Bayesian methodology for genetics of complex diseases

Genetic research of complex diseases is a challenging, but exciting, area of research. The early development of the research was limited, however, until the completion of the Human Genome and HapMap projects, along with the reduction in the cost of genotyping, which paves the way for understanding the genetic composition of complex diseases. In this thesis, we focus on the statistical methods for two aspects of genetic research: phenotype definition for diseases with complex etiology and methods for identifying potentially associated Single Nucleotide Polymorphisms (SNPs) and SNP-SNP interactions. With regard to phenotype definition for diseases with complex etiology, we firstly investigated the effects of different statistical phenotyping approaches on the subsequent analysis. In light of the findings, and the difficulties in validating the estimated phenotype, we proposed two different methods for reconciling phenotypes of different models using Bayesian model averaging as a coherent mechanism for accounting for model uncertainty. In the second part of the thesis, the focus is turned to the methods for identifying associated SNPs and SNP interactions. We review the use of Bayesian logistic regression with variable selection for SNP identification and extended the model for detecting the interaction effects for population based case-control studies. In this part of study, we also develop a machine learning algorithm to cope with the large scale data analysis, namely modified Logic Regression with Genetic Program (MLR-GEP), which is then compared with the Bayesian model, Random Forests and other variants of logic regression.

The ecological dynamics of decision-making in sailing

Competitive sailing is characterised by continuous interdependencies of decisions and actions. All actions imply a permanent monitoring of the environmental conditions, such as intensity and direction of the wind, sea characteristics, and the behaviour of the opponent sailors. These constraints on sailors’ behavior are in constant change implying continuous adjustments in sailors’ actions and decisions. Among the different parts of a regatta, tactics and strategy at the start are particularly relevant. Among coaches there is an adage that says that “the start is 50% of a regatta” (Houghton, 1984; Saltonstall, 1983/1986). Olympic sailing regattas are performed with boats of the same class, by one, two or three sailors, depending on the boat class. Normally before the start, sailors visit the racing venue and analyse wind and sea characteristics, in order to fine- tune their boats accordingly. Then, five minutes before the start, sailors initiate starting procedures in order to be in a favourable position at the starting line (at the “second zero”). This position is selected during the start period according to wind shifts tendencies and the actions of other boats (Figure 11.1). Only after the start signal can the boats cross the imaginary starting line between the race committee signal boat “A” and the pin end boat. The start takes place against the wind (upwind), and the boats start racing in the direction of mark 1. Based on the evaluation of the sea and wind characteristics (e.g. if the wind is stronger at a particular place on the course), sailors re- adjust their strategy for the regatta. This strategy may change during the regatta, according to wind changes and adversary actions. More to the point, strategic decisions constrain and are constrained by on- line decisions during the regatta.

An ecological footprint for an early learning centre : identifying opportunities for early childhood sustainability education through interdisciplinary research

In this study, engineers and educators worked together to adapt and apply the ecological footprint (EF) methodology to an early learning centre in Brisbane, Australia. Results were analysed to determine how environmental impact can be reduced at the study site and more generally across early childhood settings. It was found that food, transport and energy consumption had the largest impact on the centre’s overall footprint. In transport and energy, early childhood centres can reduce their impact through infrastructure and cultural change, in association with changed curriculum strategies. Building design, the type of energy purchased and appliance usage can all be modified to reduce the energy footprint. The transport footprint can be reduced through more families using active and public transport, which can be encouraged by providing information, support and facilities and appropriate siting of new centres. Introducing the concept of ecological footprint in early childhood education may be an effective way to educate children, staff and parents on the links between the food they eat, land usage and environmental impact. This study responds directly to the call in this journal for research focused on early childhood education and for more to be made of interdisciplinary research opportunities.

The genetics of cutaneous melanoma

Although germline mutations in CDKN2A are present in approximately 25% of large multicase melanoma families, germline mutations are much rarer in the smaller melanoma families that make up most individuals reporting a family history of this disease. In addition, only three families worldwide have been reported with germline mutations in a gene other than CDKN2A (i.e., CDK4). Accordingly, current genomewide scans underway at the National Human Genome Research Institute hope to reveal linkage to one or more chromosomal regions, and ultimately lead to the identification of novel genes involved in melanoma predisposition. Both CDKN2A and PTEN have been identified as genes involved in sporadic melanoma development; however, mutations are more common in cell lines than uncultured tumors. A combination of cytogenetic, molecular, and functional studies suggests that additional genes involved in melanoma development are located to chromosomal regions 1p, 6q, 7p, 11q, and possibly also 9p and 10q. With the near completion of the human genome sequencing effort, combined with the advent of high throughput mutation analyses and new techniques including cDNA and tissue microarrays, the identification and characterization of additional genes involved in melanoma pathogenesis seem likely in the near future.

