Latent variable models in statistical genetics

Understanding the complexities that are involved in the genetics of multifactorial diseases is still a monumental task. In addition to environmental factors that can influence the risk of disease, there is also a number of other complicating factors. Genetic variants associated with age of disease onset may be different from those variants associated with overall risk of disease, and variants may be located in positions that are not consistent with the traditional protein coding genetic paradigm. Latent Variable Models are well suited for the analysis of genetic data. A latent variable is one that we do not directly observe, but which is believed to exist or is included for computational or analytic convenience in a model. This thesis presents a mixture of methodological developments utilising latent variables, and results from case studies in genetic epidemiology and comparative genomics. Epidemiological studies have identified a number of environmental risk factors for appendicitis, but the disease aetiology of this oft thought useless vestige remains largely a mystery. The effects of smoking on other gastrointestinal disorders are well documented, and in light of this, the thesis investigates the association between smoking and appendicitis through the use of latent variables. By utilising data from a large Australian twin study questionnaire as both cohort and case-control, evidence is found for the association between tobacco smoking and appendicitis. Twin and family studies have also found evidence for the role of heredity in the risk of appendicitis. Results from previous studies are extended here to estimate the heritability of age-at-onset and account for the eect of smoking. This thesis presents a novel approach for performing a genome-wide variance components linkage analysis on transformed residuals from a Cox regression. This method finds evidence for a dierent subset of genes responsible for variation in age at onset than those associated with overall risk of appendicitis. Motivated by increasing evidence of functional activity in regions of the genome once thought of as evolutionary graveyards, this thesis develops a generalisation to the Bayesian multiple changepoint model on aligned DNA sequences for more than two species. This sensitive technique is applied to evaluating the distributions of evolutionary rates, with the finding that they are much more complex than previously apparent. We show strong evidence for at least 9 well-resolved evolutionary rate classes in an alignment of four Drosophila species and at least 7 classes in an alignment of four mammals, including human. A pattern of enrichment and depletion of genic regions in the profiled segments suggests they are functionally significant, and most likely consist of various functional classes. Furthermore, a method of incorporating alignment characteristics representative of function such as GC content and type of mutation into the segmentation model is developed within this thesis. Evidence of fine-structured segmental variation is presented.

Empirical derivation and validation of a wandering typology

OBJECTIVES: To develop and validate a wandering typology. ---------- DESIGN: Cross-sectional, correlational descriptive design. ---------- SETTING:: Twenty-two nursing homes and six assisted living facilities. ---------- PARTICIPANTS: One hundred forty-two residents with dementia who spoke English, met Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, criteria for dementia, scored less than 24 on the Mini-Mental State Examination (MMSE), were ambulatory (with or without assistive device), and maintained a stable regime of psychotropic medications were studied. ---------- MEASUREMENTS: Data on wandering were collected using direct observations, plotted serially according to rate and duration to yield 21 parameters, and reduced through factor analysis to four components: high rate, high duration, low to moderate rate and duration, and time of day. Other measures included the MMSE, Minimum Data Set 2.0 mobility items, Cumulative Illness Rating Scale—Geriatric, and tympanic body temperature readings. ---------- RESULTS: Three groups of wanderers were identified through cluster analysis: classic, moderate, and subclinical. MMSE, mobility, and cardiac and upper and lower gastrointestinal problems differed between groups of wanderers and in comparison with nonwanderers. ---------- CONCLUSION: Results have implications for improving identification of wanderers and treatment of possible contributing factors.

25th anniversary of BUA for the assessment of osteoporosis : time for a new paradigm?

The measurement of broadband ultrasonic attenuation (BUA) in cancellous bone at the calcaneus for the assessment of osteoporosis was first described within this journal 25 years ago. It was recognized in 2006 by Universities UK as being one of the ‘100 discoveries and developments in UK Universities that have changed the world’ over the past 50 years. In 2008, the UK's Department of Health also recognized BUA assessment of osteoporosis in a publication highlighting 11 projects that have contributed to ‘60 years of NHS research benefiting patients’. The BUA technique has been extensively clinically validated and is utilized worldwide, with at least seven commercial systems currently providing calcaneal BUA measurement. However, there is still no fundamental understanding of the dependence of BUA upon the material and structural properties of cancellous bone. This review aims to provide an ‘engineering in medicine’ perspective and proposes a new paradigm based upon phase cancellation due to variation in propagation transit time across the receive transducer face to explain the non-linear relationship between BUA and bone volume fraction in cancellous bone.

