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.

A Python package for Bayesian estimation using Markov Chain Monte Carlo

Markov chain Monte Carlo (MCMC) estimation provides a solution to the complex integration problems that are faced in the Bayesian analysis of statistical problems. The implementation of MCMC algorithms is, however, code intensive and time consuming. We have developed a Python package, which is called PyMCMC, that aids in the construction of MCMC samplers and helps to substantially reduce the likelihood of coding error, as well as aid in the minimisation of repetitive code. PyMCMC contains classes for Gibbs, Metropolis Hastings, independent Metropolis Hastings, random walk Metropolis Hastings, orientational bias Monte Carlo and slice samplers as well as specific modules for common models such as a module for Bayesian regression analysis. PyMCMC is straightforward to optimise, taking advantage of the Python libraries Numpy and Scipy, as well as being readily extensible with C or Fortran.

The benefits of not managing change and not communicating : towards a complex systems view of communication in evolving organisations

The relationship between change in organisations and communication about change in organisations can be analysed as a particular case of a general debate in social theory about the extent to which reality is socially constructed. Social constructivists emphasise the role of language in the construction of social realities, enacted through controlling the message agenda; material determinists assert that economic and social structural factors are more constitutive of reality as seen in strategies emphasising structural and resource interventions. Here we define a third view of language and materiality - one that leads to the potential for a reflexive, experimental approach to change based on the view that organisations are complex evolving systems.

Schooling and refugees : engaging with the complex trajectories of globalisation

This paper examines the complexities associated with educating a mobile and politically marginalised population, refugee students, in the state of Queensland, Australia. Historically, schools have been national institutions concerned with social reproduction and citizenship formation with a focus on spatially fixed populations. While education authorities in much of the developed world now acknowledge the need to prepare students for a more interconnected world of work and opportunity, they have largely failed to provide systemic support for one category of children on the move - refugees. We begin this paper with a discussion of forced migration and its links with ‘globalisation’. We then present our research findings about the educational challenges confronting individual refugee youth and schools in Queensland. This is followed with a summary of good practice in refugee education. The paper concludes with a discussion of how nation-states might play a more active role in facilitating transitions to citizenship for refugee youth.

Measurement and correlates of caregiver self-efficacy amongst family caregivers of persons with dementia living in Shanghai, China

