Pathway analysis of complex diseases for GWAS, extending to consider rare variants, multi-omics and interactions

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Association of High Myopia with Crystallin Beta A4 (CRYBA4) Gene Polymorphisms in the Linkage-Identified MYP6 Locus

Background: Myopia is the most common ocular disorder worldwide and imposes tremendous burden on the society. It is a complex disease. The MYP6 locus at 22 q12 is of particular interest because many studies have detected linkage signals at this interval. The MYP6 locus is likely to contain susceptibility gene(s) for myopia, but none has yet been identified. Methodology/Principal Findings: Two independent subject groups of southern Chinese in Hong Kong participated in the study an initial study using a discovery sample set of 342 cases and 342 controls, and a follow-up study using a replication sample set of 316 cases and 313 controls. Cases with high myopia were defined by spherical equivalent ⠤ -8 dioptres and emmetropic controls by spherical equivalent within ±1.00 dioptre for both eyes. Manual candidate gene selection from the MYP6 locus was supported by objective in silico prioritization. DNA samples of discovery sample set were genotyped for 178 tagging single nucleotide polymorphisms (SNPs) from 26 genes. For replication, 25 SNPs (tagging or located at predicted transcription factor or microRNA binding sites) from 4 genes were subsequently examined using the replication sample set. Fisher P value was calculated for all SNPs and overall association results were summarized by meta-analysis. Based on initial and replication studies, rs2009066 located in the crystallin beta A4 (CRYBA4) gene was identified to be the most significantly associated with high myopia (initial study: P = 0.02; replication study: P = 1.88e-4; meta-analysis: P = 1.54e-5) among all the SNPs tested. The association result survived correction for multiple comparisons. Under the allelic genetic model for the combined sample set, the odds ratio of the minor allele G was 1.41 (95% confidence intervals, 1.21-1.64). Conclusions/Significance: A novel susceptibility gene (CRYBA4) was discovered for high myopia. Our study also signified the potential importance of appropriate gene prioritization in candidate selection. © 2012 Ho et al.published_or_final_versio

A crossover study comparing in-plane and out-of-plane approaches for simulated ultrasound-guided central venous cannulation on phantom models by anaesthesiology trainees

This prospective crossover study compared the incidence of posterior vessel wall puncture between two approaches during ultrasound-guided simulated central venous cannulation by anaesthesiology trainees. Each phantom model, simulating a central vein and artery, was cannulated by 37 anaesthesiology trainees under ultrasound-guidance using the in-plane approach (IPA) and out-of-plane approach (OPA). Total procedural time and the time taken from starting image scanning until commencing puncture, was recorded. The number of attempts required to achieve successful venous cannulation was noted. Finally, the models were examined for posterior venous wall and arterial puncture. Total procedural time was shorter with the OPA (26.5 vs 50.3 seconds, p=0.001). The time taken from starting image scanning until commencing puncture was shorter for the OPA (2.2 vs 12.3 seconds, p<0.0001). The IPA resulted in significantly more attempts for cannulation. Twenty and eleven participants were successful within the first pass using the OPA and IPA, respectively (p=0.034). There was no difference in the incidence of posterior vessel wall puncture between these two techniques. The OPA resulted in less arterial puncture compared to the IPA (2 vs 9, p=0.022). The incidence of posterior vessel wall puncture between the IPA and OPA during ultrasound-guided simulated central venous cannulation by anaesthesiology trainees was comparable

Targeting DNA Repair in Cancer: Beyond PARP Inhibitors

Germline aberrations in critical DNA-repair and DNA damage-response (DDR) genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers. Herein, we detail how cellular DDR processes engage various proteins that sense DNA damage, initiate signaling pathways to promote cell-cycle checkpoint activation, trigger apoptosis, and coordinate DNA repair. We focus on novel therapeutic strategies targeting promising DDR targets and discuss challenges of patient selection and the development of rational drug combinations. $\textbf{SIGNIFICANCE}$: Various inhibitors of DDR components are in preclinical and clinical development. A thorough understanding of DDR pathway complexities must now be combined with strategies and lessons learned from the successful registration of PARP inhibitors in order to fully exploit the potential of DDR inhibitors and to ensure their long-term clinical success. Cancer Discov; 7(1); 20-37. ©2016 AACRJ.S. Brown, B. O'Carrigan, and T.A. Yap acknowledge support from the Experimental Cancer Medicine Centre (to The Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research). Research in The Jackson laboratory is funded by Cancer Research UK (CRUK) program grant number C6/A18796. Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P. Jackson receives his salary from the University of Cambridge, UK, supplemented by CRUK