Sudanese refugees in Australia the impact of acculturation stress

Refugees from Sudan are the fastest growing community in Australia. Australian mental health professionals have to be prepared to offer services to this ethnic group along with the other mainstream and diverse consumers. In order to offer culturally competent services, these mental health professionals are required to be familiar with this emerging community. As such a review was undertaken with two main goals. Firstly, the review aimed to educate Australian mental health professionals about the demographics and culture of Sudan, the traumas encountered as a result of the civil war, factors leading to massive exodus, and the difficulties of the transit and post migration phase. Secondly, the review intended to inform Australian mental health professionals about the possible acculturation stress that is manifested in the form of intergeneration and role conflict and marital difficulties. The review highlights that there are few studies addressing acculturation stress of Sudanese refugees, and even fewer on the impact it has on relationships. Future research directions are discussed.

Enhancing the experience of public transport users with urban screens and mobile applications

Public transportation is an environment with great potential for applying location-based services through mobile devices. This paper provides the underpinning rationale for research that will be looking at how the real-time passenger information system deployed by the Translink Transit Authority across all of South East Queensland in Australia can provide a core platform to improve commuters’ user experiences. This system relies on mobile computing and GPS technology to provide accurate information on transport vehicle locations. The proposal builds on this platform to inform the design and development of innovative social media, mobile computing and geospatial information applications. The core aim is to digitally augment the public transport environment to enhance the user experience of commuters for a more enjoyable journey.

Study of wheel-rail impact at insulated rail joint through experimental and numerical methods

As part of an ongoing research on the development of a longer life insulated rail joint (IRJ), this paper reports a field experiment and a simplified 2D numerical modelling for the purpose of investigating the behaviour of rail web in the vicinity of endpost in an insulated rail joint (IRJ) due to wheel passages. A simplified 2D plane stress finite element model is used to simulate the wheel-rail rolling contact impact at IRJ. This model is validated using data from a strain gauged IRJ that was installed in a heavy haul network; data in terms of the vertical and shear strains at specific positions of the IRJ during train passing were captured and compared with the results of the FE model. The comparison indicates a satisfactory agreement between the FE model and the field testing. Furthermore, it demonstrates that the experimental and numerical analyses reported in this paper provide a valuable datum for developing further insight into the behaviour of IRJ under wheel impacts.

Alternative analytical methods for the identification of cancer-related symptom clusters

Advances in symptom management strategies through a better understanding of cancer symptom clusters depend on the identification of symptom clusters that are valid and reliable. The purpose of this exploratory research was to investigate alternative analytical approaches to identify symptom clusters for patients with cancer, using readily accessible statistical methods, and to justify which methods of identification may be appropriate for this context. Three studies were undertaken: (1) a systematic review of the literature, to identify analytical methods commonly used for symptom cluster identification for cancer patients; (2) a secondary data analysis to identify symptom clusters and compare alternative methods, as a guide to best practice approaches in cross-sectional studies; and (3) a secondary data analysis to investigate the stability of symptom clusters over time. The systematic literature review identified, in 10 years prior to March 2007, 13 cross-sectional studies implementing multivariate methods to identify cancer related symptom clusters. The methods commonly used to group symptoms were exploratory factor analysis, hierarchical cluster analysis and principal components analysis. Common factor analysis methods were recommended as the best practice cross-sectional methods for cancer symptom cluster identification. A comparison of alternative common factor analysis methods was conducted, in a secondary analysis of a sample of 219 ambulatory cancer patients with mixed diagnoses, assessed within one month of commencing chemotherapy treatment. Principal axis factoring, unweighted least squares and image factor analysis identified five consistent symptom clusters, based on patient self-reported distress ratings of 42 physical symptoms. Extraction of an additional cluster was necessary when using alpha factor analysis to determine clinically relevant symptom clusters. The recommended approaches for symptom cluster identification using nonmultivariate normal data were: principal axis factoring or unweighted least squares for factor extraction, followed by oblique rotation; and use of the scree plot and Minimum Average Partial procedure to determine the number of factors. In contrast to other studies which typically interpret pattern coefficients alone, in these studies symptom clusters were determined on the basis of structure coefficients. This approach was adopted for the stability of the results as structure coefficients are correlations between factors and symptoms unaffected by the correlations between factors. Symptoms could be associated with multiple clusters as a foundation for investigating potential interventions. The stability of these five symptom clusters was investigated in separate common factor analyses, 6 and 12 months after chemotherapy commenced. Five qualitatively consistent symptom clusters were identified over time (Musculoskeletal-discomforts/lethargy, Oral-discomforts, Gastrointestinaldiscomforts, Vasomotor-symptoms, Gastrointestinal-toxicities), but at 12 months two additional clusters were determined (Lethargy and Gastrointestinal/digestive symptoms). Future studies should include physical, psychological, and cognitive symptoms. Further investigation of the identified symptom clusters is required for validation, to examine causality, and potentially to suggest interventions for symptom management. Future studies should use longitudinal analyses to investigate change in symptom clusters, the influence of patient related factors, and the impact on outcomes (e.g., daily functioning) over time.