Background: Caring for family members with dementia can be a long-term, burdensome task resulting in physical and emotional distress and impairment. Research has demonstrated significantly lower levels of selfefficacy among family caregivers of people with dementia (CGs) than caregivers of relatives with non-dementia diseases. Intervention studies have also suggested that the mental and physical health of dementia CGs could be improved through the enhancement of their self-efficacy. However, studies are limited in terms of the influences of caregiver self-efficacy on caregiver behaviour, subjective burden and health-related quality of life. Of particular note is that there are no studies on the applicability of caregiver self-efficacy in the social context of China. Objective: The purpose of this thesis was to undertake theoretical exploration using Bandura’s (1997) self-efficacy theory to 1) revise the Revised Caregiving Self-Efficacy Scale (C-RCSES) (Steffen, McKibbin, Zeiss, Gallagher-Thompson, & Bandura, 2002), and 2) explore determinants of caregiver self-efficacy and the role of caregiver self-efficacy and other conceptual constructs (including CGs’ socio-demographic characteristics, CRs’ impairment and CGs’ social support) in explaining and predicting caregiver behaviour, subjective burden and health-related quality of life among CGs in China. Methodology: Two studies were undertaken: a qualitative elicitation study with 10 CGs; and a cross-sectional survey with 196 CGs. In the first study, semi-structured interviews were conducted to explore caregiver behaviours and corresponding challenges for their performance. The findings of the study assisted in the development of the initial items and domains of the Chinese version of the Revised Caregiving Self-Efficacy Scale (C-RCSES). Following changes to items in the scale, the second study, a cross-sectional survey with 196 CGs was conducted to evaluate the psychometric properties of C-RCSES and to test a hypothesised self-efficacy model of family caregiving adapted from Bandura’s theory (1997). Results: 35 items were generated from the qualitative data. The content validity of the C-RCSES was assessed and ensured in Study One before being used for the cross-sectional survey. Eight items were removed and five subscales (caregiver self-efficacy for gathering information about treatment, symptoms and health care; obtaining support; responding to problematic behaviours; management of household, personal and medical care; and controlling upsetting thoughts about caregiving) were identified after principal component factor analysis on the cross-sectional survey data. The reliability of the scale is acceptable: the Cronbach’s alpha coefficients for the whole scale and for each subscale were all over .80; and the fourweek test-retest reliabilities for the whole scale and for each subscale ranged from .64 to .85. The concurrent, convergent and divergent validity were also acceptable. CGs reported moderate levels of caregiver self-efficacy. Furthermore, the level of self-efficacy for management of household, personal and medical care was relatively high in comparison to those of the other four domains of caregiver self-efficacy. Caregiver self-efficacy was also significantly influenced by CGs’ socio-demographic characteristics and the caregiving external factors (CR impairment and social support that CGs obtained). The level of caregiver behaviour that CGs reported was higher than that reported in other Chinese research. CGs’ socio-demographics significantly influenced caregiver behaviour, whereas caregiver self-efficacy did not influence caregiver behaviour. Regarding the two external factors, CGs who cared for highly impaired relatives reported high levels of caregiver behaviour, but social support did not influence caregiver behaviour. Regarding caregiver subjective burden and health-related quality of life, CGs reported moderate levels of subjective burden, and their level of healthrelated quality of life was significantly lower than that of the general population in China. The findings also indicated that CGs’ subjective burden and health-related quality of life were influenced by all major factors in the hypothesised model, including CGs’ socio-demographics, CRs’ impairment, social support that CGs obtained, caregiver self-efficacy and caregiver behaviour. Of these factors, caregiver self-efficacy and social support significantly improved their subjective burden and health-related quality of life; whereas caregiver behaviour and CRs’ impairment were detrimental to CGs, such as increasing subjective burden and worsening health-related quality of life. Conclusion: While requiring further exploration, the qualitative study was the first qualitative research conducted in China to provide an in-depth understanding of CGs’ caregiving experience, including their major caregiver behaviours and the corresponding challenges. Meanwhile, although the C-RCSES needs further psychometric testing, it is a useful tool for assessing caregiver self-efficacy in Chinese populations. Results of the qualitative and quantitative study provide useful information for future studies regarding the explanatory power of caregiver self-efficacy to caregiver behaviour, subjective burden and health-related quality of life. Additionally, integrated with Bandura’s theory, the findings from the quantitative study also suggested a further study exploring the role of outcome expectations in caregiver behaviour, subjective burden and healthrelated quality of life.

Neuronal nicotinic acetylcholine receptors as pharmacotherapeutic targets for the treatment of alcohol use disorders

Alcohol use disorders (AUDs) are complex and developing effective treatments will require the combination of novel medications and cognitive behavioral therapy approaches. Epidemiological studies have shown there is a high correlation between alcohol consumption and tobacco use, and the prevalence of smoking in alcoholics is as high as 80% compared to about 30% for the general population. Both preclinical and clinical data provide evidence that nicotine administration increases alcohol intake and nonspecific nicotinic receptor antagonists reduce alcohol-mediated behaviors. As nicotine interacts specifically with the neuronal nicotinic acetylcholine receptor (nAChR) system, this suggests that nAChRs play an important role in the behavioral effects of alcohol. In this review, we discuss the importance of nAChRs for the treatment of AUDs and argue that the use of FDA approved nAChR ligands, such as varenicline and mecamylamine, approved as smoking cessation aids may prove to be valuable treatments for AUDs. We also address the importance of combining effective medications with behavioral therapy for the treatment of alcohol dependent individuals.

Stochastic simulation of chemical reactions in spatially complex media

Discrete stochastic simulations, via techniques such as the Stochastic Simulation Algorithm (SSA) are a powerful tool for understanding the dynamics of chemical kinetics when there are low numbers of certain molecular species. However, an important constraint is the assumption of well-mixedness and homogeneity. In this paper, we show how to use Monte Carlo simulations to estimate an anomalous diffusion parameter that encapsulates the crowdedness of the spatial environment. We then use this parameter to replace the rate constants of bimolecular reactions by a time-dependent power law to produce an SSA valid in cases where anomalous diffusion occurs or the system is not well-mixed (ASSA). Simulations then show that ASSA can successfully predict the temporal dynamics of chemical kinetics in a spatially constrained environment.

