Bayesian mixtures for modelling complex medical data : a case study in Parkinson’s disease

Mixture models are a flexible tool for unsupervised clustering that have found popularity in a vast array of research areas. In studies of medicine, the use of mixtures holds the potential to greatly enhance our understanding of patient responses through the identification of clinically meaningful clusters that, given the complexity of many data sources, may otherwise by intangible. Furthermore, when developed in the Bayesian framework, mixture models provide a natural means for capturing and propagating uncertainty in different aspects of a clustering solution, arguably resulting in richer analyses of the population under study. This thesis aims to investigate the use of Bayesian mixture models in analysing varied and detailed sources of patient information collected in the study of complex disease. The first aim of this thesis is to showcase the flexibility of mixture models in modelling markedly different types of data. In particular, we examine three common variants on the mixture model, namely, finite mixtures, Dirichlet Process mixtures and hidden Markov models. Beyond the development and application of these models to different sources of data, this thesis also focuses on modelling different aspects relating to uncertainty in clustering. Examples of clustering uncertainty considered are uncertainty in a patient’s true cluster membership and accounting for uncertainty in the true number of clusters present. Finally, this thesis aims to address and propose solutions to the task of comparing clustering solutions, whether this be comparing patients or observations assigned to different subgroups or comparing clustering solutions over multiple datasets. To address these aims, we consider a case study in Parkinson’s disease (PD), a complex and commonly diagnosed neurodegenerative disorder. In particular, two commonly collected sources of patient information are considered. The first source of data are on symptoms associated with PD, recorded using the Unified Parkinson’s Disease Rating Scale (UPDRS) and constitutes the first half of this thesis. The second half of this thesis is dedicated to the analysis of microelectrode recordings collected during Deep Brain Stimulation (DBS), a popular palliative treatment for advanced PD. Analysis of this second source of data centers on the problems of unsupervised detection and sorting of action potentials or "spikes" in recordings of multiple cell activity, providing valuable information on real time neural activity in the brain.

Chaos or complex systems? Identifying factors influencing the success of international and NESB graduate research students in Engineering and Information Technology Fields

The paper explores the results an on-going research project to identify factors influencing the success of international and non-English speaking background (NESB) gradúate students in the fields of Engineering and IT at three Australian universities: the Queensland University of Technology (QUT), the University of Western Australia (UWA), and Curtin University (CU). While the larger study explores the influence of factors from both sides of the supervision equation (e.g., students and supervisors), this paper focusses primarily on the results of an online survey involving 227 international and/or NESB graduate students in the areas of Engineering and IT at the three universities. The study reveals cross-cultural differences in perceptions of student and supervisor roles, as well as differences in the understanding of the requirements of graduate study within the Australian Higher Education context. We argue that in order to assist international and NESB research students to overcome such culturally embedded challenges, it is important to develop a model which recognizes the complex interactions of factors from both sides of the supervision relationship, in order to understand this cohort‟s unique pedagogical needs and develop intercultural sensitivity within postgraduate research supervision.

Cyclin-dependent kinase-mediated phosphorylation of RBP1 and pRb promotes their dissociation to mediate release of the SAP30·mSin3·HDAC transcriptional repressor complex

Eukaryotic cell cycle progression is mediated by phosphorylation of protein substrates by cyclin-dependent kinases (CDKs). A critical substrate of CDKs is the product of the retinoblastoma tumor suppressor gene, pRb, which inhibits G1-S phase cell cycle progression by binding and repressing E2F transcription factors. CDK-mediated phosphorylation of pRb alleviates this inhibitory effect to promote G1-S phase cell cycle progression. pRb represses transcription by binding to the E2F transactivation domain and recruiting the mSin3·histone deacetylase (HDAC) transcriptional repressor complex via the retinoblastoma-binding protein 1 (RBP1). RBP1 binds to the pocket region of pRb via an LXCXE motif and to the SAP30 subunit of the mSin3·HDAC complex and, thus, acts as a bridging protein in this multisubunit complex. In the present study we identified RBP1 as a novel CDK substrate. RBP1 is phosphorylated by CDK2 on serines 864 and 1007, which are N- and C-terminal to the LXCXE motif, respectively. CDK2-mediated phosphorylation of RBP1 or pRb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation. Consistent with these findings, RBP1 phosphorylation is increased during progression from G 1 into S-phase, with a concurrent decrease in its association with pRb in MCF-7 breast cancer cells. These studies provide new mechanistic insights into CDK-mediated regulation of the pRb tumor suppressor during cell cycle progression, demonstrating that CDK-mediated phosphorylation of both RBP1 and pRb induces their dissociation to mediate release of the mSin3·HDAC transcriptional repressor complex from pRb to alleviate transcriptional repression of E2F.