Quality of life and genetics in men with prostate cancer

As family history has been established as a risk factor for prostate cancer, attempts have been made to isolate predisposing genetic variants that are related to hereditary prostate cancer. With many genetic variants still to be identified and investigated, it is not yet possible to fully understand the impact of genetic variants on prostate cancer development. The high survival rates among men with prostate cancer have meant that other issues, such as quality of life (QoL), have also become important. Through their effect on a person’s health, a range of inherited genetic variants may potentially influence QoL in men with prostate cancer, even prior to treatment. Until now, limited research has been conducted on the relationship between genetics and QoL. Thus, this study contributes to an emerging field by aiming to identify certain genetic variants related to the QoL found in men with prostate cancer. It is hoped that this study may lead to future research that will identify men who have an increased risk of a poor QoL following prostate cancer treatment, which will aid in developing treatments that are individually tailored to support them. Previous studies have established that genetic variants of Vascular Endothelial Growth Factor (VEGF) and Insulin-like Growth Factor 1 (IGF-1) may play a role in prostate cancer development. VEGF and IGF-1 have also been reported to be associated with QoL in people with ovarian cancer and colorectal cancer, respectively. This study completed a series of secondary analyses using two major data-sets (from 850 men newly diagnosed with prostate cancer, and approximately 550 men from the general Queensland population), in which genetic variants of VEGF and IGF-1 were investigated for associations with prostate cancer susceptibility and QoL. The first aim of this research was to investigate genetic variants in the VEGF and IGF-I gene for an association with the risk of prostate cancer. It was found that one IGF-1 genetic variant (rs35765) had a statistically significant association with prostate cancer (p = 0.04), and one VEGF genetic variant (rs2146323) had a statistically significant association with advanced prostate cancer (p = 0.02). The estimates suggest that carriers of the CA and AA genotype for rs35765 may have a reduced risk of developing prostate cancer (Odds Ratio (OR) = 0.72, 95% Confidence Interval (CI) = 0.55, 0.95, OR = 0.60, 95% CI = 0.26, 1.39, respectively). Meanwhile, carriers of the CA and AA genotype for rs2146323 may be at increased risk of advanced prostate cancer, which was determined by a Gleason score of above 7 (OR = 1.72, 95% CI = 1.12, 2.63, OR = 1.90, 95% CI = 1.08, 3.34, respectively). Utilising the widely used short-form health survey, the SF-36v2, the second aim of this study was to investigate the relationship between prostate cancer and QoL prior to treatment. Assessing QoL at this time-point was important as little research has been conducted to evaluate if prostate cancer affects QoL regardless of treatment. The analyses found that mean SF-36v2 scale scores related to physical health were higher by at least 0.3 Standard Deviations (SD) among men with prostate cancer than the general population comparison group. This difference was considered clinically significant (defined by group differences in mean SF-36v2 scores by at least 0.3 SD). These differences were also statistically significant (p<0.05). Mean QoL scale scores related to mental health were similar between men with prostate cancer and those from the general population comparison group. The third aim of this study was to investigate genetic variants in the VEGF and IGF-1 gene for an association with QoL in prostate cancer patients prior to their treatment. It was essential to evaluate these relationships prior to treatment, before the involvement of these genes was potentially interrupted by treatment. The analyses found that some genetic variants had a small clinically significant association (0.3 SD) to some QoL domains experienced by these men. However, most relationships were not statistically significant (p>0.05). Most of the associations found identified that a small sub-group of men with prostate cancer (approximately 2%) reported, on average, a slightly better QoL than the majority of the prostate cancer patients. The fourth aim of this research was to investigate whether associations between genetic variants in VEGF and IGF-1 and QoL were specific to men with prostate cancer, or were also applicable to the general male population. It was found that twenty out of one-hundred relationships between the genetic variants of VEGF and IGF-1 and QoL health-measures and scales examined differed between these groups. In the majority of the relationships involving VEGF SNPs that differed, a clinically significant difference (0.3 or more SD) between mean scores among the genotype groups in prostate cancer patients was found, while mean scores among men from the general-population comparison group were similar. For example, prostate cancer participants who carried at least one T allele (CT or TT genotype) for rs3024994 had a clinically significant higher (0.3 SD) mean QoL score in terms of the role-physical scale, than participants who carried the CC genotype. This was not seen among men from the general population sample, as the mean score was similar between genotype groups. The opposite was seen in regards to the IGF-1 SNPs examined. Overall, these relationships were not considered to directly impact on the clinical options for men with prostate cancer. As this study utilised secondary data from two separate studies, there are a number of important limitations that should be acknowledged including issues of multiple comparisons, power, and missing or unavailable data. It is recommended that this study be replicated as a better-designed study that takes greater consideration of the many factors involved in prostate cancer and QoL. Investigation into other genetic variants of VEGF or IGF-1 is also warranted, as is consideration of other genes and their relationship with QoL. Through identifying certain genetic variants that have a modest association to prostate cancer, this project adds to the knowledge surrounding VEGF and IGF-1 and their role in prostate cancer susceptibility. Importantly, this project has also introduced the potential role genetics plays in QoL, through investigating the relationships between genetic variants of VEGF and IGF-1 and QoL.

