Genome-wide association study identifies eight loci associated with blood pressure

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N 71,225 European ancestry, N 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10 24), CYP1A2 (P = 1 × 10 23), FGF5 (P = 1 × 10 21), SH2B3 (P = 3 × 10 18), MTHFR (P = 2 × 10 13), c10orf107 (P = 1 × 10 9), ZNF652 (P = 5 × 10 9) and PLCD3 (P = 1 × 10 8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1–3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4, 5, 6, 7, 8, 9, 10, 11. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression...

Legal duties following the discharge of mental health patients

In the recent decision of Hunter and New England Local Health District v McKenna; Hunter and New England Local Health District v Simon, the High Court of Australia held that a hospital and its medical staff owed no common law duty of care to third parties claiming for mental harm, against the background of statutory powers to detain mentally ill patients. This conclusion was based in part on the statutory framework and in part on the inconsistency which would arise if such a duty was imposed. If such a duty was imposed in these circumstances, the consequence may be that doctors would generally detain rather than discharge mentally ill persons to avoid the foreseeable risk of harm to others. Such an approach would be inconsistent with the policy of the mental health legislation , which favours personal liberty and discharge rather than detention unless no other care of a less restrictive kind is appropriate and reasonably available.

Family violence in culturally and linguistically diverse communities: An evaluation of a family relationship centre

Federal legislative changes in Australia have sought to improve how family relationship centres (FRCs) can be more responsive to culturally and linguistically diverse (CALD) communities when addressing family disputes and family violence. Research on the prevalence of family violence against women from CALD backgrounds is sparse. This article seeks to contribute to the understanding of this issue by describing findings of an evaluation of the FRC at Broadmeadows conducted by the authors. The findings focus on family violence and the appropriateness of the services offered to three CALD community groups, namely Iraqi, Lebanese and Turkish. The final section provides reflections on these findings and offers suggestions about how FRC services might better cater to the family violence needs of CALD communities by developing more extensive partnerships with community groups and by expanding the range of processes they offer beyond mediation.

Designs for phase I clinical trials with multiple courses of subjects at different doses

The goal of this article is to provide a new design framework and its corresponding estimation for phase I trials. Existing phase I designs assign each subject to one dose level based on responses from previous subjects. Yet it is possible that subjects with neither toxicity nor efficacy responses can be treated at higher dose levels, and their subsequent responses to higher doses will provide more information. In addition, for some trials, it might be possible to obtain multiple responses (repeated measures) from a subject at different dose levels. In this article, a nonparametric estimation method is developed for such studies. We also explore how the designs of multiple doses per subject can be implemented to improve design efficiency. The gain of efficiency from "single dose per subject" to "multiple doses per subject" is evaluated for several scenarios. Our numerical study shows that using "multiple doses per subject" and the proposed estimation method together increases the efficiency substantially.

Estimating equations for removal data analysis

We consider the problem of estimating a population size from successive catches taken during a removal experiment and propose two estimating functions approaches, the traditional quasi-likelihood (TQL) approach for dependent observations and the conditional quasi-likelihood (CQL) approach using the conditional mean and conditional variance of the catch given previous catches. Asymptotic covariance of the estimates and the relationship between the two methods are derived. Simulation results and application to the catch data from smallmouth bass show that the proposed estimating functions perform better than other existing methods, especially in the presence of overdispersion.

The impact of global positioning systems and plotters on fishing power in the northern prawn fishery, Australia

The impact of global positioning systems (GPS) and plotter systems on the relative fishing power of the northern prawn fishery fleet on tiger prawns (Penaeus esculentus Haswell, 1879, and P. semisulcatus de Haan, 1850) was investigated from commercial catch data. A generalized linear model was used to account for differences in fishing power between boats and changes in prawn abundance. It was found that boats that used a GPS alone had 4% greater fishing power than boats without a CPS. The addition of a plotter raised the power by 7% over boats without the equipment. For each year between the first to third that a fisher has been working with plotters, there is an additional 2 or 3% increase. It appears that when all boats have a GPS and plotter for at least 3 years, the fishing power of the fleet will increase by 12%. Management controls have reduced the efficiency of each boat and lowered the number of days available to fish, but this may not have been sufficient to counteract the increases. Further limits will be needed to maintain the desired levels of mortality.

Guest Editorial: Emerging Scholars' Section

This issue of the QUT Law Review features an Emerging Scholars’ section containing contributions from early career researchers and doctoral students. This section was conceived by the previous General Editor of the journal, Prof Dan Hunter, as a forum to showcase high-quality legal scholarship from emerging scholars. We are grateful to Prof Hunter for his work on this initiative.