The reliability, accuracy and minimal detectable difference of a multi-segment kinematic model of the foot-shoe complex

Kinematic models are commonly used to quantify foot and ankle kinematics, yet no marker sets or models have been proven reliable or accurate when wearing shoes. Further, the minimal detectable difference of a developed model is often not reported. We present a kinematic model that is reliable, accurate and sensitive to describe the kinematics of the foot–shoe complex and lower leg during walking gait. In order to achieve this, a new marker set was established, consisting of 25 markers applied on the shoe and skin surface, which informed a four segment kinematic model of the foot–shoe complex and lower leg. Three independent experiments were conducted to determine the reliability, accuracy and minimal detectable difference of the marker set and model. Inter-rater reliability of marker placement on the shoe was proven to be good to excellent (ICC = 0.75–0.98) indicating that markers could be applied reliably between raters. Intra-rater reliability was better for the experienced rater (ICC = 0.68–0.99) than the inexperienced rater (ICC = 0.38–0.97). The accuracy of marker placement along each axis was <6.7 mm for all markers studied. Minimal detectable difference (MDD90) thresholds were defined for each joint; tibiocalcaneal joint – MDD90 = 2.17–9.36°, tarsometatarsal joint – MDD90 = 1.03–9.29° and the metatarsophalangeal joint – MDD90 = 1.75–9.12°. These thresholds proposed are specific for the description of shod motion, and can be used in future research designed at comparing between different footwear.

Complex events in business processes

Flow-oriented process modeling languages have a long tradition in the area of Business Process Management and are widely used for capturing activities with their behavioral and data dependencies. Individual events were introduced for triggering process instantiation and activities. However, real-world business cases drive the need for also covering complex event patterns as they are known in the field of Complex Event Processing. Therefore, this paper puts forward a catalog of requirements for handling complex events in process models, which can be used as reference framework for assessing process definition languages and systems. An assessment of BPEL and BPMN is provided.

Infrastructure transitions toward sustainability : a complex adaptive systems perspective

To ensure infrastructure assets are procured and maintained by government on behalf of citizens, appropriate policy and institutional architecture is needed, particularly if a fundamental shift to more sustainable infrastructure is the goal. The shift in recent years from competitive and resource-intensive procurement to more collaborative and sustainable approaches to infrastructure governance is considered a major transition in infrastructure procurement systems. In order to better understand this transition in infrastructure procurement arrangements, the concept of emergence from Complex Adaptive Systems (CAS) theory is offered as a key construct. Emergence holds that micro interactions can result in emergent macro order. Applying the concept of emergence to infrastructure procurement, this research examines how interaction of agents in individual projects can result in different industry structural characteristics. The paper concludes that CAS theory, and particularly the concept of ‘emergence’, provides a useful construct to understand infrastructure procurement dynamics and progress towards sustainability.

A review of models and model usage scenarios for an airport complex system

Airports represent the epitome of complex systems with multiple stakeholders, multiple jurisdictions and complex interactions between many actors. The large number of existing models that capture different aspects of the airport are a testament to this. However, these existing models do not consider in a systematic sense modelling requirements nor how stakeholders such as airport operators or airlines would make use of these models. This can detrimentally impact on the verification and validation of models and makes the development of extensible and reusable modelling tools difficult. This paper develops from the Concept of Operations (CONOPS) framework a methodology to help structure the review and development of modelling capabilities and usage scenarios. The method is applied to the review of existing airport terminal passenger models. It is found that existing models can be broadly categorised according to four usage scenarios: capacity planning, operational planning and design, security policy and planning, and airport performance review. The models, the performance metrics that they evaluate and their usage scenarios are discussed. It is found that capacity and operational planning models predominantly focus on performance metrics such as waiting time, service time and congestion whereas performance review models attempt to link those to passenger satisfaction outcomes. Security policy models on the other hand focus on probabilistic risk assessment. However, there is an emerging focus on the need to be able to capture trade-offs between multiple criteria such as security and processing time. Based on the CONOPS framework and literature findings, guidance is provided for the development of future airport terminal models.

