A comparative analysis of family-based and population-based association tests using whole genome sequence data

The revolution in next-generation sequencing has made obtaining both common and rare high-quality sequence variants across the entire genome feasible. Because researchers are now faced with the analytical challenges of handling a massive amount of genetic variant information from sequencing studies, numerous methods have been developed to assess the impact of both common and rare variants on disease traits. In this report, whole genome sequencing data from Genetic Analysis Workshop 18 was used to compare the power of several methods, considering both family-based and population-based designs, to detect association with variants in the MAP4 gene region and on chromosome 3 with blood pressure. To prioritize variants across the genome for testing, variants were first functionally assessed using prediction algorithms and expression quantitative trait loci (eQTLs) data. Four set-based tests in the family-based association tests (FBAT) framework--FBAT-v, FBAT-lmm, FBAT-m, and FBAT-l--were used to analyze 20 pedigrees, and 2 variance component tests, sequence kernel association test (SKAT) and genome-wide complex trait analysis (GCTA), were used with 142 unrelated individuals in the sample. Both set-based and variance-component-based tests had high power and an adequate type I error rate. Of the various FBATs, FBAT-l demonstrated superior performance, indicating the potential for it to be used in rare-variant analysis. The updated FBAT package is available at: http://www.hsph.harvard.edu/fbat/

First Measurement of A_N at sqrt(s)=200 GeV in Polarized Proton-Proton Elastic Scattering at RHIC

We report on the first measurement of the single spin analyzing power (A_N) at sqrt(s)=200GeV, obtained by the pp2pp experiment using polarized proton beams at the Relativistic Heavy Ion Collider (RHIC). Data points were measured in the four momentum transfer t range 0.01 < |t| < 0.03 (GeV/c)^2. Our result, averaged over the whole t-interval is about one standard deviation above the calculation, which uses interference between electromagnetic spin-flip amplitude and hadronic non-flip amplitude, the source of A_N. The difference could be explained by an additional contribution of a hadronic spin-flip amplitude to A_N.Comment: 13 pages, 5 figures. New values of polarization errors. Final version submitted to Phys. Lett.

Double Spin Asymmetries A_NN and A_SS at sqrt{s}=200 GeV in Polarized Proton-Proton Elastic Scattering at RHIC

We present the first measurements of the double spin asymmetries A_NN and A_SS at sqrt{s}=200 GeV, obtained by the pp2pp experiment using polarized proton beams at the Relativistic Heavy Ion Collider (RHIC). The data were collected in the four momentum transfer t range 0.01<|t|<0.03 (GeV/c)^2. The measured asymmetries, which are consistent with zero, allow us to estimate upper limits on the double helicity-flip amplitudes phi_2 and phi_4 at small t as well as on the difference Delta(sigma_T) between the total cross sections for transversely polarized protons with antiparallel or parallel spin orientations.Comment: 13 pages with 3 figures. Final version accepted by Phys. Lett.

Body mass index change in gastrointestinal cancer and chronic obstructive pulmonary disease is associated with Dedicator of Cytokinesis 1

Background: There have been a number of candidate gene association studies of cancer cachexia-related traits, but no genome-wide association study (GWAS) has been published to date. Cachexia presents in patients with a number of complex traits, including both cancer and COPD. The objective of the current investigation was to search for a shared genetic aetiology for change in body mass index (ΔBMI) among cancer and COPD by using GWAS data in the Framingham Heart Study. Methods: A linear mixed effects model accounting for age, sex, and change in smoking status was used to calculate ΔBMI in participants over 40 years of age with three consecutive BMI time points (n = 4162). Four GWAS of ΔBMI using generalized estimating equations were performed among 1085 participants with a cancer diagnosis, 204 with gastrointestinal (GI) cancer, 112 with lung cancer, and 237 with COPD to test for association with 418 365 single-nucleotide polymorphisms (SNPs). Results: Two SNPs reached a level of genome-wide significance (P < 5 × 10−8) with ΔBMI: (i) rs41526344 within the CNTN4 gene, among COPD cases (β = 0.13, P = 4.3 × 10−8); and (ii) rs4751240 in the gene Dedicator of Cytokinesis 1 (DOCK1) among GI cancer cases (β = 0.10, P = 1.9 × 10−8). The DOCK1 SNP association replicated in the ΔBMI GWAS among COPD cases (βmeta-analyis = 0.10, Pmeta-analyis = 9.3 × 10−10). The DOCK1 gene codes for the dedicator of cytokinesis 1 protein, which has a role in myoblast fusion. Conclusions: In sum, one statistically significant common variant in the DOCK1 gene was associated with ΔBMI in GI cancer and COPD cases providing support for at least partially shared aetiology of ΔBMI in complex diseases

Validation of mDurance, A Wearable Surface Electromyography System for Muscle Activity Assessment

