Genome-wide association study to identify genetic determinants of severe asthma

Background: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective: To identify common genetic variants affecting susceptibility to severe asthma. Methods: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10 (-8)following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10 (-8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

Using genome-Wwide complex trait analysis to quantify 'missing heritability' in Parkinson's disease

Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered. © Published by Oxford University Press 2012.

Risedronate in adults with osteogenesis imperfecta type I: Increased bone mineral density and decreased bone turnover, but high fracture rate persists

Summary Bisphosphonates can increase bone mineral density (BMD) in children with osteogenesis imperfecta (OI). In this study of adults with OI type I, risedronate increased BMD at lumbar spine (but not total hip) and decreased bone turnover. However, the fracture rate in these patients remained high. Introduction Intravenous bisphosphonates given to children with OI can increase BMD and reduce fracture incidence. Oral and/or intravenous bisphosphonates may have similar effects in adults with OI. We completed an observational study of the effect of risedronate in adults with OI type I. Methods Thirty-two adults (mean age, 39 years) with OI type I were treated with risedronate (total dose, 35 mg weekly) for 24 months. Primary outcome measures were BMD changes at lumbar spine (LS) and total hip (TH). Secondary outcome measures were fracture incidence, bone pain, and change in bone turnover markers (serum procollagen type I aminopropeptide (P1NP) and bone ALP). A meta-analysis of published studies of oral bisphosphonates in adults and children with OI was performed. Results Twenty-seven participants (ten males and seventeen females) completed the study. BMD increased at LS by 3.9% (0.815 vs. 0.846 g/cm 2, p=0.007; mean Z-score, -1.93 vs. -1.58, p=0.002), with no significant change at TH. P1NP fell by 37% (p=0.00041), with no significant change in bone ALP (p=0.15). Bone pain did not change significantly (p=0.6). Fracture incidence remained high, with 25 clinical fractures and 10 major fractures in fourteen participants (0.18 major fractures per person per year), with historical data of 0.12 fractures per person per year. The meta-analysis did not demonstrate a significant difference in fracture incidence in patients with OI treated with oral bisphosphonates. Conclusions Risedronate in adults with OI type I results in modest but significant increases in BMD at LS, and decreased bone turnover. However, this may be insufficient to make a clinically significant difference to fracture incidence.

Common variants at 12q14 and 12q24 are associated with hippocampal volume

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10 -7. In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10 -11) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10 -11). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10 -7) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10 -7); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10-8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10-6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Ideologies and their points of view

It is well known that different arguments appeal to different people. We all process information in ways that are adapted to be consistent with our underlying ideologies. These ideologies can sometimes be framed in terms of particular axes or dimensions, which makes it possible to represent some aspects of an ideology as a region in the kind of vector space that is typical of many generalised quantum models. Such models can then be used to explain and predict, in broad strokes, whether a particular argument or proposal is likely to appeal to an individual with a particular ideology. The choice of suitable arguments to bring about desired actions is traditionally part of the art or science of rhetoric, and today's highly polarised society means that this skill is becoming more important than ever. This paper presents a basic model for understanding how different goals will appeal to people with different ideologies, and thus how different rhetorical positions can be adopted to promote the same desired outcome. As an example, we consider different narratives and hence actions with respect to the environment and climate change, an important but currently highly controversial topic.

A comparison of road traffic crashes along mountainous and non-mountainous roads in Sabah, Malaysia

Constrained topography and complex road geometry along rural mountainous roads often represent a demanding driving situation. As a result, traffic crashes along mountainous roads are likely to have different characteristics to crashes on roads in flatter areas; however, there is little research on this topic. The objective of this study is to examine the characteristics of road traffic crashes on rural mountainous roads and to compare these with the characteristics of crashes on non-mountainous roads. This paper explores and compares general crash characteristics including crash type, crash severity, roadway geometric features and environmental factors, and road user/vehicle characteristics. Five years of road traffic crash data (2008-2012) for Sabah were obtained from the Malaysian Institute of Road Safety Research. During this period, a total of 25,439 crashes occurred along federal roads in Sabah, of which 4,875 crashes occurred in mountainous areas. Categorical data analysis techniques were used to examine the differences between mountainous and non-mountainous crashes. Results show that the odds ratio of ‘out-of-control’ crashes and the crash involvement due to speeding are respectively about 4.2 times and 2.8 times higher on mountainous than non-mountainous roads. Other factors and crash characteristics that increase the odds of crashes along mountainous roads compared with non-mountainous roads include horizontal curved sections compared with straight sections, single-vehicle crashes compared with multi-vehicle crashes and weekend crashes compared with weekday crashes. This paper identifies some of the basic characteristics of crashes along rural mountainous roads to aid future research on traffic safety along mountainous roads.

A comparison of road traffic crashes along mountainous and non-mountainous roads in Sabah, Malaysia

Constrained topography and complex road geometry along rural mountainous roads often represent a demanding driving situation. As a result, traffic crashes along mountainous roads are likely to have different characteristics to crashes on roads in flatter areas; however, there is little research on this topic. The objective of this study is to examine the characteristics of road traffic crashes on rural mountainous roads and to compare these with the characteristics of crashes on non-mountainous roads. This paper explores and compares general crash characteristics including crash type, crash severity, roadway geometric features and environmental factors, and road user/vehicle characteristics. Five years of road traffic crash data (2008-2012) for Sabah were obtained from the Malaysian Institute of Road Safety Research. During this period, a total of 25,439 crashes occurred along federal roads in Sabah, of which 4,875 crashes occurred in mountainous areas. Categorical data analysis techniques were used to examine the differences between mountainous and non-mountainous crashes. Results show that the odds ratio of ‘out-of-control’ crashes and the crash involvement due to speeding are respectively about 4.2 times and 2.8 times higher on mountainous than non-mountainous roads. Other factors and crash characteristics that increase the odds of crashes along mountainous roads compared with non-mountainous roads include horizontal curved sections compared with straight sections, single-vehicle crashes compared with multi-vehicle crashes and weekend crashes compared with weekday crashes. This paper identifies some of the basic characteristics of crashes along rural mountainous roads to aid future research on traffic safety along mountainous roads.

Analysis of differential gene expression based on Bayesian estimation of variance

Gene expression is arguably the most important indicator of biological function. Thus identifying differentially expressed genes is one of the main aims of high throughout studies that use microarray and RNAseq platforms to study deregulated cellular pathways. There are many tools for analysing differentia gene expression from transciptomic datasets. The major challenge of this topic is to estimate gene expression variance due to the high amount of ‘background noise’ that is generated from biological equipment and the lack of biological replicates. Bayesian inference has been widely used in the bioinformatics field. In this work, we reveal that the prior knowledge employed in the Bayesian framework also helps to improve the accuracy of differential gene expression analysis when using a small number of replicates. We have developed a differential analysis tool that uses Bayesian estimation of the variance of gene expression for use with small numbers of biological replicates. Our method is more consistent when compared to the widely used cyber-t tool that successfully introduced the Bayesian framework to differential analysis. We also provide a user-friendly web based Graphic User Interface for biologists to use with microarray and RNAseq data. Bayesian inference can compensate for the instability of variance caused when using a small number of biological replicates by using pseudo replicates as prior knowledge. We also show that our new strategy to select pseudo replicates will improve the performance of the analysis. - See more at: http://www.eurekaselect.com/node/138761/article#sthash.VeK9xl5k.dpuf

Informed learning in the undergraduate classroom: The role of information experiences in shaping outcomes

This research aimed to inform the design of effective information literacy lessons in higher education. Phenomenography, a research approach designed to study human experience, was used to explore the experiences of a teacher and undergraduate students using information to learn about language and gender issues. The findings show that the way learners use information influences content-focused learning outcomes, and reveal an instructional pattern for enabling students to use information while becoming aware of the topic they are investigating. Based on the findings, a design model is offered in which learning outcomes are realized through targeted information literacy activities.

Dangerous Coagulations? The Uses of Foucault in the Study of Education

This book brings together an outstanding group of scholars who draw on the works of Michel Foucault. Eclectic in topic and method, the essays illustrate Foucault’s usefulness. Dangerous Coagulations? constitutes a departure from the more formulaic Foucault work that has emerged and highlights new possibilities for undertaking problematizing approaches to educational research.

Improving spoken term detection using complementary information

This research has made contributions to the area of spoken term detection (STD), defined as the process of finding all occurrences of a specified search term in a large collection of speech segments. The use of visual information in the form of lip movements of the speaker in addition to audio and the use of topic of the speech segments, and the expected frequency of words in the target speech domain, are proposed. By using these complementary information, improvement in the performance of STD has been achieved which enables efficient search of key words in large collection of multimedia documents.

Submission to the Senate Economics References Committee Inquiry into affordable housing 20 August 2014: De-risking development of medium density housing to improve housing affordability and boost supply

This submission addresses the problem of housing price inflation, the chronic under-supply of new housing stock, and the resultant decline in housing affordability for low and middle income households. It specifically focusses on the supply of medium density housing (multi-unit development) in Melbourne, although we believe that the observations made about housing in supply in Melbourne are relevant in other urban centres and to other types of housing supply. In terms of medium density housing (MDH) our concern also extends to the poor quality and design. Why the market tends to deliver generic apartments of poor quality and design which are uncompetitive with lower density housing and amenity despite planning objectives, and how this apparently intractable problem can be overcome is the topic of this submission...

Hashtag as hybrid forum: The case of #agchatoz

This chapter imports Michel Callon’s model of the ‘hybrid forum’ (Callon et al, 2009, p. 18) into social media research, arguing that certain kinds of hashtag publics can be mapped onto this model. It explores this idea of the hashtag as hybrid forum through the worked example of #agchatoz—a hashtag used as both ‘meetup’ organizer for Australian farmers and other stakeholders in Australian agriculture, and as a topic marker for general discussion of related issues. Applying the principles and techniques of digital methods (Rogers, 2013), we employ a standard suite of analytics to a longitudinal dataset of #agchatoz tweets. The results are used not only to describe various elements and dynamics of this hashtag, but also to experiment with the articulation of such approaches with the theoretical model of the hybrid forum, as well as exploring the ways that controversies animate and transform such forums as part of the emergence and cross-pollination of issue publics.