Association of high myopia with crystallin beta A4 (CRYBA4) gene polymorphisms in the linkage-identified MYP6 locus

Author name used in this publication: Maurice K. H. Yap2011-2012 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Genetic susceptibility to refractive error : association of vasoactive intestinal peptide receptor 2 (VIPR2) with high myopia in Chinese

Author name used in this publication: Maurice K. H. Yap2012-2013 > Academic research: refereed > Publication in refereed journalpublished_fina

Evaluation of proteoglycan gene polymorphisms as risk factors in the genetic susceptibility to high myopia

Author name used in this manuscript: Maurice K. H. Yap2011-2012 > Academic research: refereed > Publication in refereed journalAccepted ManuscriptPublishe

Transdisciplinary learning: Transformative collaborations between students, industry, academia and communities.

Background and objectives of the case An analogy: Imagine you are invited to a dinner party, but instead of a stuffy sit-down affair, your host asks you to bring your favourite ingredient, and together you prepare a delicious feast of unique and distinct flavours. UTS’s transdisciplinary initiatives are changing the shape of higher education and forging innovative partnerships by bringing together diverse professional fields. With a focus on practice-based and problem-focused learning, UTS educational programs combine the strengths of multiple disciplines, industries, public sector organisations, and the community to turn real-world problems into rewarding opportunities for education and also “learning for a lifetime”. In place of the limitations of artificial disciplinary boundaries, transdisciplinary learning practices create synergistic and innovative approaches to grappling with complex applied challenges. Students, researchers, practitioners, community members and other stakeholders combine their knowledge, tools, techniques, methods, theories, concepts, as well as cultural and personal perspectives. By understanding problems holistically, the solutions that emerge are bold, innovative, and creative, as well as mutually beneficial. We view this as the future of education: good to work with, and good to think with — problem solving for (and with) industry and society. The Faculty of Transdisciplinary Innovation is re-imagining how education, research, and professional practice can work together to navigate today’s complex problems, and create commercially attractive and socially responsible futures. We also practice what we preach: for example, staff professional development to enact these models in our own teaching; educational programs to provide experiential learning around problem solving within a rapidly-changing environment involving students from across different disciplines and cultural backgrounds; as well as policy development and research on today’s pressing “wicked problems” with industry and government. Primary objectives of this next practice concept of transdisciplinary learning, include: - To promote a shift in industry-university engagement from producing “knowledge for society” to co-generating “knowledge with society”; - To build a resilient ecosystem for co-learning; - To create and sustain future-oriented degree programs with collaboration between industry, government, and community at the centre, geared to prepare our graduates for the complex challenges of a networked world; - To create an agile and responsive industry-university lab environment for generating and testing new experimental models; - To enable industry – by collaborating with our students and academics – to see their problems from a fresh perspective, often through different and revealing lenses, and to notice opportunities and spot challenges that may have otherwise been overlooked; - To prepare students to lead innovation in a rapidly-changing and challenging world; and - To graduate students who are ‘complexity-fluent’, systems thinkers, creative problem-posers and -solvers, and imaginative, ethical citizens

Genotyping performance assessment of whole genome amplified DNA with respect to multiplexing level of assay and its period of storage

Author name used in this publication: Maurice K. H. Yap2011-2012 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

A DNA pooling-based case-control study of myopia candidate genes COL11A1, COL18A1, FBN1, and PLOD1 in a Chinese population

Author name used in this publication: Maurice K. H. Yap2010-2011 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe