show how to control these generalised error rates when using the graphical approach and its extensions. We demonstrate the utility of the resulting graphical procedures on three clinical trial case studies.Biometrika Trust; Medical Research Council, Grant/Award Numbers: MC∖UU∖00002/6, MR/N028171/

BENEFITS OF FIRE INSURANCE AND CONSEQUENCES OF NONCOMPLIANCE IN GHANA: A CASE STUDY OF DANSOMAN COMMUNITY

The topic of the study is Benefits of Fire Insurance and Consequences of Noncompliance. This study was carried out to determine the level of public awareness of insurance benefits and to identify the reasons for non- compliance with fire insurance policies. Convenience sampling technique was used in the collection of data. The study indicated that electrical faults, carelessness, improper use of LPG gas and illegal connections cause fire outbreaks. Most Ghanaians do not comply with fire insurance policy; hence they do not know the benefit of fire insurance policy. Ghanaians do not comply with fire insurance policy due to inadequate education on fire insurance policies and their benefits, insurance companies not being reliable, lack of enforcement of the Insurance Act 2006, Act 724 section 184, and lack of interest in the fire insurance policy. Also the economy experiences unemployment, loss of property, loss of lives, decreases in output and low level of investment whenever there are fire outbreaks. The study revealed that the majority of Ghanaians are not aware of the Insurance Policy Act and its associated benefits. It is recommended that active education about the benefits of insurance and strict enforcement procedures should be followed. . Key words: Benefits, Fire Insurance, Consequences, Dansoman-Community, Ghan

A fixed-target platform for serial femtosecond crystallography in a hydrated environment.

For serial femtosecond crystallography at X-ray free-electron lasers, which entails collection of single-pulse diffraction patterns from a constantly refreshed supply of microcrystalline sample, delivery of the sample into the X-ray beam path while maintaining low background remains a technical challenge for some experiments, especially where this methodology is applied to relatively low-ordered samples or those difficult to purify and crystallize in large quantities. This work demonstrates a scheme to encapsulate biological samples using polymer thin films and graphene to maintain sample hydration in vacuum conditions. The encapsulated sample is delivered into the X-ray beam on fixed targets for rapid scanning using the Roadrunner fixed-target system towards a long-term goal of low-background measurements on weakly diffracting samples. As a proof of principle, we used microcrystals of the 24 kDa rapid encystment protein (REP24) to provide a benchmark for polymer/graphene sandwich performance. The REP24 microcrystal unit cell obtained from our sandwiched in-vacuum sample was consistent with previously established unit-cell parameters and with those measured by us without encapsulation in humidified helium, indicating that the platform is robust against evaporative losses. While significant scattering from water was observed because of the sample-deposition method, the polymer/graphene sandwich itself was shown to contribute minimally to background scattering

Slim Epistemology with a Thick Skin

The distinction between ‘thick’ and ‘thin’ value concepts, and its importance to ethical theory, has been an active topic in recent meta-ethics. This paper defends three claims regarding the parallel issue about thick and thin epistemic concepts. (1) Analogy with ethics offers no straightforward way to establish a good, clear distinction between thick and thin epistemic concepts. (2) Assuming there is such a distinction, there are no semantic grounds for assigning thick epistemic concepts priority over the thin. (3) Nor does the structure of substantive epistemological theory establish that thick epistemic concepts enjoy systematic theoretical priority over the thin. In sum, a good case has yet to be made for any radical theoretical turn to thicker epistemology

Effect of Prior Anterior Superior Iliac Spine Compression Testing on Second Assessor Findings: Implications for Inter-Examiner Reliability Testing

BACKGROUND: Osteopathic physicians use palpation to diagnose sacroiliac joint somatic dysfunction (SD) -- including the Anterior Superior Iliac Spine (ASIS) Compression Test for dysfunctional side lateralization. (Literature suggests right-sided lateralization in 80% of asymptomatic individuals). Accurate, reliable tests are crucial however to diagnose SD and kappa (κ) analysis is a gold-standard to determine the degree of interexaminer reliability for tests. Few studies have examined the effect the palpatory examination has on subsequent diagnostic findings and therefore on κ-values

Inter-Examiner Reliability of an Anterior Superior Iliac Spine Compression Test used to Lateralize Pelvic Somatic Dysfunction to the Right Side or Not

BACKGROUND: Osteopathic physicians use a number of palpatory structural examinations to diagnose pelvic somatic dysfunction (SD). They may elect to use the Anterior Superior Iliac Spine (ASIS) Compression Test to lateralize the dysfunctional side. Accurate, reliable tests are crucial to neuromusculoskeletal diagnosis and this study employs the kappa (κ) analysis protocol recommended for assessing interexaminer reliability of manual medicine tests (published by the Fédération Internationale de Médecine Manuelle [FIMM]). κ-values ≥0.40 (moderate agreement) are considered to be acceptable for use in the clinical setting

The Use of Objective Data to Improve Interexaminer Reliability

BACKGROUND: In Osteopathic Manipulative Medicine (OMM) and Manual/Musculoskeletal Medicine (MMM), palpatory diagnosis is performed on a regular basis to diagnose somatic dysfunction (SD). This examination requires careful and precise touch coupled with subjective interpretation by individual examiners who may have been trained to evaluate SD through different methods. Interexaminer reliability studies aim to minimize variance by providing quantifiable scientific data to evaluate specific test protocols which can then be taught to practitioners. In a previous PCOM study, two examiners independently diagnosed innominate bone dysfunction lateralized using the ASIS compression test on a large group of subjects. A pressure monitoring system (IsoTOUCH®, Chattanooga TN) has been used in various studies at the PCOM Human Performance & Biomechanics Laboratory (Kuchera, Jean et al 2006 & Kuchera, Vardy et al 2005) to quantify or standardize forces used in palpatory diagnosis or OMM/MMM treatment applications. This study gathered data during the tesing phase of a new and improved model of this system, using the protocol of the previous ASIS interexaminer reliability study. The data collected during standardization of the system was analyzed in the same manner as the previous study to compare the results of interexaminer reliability to results achieved using live data feed for baseline pressure synchronization between examiners