Using complex network metrics to predict the persistence of metapopulations with asymmetric connectivity patterns

Almost all metapopulation modelling assumes that connectivity between patches is only a function of distance, and is therefore symmetric. However, connectivity will not depend only on the distance between the patches, as some paths are easy to traverse, while others are difficult. When colonising organisms interact with the heterogeneous landscape between patches, connectivity patterns will invariably be asymmetric. There have been few attempts to theoretically assess the effects of asymmetric connectivity patterns on the dynamics of metapopulations. In this paper, we use the framework of complex networks to investigate whether metapopulation dynamics can be determined by directly analysing the asymmetric connectivity patterns that link the patches. Our analyses focus on “patch occupancy” metapopulation models, which only consider whether a patch is occupied or not. We propose three easily calculated network metrics: the “asymmetry” and “average path strength” of the connectivity pattern, and the “centrality” of each patch. Together, these metrics can be used to predict the length of time a metapopulation is expected to persist, and the relative contribution of each patch to a metapopulation’s viability. Our results clearly demonstrate the negative effect that asymmetry has on metapopulation persistence. Complex network analyses represent a useful new tool for understanding the dynamics of species existing in fragmented landscapes, particularly those existing in large metapopulations.

Using participatory action research in a community-based initiative addressing complex mental health needs

Objective: This paper describes the first phase of a larger project that utilizes participatory action research to examine complex mental health needs across an extensive group of stakeholders in the community. Method: Within an objective qualitative analysis of focus group discussions the social ecological model is utilized to explore how integrative activities can be informed, planned and implemented across multiple elements and levels of a system. Seventy-one primary care workers, managers, policy-makers, consumers and carers from across the southern metropolitan and Gippsland regions of Victoria, Australia took part in seven focus groups. All groups responded to an identical set of focusing questions. Results: Participants produced an explanatory model describing the service system, as it relates to people with complex needs, across the levels of social ecological analysis. Qualitative themes analysis identified four priority areas to be addressed in order to improve the system's capacity for working with complexity. These included: (i) system fragmentation; (ii) integrative case management practices; (iii) community attitudes; and (iv) money and resources. Conclusions: The emergent themes provide clues as to how complexity is constructed and interpreted across the system of involved agencies and interest groups. The implications these findings have for the development and evaluation of this community capacity-building project were examined from the perspective of constructing interventions that address both top-down and bottom-up processes.

The contribution of leadership attributes to large scale, complex project success

Mismanagement of large-scale, complex projects has resulted in spectacular failures, cost overruns, time blowouts, and stakeholder dissatisfaction. We focus discussion on the interaction of key management and leadership attributes which facilitate leaders’ adaptive behaviors. These behaviors should in turn influence adaptive team member behavior, stakeholder engagement and successful project outcomes, outputs and impacts. An understanding of this type of management will benefit from a perspective based in managerial and organizational cognition. The research question we explore is whether successful leaders of large-scale complex projects have an internal process leading to a display of administrative, adaptive, and enabling behaviors that foster adaptive processes and enabling behaviors within their teams and with external stakeholders. At the core of the model we propose interactions of key attributes, namely cognitive flexibility, affect, and emotional intelligence. The result of these cognitive-affective attribute interactions is leadership leading to enhanced likelihood of complex project success.