Pathogenicity of Plesiomonas shigelloides : interactions with eukaryotic host cells in vitro

Diarrhoea is one of the leading causes of morbidity and mortality in populations in developing countries and is a significant health issue throughout the world. Despite the frequency and the severity of the diarrhoeal disease, mechanisms of pathogenesis for many of the causative agents have been poorly characterised. Although implicated in a number of intestinal and extra-intestinal infections in humans, Plesiomonas shigelloides generally has been dismissed as an enteropathogen due to the lack of clearly demonstrated virulence-associated properties such as production of cytotoxins and enterotoxins or invasive abilities. However, evidence from a number of sources has indicated that this species may be the cause of a number of clinical infections. The work described in this thesis seeks to resolve this discrepancy by investigating the pathogenic potential of P. shigelloides using in vitro cell models. The focus of this research centres on how this organism interacts with human host cells in an experimental model. Very little is known about the pathogenic potential of P. shigel/oides and its mechanisms in human infections and disease. However, disease manifestations mimic those of other related microorganisms. Chapter 2 reviews microbial pathogenesis in general, with an emphasis on understanding the mechanisms resulting from infection with bacterial pathogens and the alterations in host cell biology. In addition, this review analyses the pathogenic status of a poorly-defined enteropathogen, P. shigelloides. Key stages of pathogenicity must occur in order for a bacterial pathogen to cause disease. Such stages include bacterial adherence to host tissue, bacterial entry into host tissues (usually required), multiplication within host tissues, evasion of host defence mechanisms and the causation of damage. In this study, these key strategies in infection and disease were sought to help assess the pathogenic potential of P. shigelloides (Chapter 3). Twelve isolates of P. shigelloides, obtained from clinical cases of gastroenteritis, were used to infect monolayers of human intestinal epithelial cells in vitro. Ultrastructural analysis demonstrated that P. shigelloides was able to adhere to the microvilli at the apical surface of the epithelial cells and also to the plasma membranes of both apical and basal surfaces. Furthermore, it was demonstrated that these isolates were able to enter intestinal epithelial cells. Internalised bacteria often were confined within vacuoles surrounded by single or multiple membranes. Observation of bacteria within membranebound vacuoles suggests that uptake of P. shigelloides into intestinal epithelial cells occurs via a process morphologically comparable to phagocytosis. Bacterial cells also were observed free in the host cell cytoplasm, indicating that P. shige/loides is able to escape from the surrounding vacuolar membrane and exist within the cytosol of the host. Plesiomonas shigelloides has not only been implicated in gastrointestinal infections, but also in a range of non-intestinal infections such as cholecystitis, proctitis, septicaemia and meningitis. The mechanisms by which P. shigelloides causes these infections are not understood. Previous research was unable to ascertain the pathogenic potential of P. shigel/oides using cells of non-intestinal origin (HEp-2 cells derived from a human larynx carcinoma and Hela cells derived from a cervical carcinoma). However, with the recent findings (from this study) that P. shigelloides can adhere to and enter intestinal cells, it was hypothesised, that P. shigel/oides would be able to enter Hela and HEp-2 cells. Six clinical isolates of P. shigelloides, which previously have been shown to be invasive to intestinally derived Caco-2 cells (Chapter 3) were used to study interactions with Hela and HEp-2 cells (Chapter 4). These isolates were shown to adhere to and enter both nonintestinal host cell lines. Plesiomonas shigelloides were observed within vacuoles surrounded by single and multiple membranes, as well as free in the host cell cytosol, similar to infection by P. shigelloides of Caco-2 cells. Comparisons of the number of bacteria adhered to and present intracellularly within Hela, HEp-2 and Caco-2 cells revealed a preference of P. shigelloides for Caco-2 cells. This study conclusively showed for the first time that P. shigelloides is able to enter HEp-2 and Hela cells, demonstrating the potential ability to cause an infection and/or disease of extra-intestinal sites in humans. Further high resolution ultrastructural analysis of the mechanisms involved in P. shigelloides adherence to intestinal epithelial cells (Chapter 5) revealed numerous prominent surface features which appeared to be involved in the binding of P. shige/loides to host cells. These surface structures varied in morphology from small bumps across the bacterial cell surface to much longer filaments. Evidence that flagella might play a role in bacterial adherence also was found. The hypothesis that filamentous appendages are morphologically expressed when in contact with host cells also was tested. Observations of bacteria free in the host cell cytosol suggests that P. shigelloides is able to lyse free from the initial vacuolar compartment. The vacuoles containing P. shigel/oides within host cells have not been characterised and the point at which P. shigelloides escapes from the surrounding vacuolar compartment has not been determined. A cytochemical detection assay for acid phosphatase, an enzymatic marker for lysosomes, was used to analyse the co-localisation of bacteria-containing vacuoles and acid phosphatase activity (Chapter 6). Acid phosphatase activity was not detected in these bacteria-containing vacuoles. However, the surface of many intracellular and extracellular bacteria demonstrated high levels of acid phosphatase activity, leading to the proposal of a new virulence factor for P. shigelloides. For many pathogens, the efficiency with which they adhere to and enter host cells is dependant upon the bacterial phase of growth. Such dependency reflects the timing of expression of particular virulence factors important for bacterial pathogenesis. In previous studies (Chapter 3 to Chapter 6), an overnight culture of P. shigelloides was used to investigate a number of interactions, however, it was unknown whether this allowed expression of bacterial factors to permit efficient P. shigelloides attachment and entry into human cells. In this study (Chapter 7), a number of clinical and environmental P. shigelloides isolates were investigated to determine whether adherence and entry into host cells in vitro was more efficient during exponential-phase or stationary-phase bacterial growth. An increase in the number of adherent and intracellular bacteria was demonstrated when bacteria were inoculated into host cell cultures in exponential phase cultures. This was demonstrated clearly for 3 out of 4 isolates examined. In addition, an increase in the morphological expression of filamentous appendages, a suggested virulence factor for P. shigel/oides, was observed for bacteria in exponential growth phase. These observations suggest that virulence determinants for P. shigel/oides may be more efficiently expressed when bacteria are in exponential growth phase. This study demonstrated also, for the first time, that environmental water isolates of P. shigelloides were able to adhere to and enter human intestinal cells in vitro. These isolates were seen to enter Caco-2 host cells through a process comparable to the clinical isolates examined. These findings support the hypothesis of a water transmission route for P. shigelloides infections. The results presented in this thesis contribute significantly to our understanding of the pathogenic mechanisms involved in P. shigelloides infections and disease. Several of the factors involved in P. shigelloides pathogenesis have homologues in other pathogens of the human intestine, namely Vibrio, Aeromonas, Salmonella, Shigella species and diarrhoeaassociated strains of Escherichia coli. This study emphasises the relevance of research into Plesiomonas as a means of furthering our understanding of bacterial virulence in general. As well it provides tantalising clues on normal and pathogenic host cell mechanisms.