Guest Editorial: Emerging Scholars' Section

This issue of the QUT Law Review also features an Emerging Scholars’ section containing contributions from early career researchers and doctoral students. This section was conceived by the previous General Editor of the journal, Prof Dan Hunter, as a forum to showcase high-quality legal scholarship from emerging scholars. We are grateful to Prof Hunter for his work on this initiative.

Indigenous legal education at UNSW: A work in progress

Since the 1970s Australian law schools have provided alternative entry routes and, since the 1980s, pre-law programs and bridging programs. On-going support, once Indigenous students reach university law schools, has been an issue that has not been formally or appropriately addressed in most university law schools. In this way Indigenous students’ chances of entry are disguised as chances of success. Thus once Indigenous students start their law school studies, they are often expected to perform on a level playing field – their success or failure then depends on ‘gifts, merits or skills’ which are culturally appropriate for law school. This attitude fails to recognise the privilege which allows the development of such gifts, merits or skills...

Lower preoperative quality of life increases postoperative risk of adverse events in women with endometrial cancer: results from the LACE trial

Objective: To examine the association between preoperative quality of life (QoL) and postoperative adverse events in women treated for endometrial cancer. Methods: 760 women with apparent Stage I endometrial cancer were randomised into a clinical trial evaluating laparoscopic versus open surgery. This analysis includes women with preoperative QoL measurements, from the Functional Assessment of Cancer Therapy- General (FACT-G) questionnaire, and who were followed up for at least 6 weeks after surgery (n=684). The outcomes for this study were defined as (1) the occurrence of moderate to severe AEs adverse events within 6 months (Common Toxicology Criteria (CTC) grade ≥3); and (2) any Serious Adverse Event (SAE). The association between preoperative QoL and the occurrence of AE was examined, after controlling for baseline comorbidity and other factors. Results: After adjusting for other factors, odds of occurrence of AE of CTC grade ≥3 were significantly increased with each unit decrease in baseline FACT-G score (OR=1.02, 95% CI 1.00-1.03, p=0.030), which was driven by physical well-being (PWB) (OR=1.09, 95% CI 1.04-1.13, p=0.0002) and functional well-being subscales (FWB) (OR=1.04, 95% CI 1.00-1.07, p=0.035). Similarly, odds of SAE occurrence were significantly increased with each unit decrease in baseline FACT-G score (OR=1.02, 95% CI 1.01-1.04, p=0.011), baseline PWB (OR=1.11, 95% CI 1.06-1.16, p<0.0001) or baseline FWB subscales (OR=1.05, 95% CI 1.01-1.10, p=0.0077). Conclusion: Women with early endometrial cancer presenting with lower QoL prior to surgery are at higher risk of developing a serious adverse event following surgery. Funding: Cancer Council Queensland, Cancer Council New South Wales, Cancer Council Victoria, Cancer Council, Western Australia; NHMRC project grant 456110; Cancer Australia project grant 631523; The Women and Infants Research Foundation, Western Australia; Royal Brisbane and Women’s Hospital Foundation; Wesley Research Institute; Gallipoli Research Foundation; Gynetech; TYCO Healthcare, Australia; Johnson and Johnson Medical, Australia; Hunter New England Centre for Gynaecological Cancer; Genesis Oncology Trust; and Smart Health Research Grant QLD Health.

Probabilistic load flow for distribution systems with uncertain PV generation

Large integration of solar Photo Voltaic (PV) in distribution network has resulted in over-voltage problems. Several control techniques are developed to address over-voltage problem using Deterministic Load Flow (DLF). However, intermittent characteristics of PV generation require Probabilistic Load Flow (PLF) to introduce variability in analysis that is ignored in DLF. The traditional PLF techniques are not suitable for distribution systems and suffer from several drawbacks such as computational burden (Monte Carlo, Conventional convolution), sensitive accuracy with the complexity of system (point estimation method), requirement of necessary linearization (multi-linear simulation) and convergence problem (Gram–Charlier expansion, Cornish Fisher expansion). In this research, Latin Hypercube Sampling with Cholesky Decomposition (LHS-CD) is used to quantify the over-voltage issues with and without the voltage control algorithm in the distribution network with active generation. LHS technique is verified with a test network and real system from an Australian distribution network service provider. Accuracy and computational burden of simulated results are also compared with Monte Carlo simulations.

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10−8). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.