Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

Generalizability of established prostate cancer risk variants in men of African ancestry

Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

Travel behaviours of immigrants in Queensland, Australia

The aim of this research is to determine if there is a significant difference in public transport usage between Australian-born and overseas-born travellers in South East Queensland and identify if further investigation into this demographic factor is necessary. Using the household travel survey data of Southeast Queensland, Australia, this paper analyses the travel behaviours of immigrants and non-immigrants in the region. The immigrant population is divided into six sub-groups based on their continent of origin. The analysis results suggest that immigrants are more likely to use public transit in Brisbane over other regions in the study. Overall, this research strongly suggests that in Australia, a higher proportion of the immigrant population is more likely to use public transit compared to the proportion of the local population.

De Profundis (Theatre Soundtrack)

This creative work is an original soundtrack for the multimedia performance adaptation of Oscar Wilde’s De Profundis, led by David Fenton and Brian Lucas and produced by Metro Arts. Intermediality offers unique challenges to the composer creating towards live performance. Given the text-based nature of the piece, and the prevalence of screen content, music had a distinct role to play in supporting the intermedial performance environment. Drawing from Oscar Wilde’s own writings in the initial stages [“...richer cadences…more curious effects” “…the cry of Marysas” and the “deferred resolution of Chopin”] , the deliberately risky compositional process experimented with improvised location recordings and found sounds, random and fragmented assemblages of vintage recordings, rough methods and obsolete recording technology, and the sonic kinship of the hissing sibilances of the sea, theatrical applause and the crackle of antique recording devices (which had just been invented in Wilde’s time) worked into wefts of sound. As the soundtrack emerged, is was clearly resistant to ‘concepts’ imposed from the outside, and as the field of possibilities expanded and engaged in dialogue with the other elements of the performance (live and projected) certain pieces were selected by the director and curated into the emerging work. Thus leitmotifs emerged, rather than being imposed from the outset, with a particular through line holding: if it was too obviously like ‘music’, (which is usually used in theatre as emotional lubrication and narrative signpost) it didn’t work, and if it sounded like avant-garde sound-art, it was too grating and detracted from the primacy of the text. As a composer I worked this sweet spot inbetween these two poles as well as serving David Fenton’s curation: he determined which compositions to incorporate, reiterate and omit as part of the process of writing text, action and image and the compositional process responded with organic elaborations and variations on these selections. Musical resolution was mostly deferred until the closing stages of the performance. The soundtrack was present for the duration of the show, and Artshub reviewed the musical component thus: “...the score by David Megarrity is a refined, understated ambient scaffolding.” It premiered at the Visy Theatre, Brisbane Powerhouse, on 22 April 2015.

A thermometer for interdependence: Exploring patterns of interdependence using networks of affordances

Interdependence is a central concept in systems and organizations, yet our methods for measuring it are not well developed. Here, we report on a novel method for transforming digital trace data into networks of events that can be used to visualize and measure interdependence. The edges in the network represent sequential flow and the vertices represent actors, actions and artifacts. We refer to this representation as an affordance network. As with conventional approaches such as process mining, our method uses input from a stream of time-stamped occurrences, but the representation is simpler and more appropriate for exploration and theory building. As digital trace data becomes more widely available, this method may become more useful in information systems research and practice. Like a thermometer, it helps us measure a basic property of a system that would otherwise be difficult to see.

Effect of an interactive therapeutic robotic animal on engagement, mood states, agitation and psychotropic drug use in people with dementia: A cluster-randomised controlled trial protocol

Introduction: Apathy, agitated behaviours, loneliness and depression are common consequences of dementia. This trial aims to evaluate the effect of a robotic animal on behavioural and psychological symptoms of dementia in people with dementia living in long-term aged care. Methods and analysis: A cluster-randomised controlled trial with three treatment groups: PARO (robotic animal), Plush-Toy (non-robotic PARO) or Usual Care (Control). The nursing home sites are Australian Government approved and accredited facilities of 60 or more beds. The sites are located in South-East Queensland, Australia. A sample of 380 adults with a diagnosis of dementia, aged 60 years or older living in one of the participating facilities will be recruited. The intervention consists of three individual 15 min non-facilitated sessions with PARO or Plush- Toy per week, for a period of 10 weeks. The primary outcomes of interest are improvement in agitation, mood states and engagement. Secondary outcomes include sleep duration, step count, change in psychotropic medication use, change in treatment costs, and staff and family perceptions of PARO or Plush-Toy. Video data will be analysed using Noldus XT Pocket Observer; descriptive statistics will be used for participants’ demographics and outcome measures; cluster and individual level analyses to test all hypotheses and Generalised Linear Models for cluster level and Generalised Estimation Equations and/or Multi-level Modeling for individual level data. Ethics and dissemination: The study participants or their proxy will provide written informed consent. The Griffith University Human Research Ethics Committee has approved the study (NRS/03/14/HREC). The results of the study will provide evidence of the efficacy of a robotic animal as a psychosocial treatment for the behavioural and psychological symptoms of dementia. Findings will be presented at local and international conference meetings and published in peer-reviewed journals.

Unsupervised Domain Adaptation by Domain Invariant Projection

Domain-invariant representations are key to addressing the domain shift problem where the training and test exam- ples follow different distributions. Existing techniques that have attempted to match the distributions of the source and target domains typically compare these distributions in the original feature space. This space, however, may not be di- rectly suitable for such a comparison, since some of the fea- tures may have been distorted by the domain shift, or may be domain specific. In this paper, we introduce a Domain Invariant Projection approach: An unsupervised domain adaptation method that overcomes this issue by extracting the information that is invariant across the source and tar- get domains. More specifically, we learn a projection of the data to a low-dimensional latent space where the distance between the empirical distributions of the source and target examples is minimized. We demonstrate the effectiveness of our approach on the task of visual object recognition and show that it outperforms state-of-the-art methods on a stan- dard domain adaptation benchmark dataset

Domain Adaptation on the Statistical Manifold

In this paper, we tackle the problem of unsupervised domain adaptation for classification. In the unsupervised scenario where no labeled samples from the target domain are provided, a popular approach consists in transforming the data such that the source and target distributions be- come similar. To compare the two distributions, existing approaches make use of the Maximum Mean Discrepancy (MMD). However, this does not exploit the fact that prob- ability distributions lie on a Riemannian manifold. Here, we propose to make better use of the structure of this man- ifold and rely on the distance on the manifold to compare the source and target distributions. In this framework, we introduce a sample selection method and a subspace-based method for unsupervised domain adaptation, and show that both these manifold-based techniques outperform the cor- responding approaches based on the MMD. Furthermore, we show that our subspace-based approach yields state-of- the-art results on a standard object recognition benchmark.

Copyright, fair use and the Australian Constitution

There has been much debate over recent years about whether Australian copyright law should adopt a fair use doctrine. In this chapter we argue by pointing to the historical record that the incorporation of the term 'copyrights' in the Australian Constitution embeds a notion of balance and fair use in Australian law and that this should be taken into account when interpreting the Australian Copyright Act 1968. English case law in the 18th and 19th centuries developed a principle that copyright infringement did not occur where a person had made a fair use of a work. Fair use was generally established where the defendant had made a productive use that did more than alter the original work for the purpose of evading liability, and where the defendant had made an original contribution to the resulting work. Additionally, fairness was shown by a use that did not supersede or prejudice the market for the original work. At the time of including the copyright power in the Constitution, the UK Parliament’s understanding of “copyrights” included the notion of fair use as it had been developed in U.K. precedent. In this chapter we argue that the work “copyrights” in the Australia Constitution takes its definition from copyright in 1900 and as it has evolved since. Importantly, the word “copyrights” is infused with a particular meaning that incorporates the principle of copyright balance. The constitutional notion of copyright, therefore, is not that of an unlimited power to prevent all copying. Rather, copyright distinguishes between infringing copying and non-infringing copying and grants to the copyright owner only the power to control the former. Non-infringing copying includes well-accepted limitations on the copyright owner’s rights, including the copying of ideas, the copying of public domain works and the copying of insubstantial parts of copyrighted works. In this chapter we argue that non-infringing copying also includes copying to make a fair use of a work. The sections that distinguish infringing copying from non-infringing copying in the Copyright Act 1968 are sections 36(1) and 101(1), which define infringement as the doing, without licence, of an “act comprised in the copyright”. An infringing copy is an act comprised the copyright, whereas a non-infringing copy is not. We argue that space for fair uses of copyrighted works is built into the Copyright Act 1968 through these sections, because a fair use will not produce an infringing copy and so is not an act comprised in the copyright.