An explorative qualitative analysis of participants' experience of using kava versus placebo in an RCT. (Clinical report)

Many randomised controlled trials (RCT) have been conducted using Piper methysticum (kava), however no qualitative research exploring the experience of taking kava during a clinical trial has previously been reported. ---------- Patients and methods: A qualitative research component (in the form of semi structured and open ended written questions) was incorporated into an RCT to explore the experiences of those participating in a clinical trial of kava. The written questions were provided to participants at weeks 2 and 3 (after randomisation, after each controlled phase). The researcher and participants were blinded as to whether they were taking kava or placebo. Two open ended questions were posed to elucidate their experiences from taking either kava or placebo. Thematic analysis was undertaken and researcher triangulation employed to ensure analytical rigour. Key themes after the kava phases were a reduction in anxiety and stress, and calming or relaxing mental effects. Other themes related to improvement in sleep and in somatic anxiety symptoms. ---------- Results: Kava use did not cause any serious adverse reactions although a few respondents reported nausea or other gastrointestinal side effects. This represents the first documented qualitative investigation of the experience of taking kava during a clinical trial. The primary themes involved anxiolytic and calming effects, with only a minor theme reflecting side effects. Our exploratory qualitative data was consistent with the significant quantitative results revealed in the study and provides additional support to suggest the trial results did not exclude any important positive or negative effects (at least as experienced by the trial participants).

Peak power demand reduction under moving block signalling using an expert system

The concept of moving block signallings (MBS) has been adopted in a few mass transit railway systems. When a dense queue of trains begins to move from a complete stop, the trains can re-start in very close succession under MBS. The feeding substations nearby are likely to be overloaded and the service will inevitably be disturbed unless substations of higher power rating are used. By introducing starting time delays among the trains or limiting the trains’ acceleration rate to a certain extent, the peak energy demand can be contained. However, delay is introduced and quality of service is degraded. An expert system approach is presented to provide a supervisory tool for the operators. As the knowledge base is vital for the quality of decisions to be made, the study focuses on its formulation with a balance between delay and peak power demand.

Railway junction conflict resolution by local search method

This study investigates the application of local search methods on the railway junction traffic conflict-resolution problem, with the objective of attaining a quick and reasonable solution. A procedure based on local search relies on finding a better solution than the current one by a search in the neighbourhood of the current one. The structure of neighbourhood is therefore very important to an efficient local search procedure. In this paper, the formulation of the structure of the solution, which is the right-of-way sequence assignment, is first described. Two new neighbourhood definitions are then proposed and the performance of the corresponding local search procedures is evaluated by simulation. It has been shown that they provide similar results but they can be used to handle different traffic conditions and system requirements.