Grounded Media: Expanding the Scope of Ecological Art Practices Within New Media Arts Culture

‘Grounded Media’ is a form of art practice focused around the understanding that our ecological crisis is also a cultural crisis, perpetuated by our sense of separation from the material and immaterial ecologies upon which we depend. This misunderstanding of relationships manifests not only as environmental breakdown, but also in the hemorrhaging of our social fabric. ‘Grounded Media’ is consistent with an approach to media art making that I name ‘ecosophical’ and ‘praxis-led’ – which seeks through a range of strategies, to draw attention to the integrity, diversity and efficacy of the biophysical, social and electronic environments of which we are an integral part. It undertakes this through particular choices of location, interaction design,participative strategies and performative direction. This form of working emerged out of the production of two major projects, Grounded Light [8] and Shifting Intimacies [9] and is evident in a recent prototypical wearable art project called In_Step [6]. The following analysis and reflections will assist in promoting new, sustainable roles for media artists who are similarly interested in attuning their practices.

'Homes for Life' : a critical ecological study of an independent living project

In this paper, an ‘ecological’ lens is applied to an independent living project aiming to provide ‘homes for life’ for adult children with disabilities. The qualities of the project as ecological praxis are highlighted along with the implications for an open-ended enquiry into ecologies for and of the interior. In terms of the ecological concern for intimate modes of being, interior design is shown to be well placed through its association with environments in which people spend most of their life and through powerful concepts such as ‘interiority’ and ‘home’ which link to fundamental existential notions of ‘self ’ and ‘identity’. However, despite the interior being a significant generative force, this has not happened to the exclusion of other disciplines. Ignoring territorial urges to claim areas and concepts as one’s own, the paper describes how the project has actively encouraged design disciplines to trespass in each other’s territories. Ecologies for and of the interior, while recognising the need for discipline emphasis, also demand an integrated and collective approach through what is in effect transdisciplinary practice.

Government initiative and start-up firms’ eco-innovation : A case study through the ecological modernisation lens

Government programs to finance small firms or start-ups have attracted a little empirical attention. From an economical perspective, the effect of government grants is evaluated by a measure of innovation or firm productivity. Yet, this paper takes a different approach from economical view aiming to address the research question “How do start ups firms view the relationship between government grants and their co-efficient innovation effort?” Semi-structured interviews with grant recipients (start-up business owners revealed that the grants assist firms to leverage their resource limitations but at the same time the grants also act as a major roadblock for their product development success.

Processpedia : an ecological environment for BPM stakeholders' collaboration

Purpose: The purpose of this paper is to clarify how end-users’ tacit knowledge can be captured and integrated in an overall business process management (BPM) approach. Current approaches to support stakeholders’ collaboration in the modelling of business processes envision an egalitarian environment where stakeholders interact in the same context, using the same languages and sharing the same perspectives on the business process. Therefore, such stakeholders have to collaborate in the context of process modelling using a language that some of them do not master, and have to integrate their various perspectives. Design/methodology/approach: The paper applies the SECI knowledge management process to analyse the problems of traditional top-down BPM approaches and BPM collaborative modelling tools. Besides, the SECI model is also applied to Wikipedia, a successful Web 2.0-based knowledge management environment, to identify how tacit knowledge is captured in a bottom-up approach. Findings – The paper identifies a set of requirements for a hybrid BPM approach, both top-down and bottom-up, and describes a new BPM method based on a stepwise discovery of knowledge. Originality/value: This new approach, Processpedia, enhances collaborative modelling among stakeholders without enforcing egalitarianism. In Processpedia tacit knowledge is captured and standardised into the organisation’s business processes by fostering an ecological participation of all the stakeholders and capitalising on stakeholders’ distinctive characteristics.