A multi-hierarchical strategy for on-ramp coordination

Ramp metering (RM) is an access control for motorways, in which a traffic signal is placed at on-ramps to regulate the rate of vehicles entering the motorway and thus to preserve the motorway capacity. In general, RM algorithms fall into two categories by their effective scope: local control and coordinated control. Local control algorithm determines the metering rate based on the traffic condition on adjacent motorway mainline and the on-ramp. Conversely, coordinated RM strategies make use of measurements from the entire motorway network to operate individual ramp signals for optimal performance at the network level. This study proposes a multi-hierarchical strategy for on-ramp coordination. The strategy is structured in two layers. At the higher layer, a centralised, predictive controller plans the coordination control within a long update interval based on the location of high-risk breakdown flow. At the lower layer, reactive controllers determine the metering rates of those ramps involved in the ramp coordination with a short update interval. This strategy is modelled and applied to the northbound model of the Pacific Motorway in a micro-simulation platform (AIMSUN). The simulation results show that the proposed strategy effectively delays the onset of congestion and reduces total congestion with better managed on-ramp queues.

Country of Origin and Internet Publication: Applying the Berne Convention in the Digital Age

Historically, determining the country of origin of a published work presented few challenges, because works were generally published physically – whether in print or otherwise – in a distinct location or few locations. However, publishing opportunities presented by new technologies mean that we now live in a world of simultaneous publication – works that are first published online are published simultaneously to every country in world in which there is Internet connectivity. While this is certainly advantageous for the dissemination and impact of information and creative works, it creates potential complications under the Berne Convention for the Protection of Literary and Artistic Works (“Berne Convention”), an international intellectual property agreement to which most countries in the world now subscribe. Under the Berne Convention’s national treatment provisions, rights accorded to foreign copyright works may not be subject to any formality, such as registration requirements (although member countries are free to impose formalities in relation to domestic copyright works). In Kernel Records Oy v. Timothy Mosley p/k/a Timbaland, et al. however, the Florida Southern District Court of the United States ruled that first publication of a work on the Internet via an Australian website constituted “simultaneous publication all over the world,” and therefore rendered the work a “United States work” under the definition in section 101 of the U.S. Copyright Act, subjecting the work to registration formality under section 411. This ruling is in sharp contrast with an earlier decision delivered by the Delaware District Court in Håkan Moberg v. 33T LLC, et al. which arrived at an opposite conclusion. The conflicting rulings of the U.S. courts reveal the problems posed by new forms of publishing online and demonstrate a compelling need for further harmonization between the Berne Convention, domestic laws and the practical realities of digital publishing. In this chapter, we argue that even if a work first published online can be considered to be simultaneously published all over the world it does not follow that any country can assert itself as the “country of origin” of the work for the purpose of imposing domestic copyright formalities. More specifically, we argue that the meaning of “United States work” under the U.S. Copyright Act should be interpreted in line with the presumption against extraterritorial application of domestic law to limit its application to only those works with a real and substantial connection to the United States. There are gaps in the Berne Convention’s articulation of “country of origin” which provide scope for judicial interpretation, at a national level, of the most pragmatic way forward in reconciling the goals of the Berne Convention with the practical requirements of domestic law. We believe that the uncertainties arising under the Berne Convention created by new forms of online publishing can be resolved at a national level by the sensible application of principles of statutory interpretation by the courts. While at the international level we may need a clearer consensus on what amounts to “simultaneous publication” in the digital age, state practice may mean that we do not yet need to explore textual changes to the Berne Convention.

Duty and Control in Intermediary Copyright Liability: An Australian Perspective

In the internet age, copyright owners are increasingly looking to online intermediaries to take steps to prevent copyright infringement. Sometimes these intermediaries are closely tied to the acts of infringement; sometimes – as in the case of ISPs – they are not. In 2012, the Australian High Court decided the Roadshow Films v iiNet case, in which it held that an Australian ISP was not liable under copyright’s authorization doctrine, which asks whether the intermediary has sanctioned, approved or countenanced the infringement. The Australian Copyright Act 1968 directs a court to consider, in these situations, whether the intermediary had the power to prevent the infringement and whether it took any reasonable steps to prevent or avoid the infringement. It is generally not difficult for a court to find the power to prevent infringement – power to prevent can include an unrefined technical ability to disconnect users from the copyright source, such as an ISP terminating users’ internet accounts. In the iiNet case, the High Court eschewed this broad approach in favor of focusing on a notion of control that was influenced by principles of tort law. In tort, when a plaintiff asserts that a defendant should be liable for failing to act to prevent harm caused to the plaintiff by a third party, there is a heavy burden on the plaintiff to show that the defendant had a duty to act. The duty must be clear and specific, and will often hinge on the degree of control that the defendant was able to exercise over the third party. Control in these circumstances relates directly to control over the third party’s actions in inflicting the harm. Thus, in iiNet’s case, the control would need to be directed to the third party’s infringing use of BitTorrent; control over a person’s ability to access the internet is too imprecise. Further, when considering omissions to act, tort law differentiates between the ability to control and the ability to hinder. The ability to control may establish a duty to act, and the court will then look to small measures taken to prevent the harm to determine whether these satisfy the duty. But the ability to hinder will not suffice to establish liability in the absence of control. This chapter argues that an inquiry grounded in control as defined in tort law would provide a more principled framework for assessing the liability of passive intermediaries in copyright. In particular, it would set a higher, more stable benchmark for determining the copyright liability of passive intermediaries, based on the degree of actual, direct control that the intermediary can exercise over the infringing actions of its users. This approach would provide greater clarity and consistency than has existed to date in this area of copyright law in Australia.

Associations with low rates of postpartum glucose screening after gestational diabetes among Indigenous and non-Indigenous Australian women

OBJECTIVES To explore factors associated with postpartum glucose screening among women with Gestational Diabetes Mellitus (GDM). METHODS A retrospective study using linked records from women with GDM who gave birth at Cairns Hospital in Far North Queensland, Australia, from 1 January 2004 to 31 December 2010. RESULTS The rates of postpartum Oral Glucose Tolerance Test (OGTT) screening, while having increased significantly among both Indigenous* and non-Indigenous women from 2004 to 2010 (HR 1.15 per year, 95%CI 1.08-1.22, p<0.0001), remain low, particularly among Indigenous women (10% versus 27%, respectively at six months postpartum). Indigenous women in Cairns had a longer time to postpartum OGTT than Indigenous women in remote areas (HR 0.58, 0.38-0.71, p=0.01). Non-Indigenous women had a longer time to postpartum OGTT if they: were born in Australia (HR 0.76, 0.59-1.00, 0.05); were aged <25 years (HR 0.45, 0.23-0.89, p=0.02); had parity >5 (HR 0.33, 0.12-0.90, p=0.03); smoked (HR 0.48, 0.31-0.76, p=0.001); and did not breastfeed (HR 0.09, 0.01-0.64, p=0.02). CONCLUSIONS Postpartum diabetes screening rates following GDM in Far North Queensland are low, particularly among Indigenous women, with lower rates seen in the regional centre; and among non-Indigenous women with indicators of low socioeconomic status. IMPLICATIONS Strategies are urgently needed to improve postpartum diabetes screening after GDM that reach women most at risk.

A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications

BACKGROUND Given moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50% to 60% heritability) with high correlation of genetic influences, we have conducted a quantitative trait genome-wide association study (GWAS) for phenotypes related to alcohol use and dependence. METHODS Diagnostic interview and blood/buccal samples were obtained from sibships ascertained through the Australian Twin Registry. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed with 8754 individuals (2062 alcohol-dependent cases) selected for informativeness for alcohol use disorder and associated quantitative traits. Family-based association tests were performed for alcohol dependence, dependence factor score, and heaviness of drinking factor score, with confirmatory case-population control comparisons using an unassessed population control series of 3393 Australians with genome-wide SNP data. RESULTS No findings reached genome-wide significance (p = 8.4 x 10(-8) for this study), with lowest p value for primary phenotypes of 1.2 x 10(-7). Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk. CONCLUSIONS We conclude that: - 1) meta-analyses of consumption data may contribute usefully to gene discovery; - 2) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging, and; - 3) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e.g., prospective high-risk or resilience studies).

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.