Caregiving experience and its influencing factors : rural versus urban adult-child caregivers caring for parents with dementia in China

Background: It is predicted that China will have the largest number of cases of dementia in the world by 2025 (Ferri et al., 2005). Research has demonstrated that caring for family members with dementia can be a long-term, burdensome activity resulting in physical and emotional distress and impairment (Pinquart & Sorensen, 2003b). The establishment of family caregiver supportive services in China can be considered urgent; and the knowledge of the caregiving experience and related influencing factors is necessary to inform such services. Nevertheless, in the context of rapid demographic and socioeconomic change, the impact of caregiving for rural and urban Chinese adult-child caregivers may be different, and different needs in supportive services may therefore be expected. Objectives: The aims of this research were 1) to examine the potential differences existing in the caregiving experience between rural and urban adult-child caregivers caring for parents with dementia in China; and 2) to examine the potential differences existing in the influencing factors of the caregiving experience for rural as compared with urban adult-child caregivers caring for parents with dementia in China. Based on the literature review and Kramer.s (1997) caregiver adaptation model, six concepts and their relationships of caregiving experience were studied: severity of the care receivers. dementia, caregivers. appraisal of role strain and role gain, negative and positive well-being outcomes, and health related quality of life. Furthermore, four influencing factors (i.e., filial piety, social support, resilience, and personal mastery) were studied respectively. Methods: A cross-sectional, comparative design was used to achieve the aims of the study. A questionnaire, which was designed based on the literature review and on Kramer.s (1997) caregiver adaptation model, was completed by 401 adult-child caregivers caring for their parents with dementia from the mental health outpatient departments in five hospitals in the Yunnan province, P.R. China. Structural equation modelling (SEM) was employed as the main statistical technique for data analyses. Other statistical techniques (e.g., t-tests and Chi-Square tests) were also conducted to compare the demographic characteristics and the measured variables between rural and urban groups. Results: For the first research aim, the results indicated that urban adult-child caregivers in China experienced significantly greater strain and negative well-being outcomes than their rural peers; whereas, the difference on the appraisal of role gain and positive outcomes was nonsignificant between the two groups. The results also indicated that the amounts of severity of care receivers. dementia and caregivers. health related quality of life do not have the same meanings between the two groups. Thus, the levels of these two concepts were not comparable between the rural and urban groups in this study. Moreover, the results also demonstrated that the negative direct effect of gain on negative outcomes in urban caregivers was stronger than that in rural caregivers, suggesting that the urban caregivers tended to use appraisal of role gain to protect themselves from negative well-being outcomes to a greater extent. In addition, the unexplained variance in strain in the urban group was significantly more than that in the rural group, suggesting that there were other unmeasured variables besides the severity of care receivers. dementia which would predict strain in urban caregivers compared with their rural peers. For the second research aim, the results demonstrated that rural adult-child caregivers reported a significantly higher level of filial piety and more social support than their urban counterparts, although the two groups did not significantly differ on the levels of their resilience and personal mastery. Furthermore, although the mediation effects of these four influencing factors on both positive and negative aspects remained constant across rural and urban adult-child caregivers, urban caregivers tended to be more effective in using personal mastery to protect themselves from role strain than rural caregivers, which in turn protects them more from the negative well-being outcomes than was the case with their rural peers. Conclusions: The study extends the application of Kramer.s caregiving adaptation process model (Kramer, 1997) to a sample of adult-child caregivers in China by demonstrating that both positive and negative aspects of caregiving may impact on the caregiver.s health related quality of life, suggesting that both aspects should be targeted in supportive interventions for Chinese family caregivers. Moreover, by demonstrating partial mediation effects, the study provides four influencing factors (i.e., filial piety, social support, resilience, and personal mastery) as specific targets for clinical interventions. Furthermore, the study found evidence that urban adult-child caregivers had more negative but similar positive experience compared to their rural peers, suggesting that the establishment of supportive services for urban caregivers may be more urgent at present stage in China. Additionally, since urban caregivers tended to use appraisal of role gain and personal mastery to protect themselves from negative well-being outcomes than rural caregivers to a greater extend, interventions targeting utility of gain or/and personal mastery to decrease negative outcomes might be more effective in urban caregivers than in rural caregivers. On the other hand, as cultural expectations and expression of filial piety tend to be more traditional in rural areas, interventions targeting filial piety could be more effective among rural caregivers. Last but not least, as rural adult-child caregivers have more existing natural social support than their urban counterparts, mobilising existing natural social support resources may be more beneficial for rural caregivers, whereas, formal supports (e.g., counselling services, support groups and adult day care centres) should be enhanced for urban caregivers.