The authors wish to thank all participants for their assistance and to Irene Cantarero-Villanueva Ph.D. and Paula Postigo-Martín, of the Department of Physiotherapy (University of Granada, Spain), for providing us with their laboratories and materials so that this study could be carried out.The mDurance® system is an innovative digital tool that combines wearable surface electromyography (sEMG), mobile computing and cloud analysis to streamline and automatize the assessment of muscle activity. The tool is particularly devised to support clinicians and sport professionals in their daily routines, as an assessment tool in the prevention, monitoring rehabilitation and training field. This study aimed at determining the validity of the mDurance system for measuring muscle activity by comparing sEMG output with a reference sEMG system, the Delsys® system. Fifteen participants were tested during isokinetic knee extensions at three different speeds (60, 180, and 300 deg/s), for two muscles (rectus femoris [RF] and vastus lateralis [VL]) and two different electrodes locations (proximal and distal placement). The maximum voluntary isometric contraction was carried out for the normalization of the signal, followed by dynamic isokinetic knee extensions for each speed. The sEMG output for both systems was obtained from the raw sEMG signal following mDurance's processing and filtering. Mean, median, first quartile, third quartile and 90th percentile was calculated from the sEMG amplitude signals for each system. The results show an almost perfect ICC relationship for the VL (ICC > 0.81) and substantial to almost perfect for the RF (ICC > 0.762) for all variables and speeds. The Bland-Altman plots revealed heteroscedasticity of error for mean, quartile 3 and 90th percentile (60 and 300 deg/s) for RF and at mean and 90th percentile for VL (300 deg/s). In conclusion, the results indicate that the mDurance® sEMG system is a valid tool to measure muscle activity during dynamic contractions over a range of speeds. This innovative system provides more time for clinicians (e.g., interpretation patients' pathologies) and sport trainers (e.g., advising athletes), thanks to automatic processing and filtering of the raw sEMG signal and generation of muscle activity reports in real-time

Toxin studies using an integrated biophysical and structural biology approach.

Clostridial neurotoxins, such as botulinum and tetanus, are generally thought to invade neural cells through a process of high affinity binding mediated by gangliosides, internalization via endosome formation, and subsequent membrane penetration of the catalytic domain activated by a pH drop in the endosome. This surface recognition and internalization process is still not well understood with regard to what specific membrane features the toxins target, the intermolecular interactions between bound toxins, and the molecular conformational changes that occur as a result of pH lowering. In an effort to elucidate the mechanism of tetanus toxin binding and permeation through the membrane a simple yet representative model was developed that consisted of the ganglioside G{sub tlb} incorporated in a bilayer of cholesterol and DPPC (dipalmitoylphosphatidyl choline). The bilayers were stable over time yet sensitive towards the binding and activity of whole toxin. A liposome leakage study at constant pH as well as with a pH gradient, to mimic the processes of the endosome, was used to elucidate the effect of pH on the toxin's membrane binding and permeation capability. Topographic imaging of the membrane surface, via in situ tapping mode AFM, provided nanoscale characterization of the toxin's binding location and pore formation activity

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

The influence of organizational and national culture on new product performance

The authors conduct a meta-analysis on the combined influence of organizational and national culture on new product performance. For this purpose, they refer to the effectiveness of value congruency and develop a conceptual model describing the fit between organizational culture types as suggested by the competing values framework and national culture, as described by Hofstede's cultural dimensions. The meta-analysis is based on 489 effect sizes taken from 123 manuscripts. The findings show that organizations with a market culture show the highest new product performance, while hierarchy-type organizations show the lowest performance. The influence of national culture variables supports the effect of value congruency, and shows that in individualistic cultures the impact of a clan culture decreases, the impact of an adhocracy culture type decreases with uncertainty avoidance, and the influence of a hierarchy culture type increases with power distance. The superior effect of a market culture type can be matched by other organizational orientations, but in particular national cultures only. The combined findings underline the importance for firms that seek to improve the success rate of new products on international markets to consider the fit of a national culture with a firm's organizational culture

Iron and zinc nutrition in the economically-developed world : a review

This review compares iron and zinc food sources, dietary intakes, dietary recommendations, nutritional status, bioavailability and interactions, with a focus on adults in economically-developed countries. The main sources of iron and zinc are cereals and meat, with fortificant iron and zinc potentially making an important contribution. Current fortification practices are concerning as there is little regulation or monitoring of intakes. In the countries included in this review, the proportion of individuals with iron intakes below recommendations was similar to the proportion of individuals with suboptimal iron status. Due to a lack of population zinc status information, similar comparisons cannot be made for zinc intakes and status. Significant data indicate that inhibitors of iron absorption include phytate, polyphenols, soy protein and calcium, and enhancers include animal tissue and ascorbic acid. It appears that of these, only phytate and soy protein also inhibit zinc absorption. Most data are derived from single-meal studies, which tend to amplify impacts on iron absorption in contrast to studies that utilize a realistic food matrix. These interactions need to be substantiated by studies that account for whole diets, however in the interim, it may be prudent for those at risk of iron deficiency to maximize absorption by reducing consumption of inhibitors and including enhancers at mealtimes.<br /

Five endometrial cancer risk loci identified through genome-wide association analysis.

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.I.T. is supported by Cancer Research UK and the Oxford Comprehensive Biomedical Research Centre. T.H.T.C. is supported by the Rhodes Trust and the Nuffield Department of Medicine. Funding for iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and C8197/A16565), the US National Institutes of Health (R01 CA128978, U19 CA148537, U19 CA148065 and U19 CA148112), the US Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Susan G. Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. SEARCH recruitment was funded by a programme grant from Cancer Research UK (C490/A10124). Stage 1 and stage 2 case genotyping was supported by the NHMRC (552402 and 1031333). Control data were generated by the WTCCC, and a full list of the investigators who contributed to the generation of the data is available from the WTCCC website. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by UK Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02; funding for this project was provided by the Wellcome Trust under award 085475. NSECG was supported by the European Union's Framework Programme 7 CHIBCHA grant and Wellcome Trust Centre for Human Genetics Core Grant 090532/Z/09Z, and CORGI was funded by Cancer Research UK. BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/A12014). OCAC is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07) and the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.356