Limestone and speleothem trace element geochemistry as tools for palaeoclimatic reconstruction, Mount Etna region, central-coastal Queensland

This study investigated potential palaeoclimate proxies provided by rare earth element (REE) geochemistry in speleothems and in clay mineralogy of cave sediments. Speleothem and sediment samples were collected from a series of cave fill deposits that occurred with rich vertebrate fossil assemblages in and around Mount Etna National Park, Rockhampton (central coastal Queensland). The fossil deposits range from Plio- Pleistocene to Holocene in age (based on uranium/thorium dating) and appear to represent depositional environments ranging from enclosed rainforest to semi-arid grasslands. Therefore, the Mount Etna cave deposits offer the perfect opportunity to test new palaeoclimate tools as they include deposits that span a known significant climate shift on the basis of independent faunal data. The first section of this study investigates the REE distribution of the host limestone to provide baseline geochemistry for subsequent speleothem investigations. The Devonian Mount Etna Beds were found to be more complex than previous literature had documented. The studied limestone massif is overturned, highly recrystallised in parts and consists of numerous allochthonous blocks with different spatial orientations. Despite the complex geologic history of the Mount Etna Beds, Devonian seawater-like REE patterns were recovered in some parts of the limestone and baseline geochemistry was determined for the bulk limestone for comparison with speleothem REE patterns. The second part of the study focused on REE distribution in the karst system and the palaeoclimatic implications of such records. It was found that REEs have a high affinity for calcite surfaces and that REE distributions in speleothems vary between growth bands much more than along growth bands, thus providing a temporal record that may relate to environmental changes. The morphology of different speleothems (i.e., stalactites, stalagmites, and flowstones) has little bearing on REE distributions provided they are not contaminated with particulate fines. Thus, baseline knowledge developed in the study suggested that speleothems were basically comparable for assessing palaeoclimatically controlled variations in REE distributions. Speleothems from rainforest and semi-arid phases were compared and it was found that there are definable differences in REE distribution that can be attributed to climate. In particular during semiarid phases, total REE concentration decreased, LREE became more depleted, Y/Ho increased, La anomalies were more positive and Ce anomalies were more negative. This may reflect more soil development during rainforest phases and more organic particles and colloids, which are known to transport REEs, in karst waters. However, on a finer temporal scale (i.e. growth bands) within speleothems from the same climate regime, no difference was seen. It is suggested that this may be due to inadequate time for soil development changes on the time frames represented by differences in growth band density. The third part of the study was a reconnaissance investigation focused on mineralogy of clay cave sediments, illite/kaolinite ratios in particular, and the potential palaeoclimatic implications of such records. Although the sample distribution was not optimal, the preliminary results suggest that the illite/kaolinite ratio increased during cold and dry intervals, consistent with decreased chemical weathering during those times. The study provides a basic framework for future studies at differing latitudes to further constrain the parameters of the proxy. The identification of such a proxy recorded in cave sediment has broad implications as clay ratios could potentially provide a basic local climate proxy in the absence of fossil faunas and speleothem material. This study suggests that REEs distributed in speleothems may provide information about water throughput and soil formation, thus providing a potential palaeoclimate proxy. It highlights the importance of understanding the host limestone geochemistry and broadens the distribution and potential number of cave field sites as palaeoclimate information no longer relies solely on the presence of fossil faunas and or speleothems. However, additional research is required to better understand the temporal scales required for the proxies to be recognised.

Homo- and heteronuclear meso,meso-(E)-Ethene-1,2-diyl-Linked Diporphyrins : preparation, X-ray crystal structure, electronic absorption and emission spectra and density functional theory calculations