Russian wheat aphids (Diuraphis noxia) in China : native range expansion or recent introduction?

In this study, we explore the population genetics of the Russian wheat aphid (RWA) (Diuraphis noxia), one of the world’s most invasive agricultural pests, in north-western China. We have analysed the data of 10 microsatellite loci and mitochondrial sequences from 27 populations sampled over 2 years in China. The results confirm that the RWAs are holocyclic in China with high genetic diversity indicating widespread sexual reproduction. Distinct differences in microsatellite genetic diversity and distribution revealed clear geographic isolation between RWA populations in northern and southern Xinjiang, China, with gene flow interrupted across extensive desert regions. Despite frequent grain transportation from north to south in this region, little evidence for RWA translocation as a result of human agricultural activities was found. Consequently, frequent gene flow among northern populations most likely resulted from natural dispersal, potentially facilitated by wind currents. We also found evidence for the longterm existence and expansion of RWAs in China, despite local opinion that it is an exotic species only present in China since 1975. Our estimated date of RWA expansion throughout China coincides with the debut of wheat domestication and cultivation practices in western Asia in the Holocene. We conclude that western China represents the limit of the far eastern native range of this species. This study is the most comprehensive molecular genetic investigation of the RWA in its native range undertaken to date and provides valuable insights into the history of the association of this aphid with domesticated cereals and wild grasses.

The unfinished landscape fractal geometry and the aesthetics of ecological design

During the late 20th century it was proposed that a design aesthetic reflecting current ecological concerns was required within the overall domain of the built environment and specifically within landscape design. To address this, some authors suggested various theoretical frameworks upon which such an aesthetic could be based. Within these frameworks there was an underlying theme that the patterns and processes of Nature may have the potential to form this aesthetic — an aesthetic based on fractal rather than Euclidean geometry. In order to understand how fractal geometry, described as the geometry of Nature, could become the referent for a design aesthetic, this research examines the mathematical concepts of fractal Geometry, and the underlying philosophical concepts behind the terms ‘Nature’ and ‘aesthetics’. The findings of this initial research meant that a new definition of Nature was required in order to overcome the barrier presented by the western philosophical Nature¯culture duality. This new definition of Nature is based on the type and use of energy. Similarly, it became clear that current usage of the term aesthetics has more in common with the term ‘style’ than with its correct philosophical meaning. The aesthetic philosophy of both art and the environment recognises different aesthetic criteria related to either the subject or the object, such as: aesthetic experience; aesthetic attitude; aesthetic value; aesthetic object; and aesthetic properties. Given these criteria, and the fact that the concept of aesthetics is still an active and ongoing philosophical discussion, this work focuses on the criteria of aesthetic properties and the aesthetic experience or response they engender. The examination of fractal geometry revealed that it is a geometry based on scale rather than on the location of a point within a three-dimensional space. This enables fractal geometry to describe the complex forms and patterns created through the processes of Wild Nature. Although fractal geometry has been used to analyse the patterns of built environments from a plan perspective, it became clear from the initial review of the literature that there was a total knowledge vacuum about the fractal properties of environments experienced every day by people as they move through them. To overcome this, 21 different landscapes that ranged from highly developed city centres to relatively untouched landscapes of Wild Nature have been analysed. Although this work shows that the fractal dimension can be used to differentiate between overall landscape forms, it also shows that by itself it cannot differentiate between all images analysed. To overcome this two further parameters based on the underlying structural geometry embedded within the landscape are discussed. These parameters are the Power Spectrum Median Amplitude and the Level of Isotropy within the Fourier Power Spectrum. Based on the detailed analysis of these parameters a greater understanding of the structural properties of landscapes has been gained. With this understanding, this research has moved the field of landscape design a step close to being able to articulate a new aesthetic for ecological design.