Homo-and heteronuclear meso,meso-(E)-ethene-1,2-diyl-linked diporphyrins have been prepared by the Suzuki coupling of porphyrinylboronates and iodovinylporphyrins. Combinations comprising 5,10,15-triphenylporphyrin (TriPP) on both ends of the ethene-1,2-diyl bridge M 210 (M 2=H 2/Ni, Ni 2, Ni/Zn, H 4, H 2Zn, Zn 2) and 5,15-bis(3,5-di-tert-butylphenyl)porphyrinato-nickel(II) on one end and H 2, Ni, and ZnTriPP on the other (M 211), enable the first studies of this class of compounds possessing intrinsic polarity. The compounds were characterized by electronic absorption and steady state emission spectra, 1H NMR spectra, and for the Ni 2 bis(TriPP) complex Ni 210, single crystal X-ray structure determination. The crystal structure shows ruffled distortions of the porphyrin rings, typical of Ni II porphyrins, and the (E)-C 2H 2 bridge makes a dihedral angle of 50° with the mean planes of the macrocycles. The result is a stepped parallel arrangement of the porphyrin rings. The dihedral angles in the solid state reflect the interplay of steric and electronic effects of the bridge on interporphyrin communication. The emission spectra in particular, suggest energy transfer across the bridge is fast in conformations in which the bridge is nearly coplanar with the rings. Comparisons of the fluorescence behaviour of H 410 and H 2Ni10 show strong quenching of the free base fluorescence when the complex is excited at the lower energy component of the Soret band, a feature associated in the literature with more planar conformations. TDDFT calculations on the gas-phase optimized geometry of Ni 210 reproduce the features of the experimental electronic absorption spectrum within 0.1 eV. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Creativity in policing: building the necessary skills to solve complex and protracted investigations

Despite an increased focus on proactive policing in recent years, criminal investigation is still perhaps the most important task of any law enforcement agency. As a result, the skills required to carry out a successful investigation or to be an ‘effective detective’ have been subjected to much attention and debate (Smith and Flanagan, 2000; Dean, 2000; Fahsing and Gottschalk, 2008:652). Stelfox (2008:303) states that “The service’s capacity to carry out investigations comprises almost entirely the expertise of investigators.” In this respect, Dean (2000) highlighted the need to profile criminal investigators in order to promote further understanding of the cognitive approaches they take to the process of criminal investigation. As a result of his research, Dean (2000) produced a theoretical framework of criminal investigation, which included four disparate cognitive or ‘thinking styles’. These styles were the ‘Method’, ‘Challenge’, ‘Skill’ and ‘Risk’. While the Method and Challenge styles deal with adherence to Standard Operating Procedures (SOPs) and the internal ‘drive’ that keeps an investigator going, the Skill and Risk styles both tap on the concept of creativity in policing. It is these two latter styles that provide the focus for this paper. This paper presents a brief discussion on Dean’s (2000) Skill and Risk styles before giving an overview of the broader literature on creativity in policing. The potential benefits of a creative approach as well as some hurdles which need to be overcome when proposing the integration of creativity within the policing sector are then discussed. Finally, the paper concludes by proposing further research into Dean’s (2000) skill and risk styles and also by stressing the need for significant changes to the structure and approach of the traditional policing organisation before creativity in policing is given the status it deserves.

Syntaxin 6 and Vti1b form a novel SNARE complex, which is upregulated in activated macrophages to facilitate exocytosis of TNF.

A key function of activated macrophages is to secrete proinflammatory cytokines such as TNF; however, the intracellular pathway and machinery responsible for cytokine trafficking and secretion is largely undefined. Here we show that individual SNARE proteins involved in vesicle docking and fusion are regulated at both gene and protein expression upon stimulation with the bacterial cell wall component lipopolysaccharide. Focusing on two intracellular SNARE proteins, Vti1b and syntaxin 6 (Stx6), we show that they are up-regulated in conjunction with increasing cytokine secretion in activated macrophages and that their levels are selectively titrated to accommodate the volume and timing of post-Golgi cytokine trafficking. In macrophages, Vti1b and syntaxin 6 are localized on intracellular membranes and are present on isolated Golgi membranes and on Golgi-derived TNF� vesicles budded in vitro. By immunoprecipitation, we find that Vti1b and syntaxin 6 interact to form a novel intracellular Q-SNARE complex. Functional studies using overexpression of full-length and truncated proteins show that both Vti1b and syntaxin 6 function and have rate-limiting roles in TNF� trafficking and secretion. This study shows how macrophages have uniquely adapted a novel Golgi-associated SNARE complex to accommodate their requirement for increased cytokine secretion.

A new geological model of Cenozoic New Zealand suggests a complex phylogeographic history for New Zealand terrestrial taxa

The new model of North Island Cenozoic palaeogeography developed by Kamp et al. has a range of important implications for the evolution of New Zealand terrestrial taxa over the past 30 Ma. Key aspects include the prolonged isolation of the biota on the North Island landmass from the larger and more diverse greater South Island, and the founding of North Island taxa from the potentially unusual ecosystem of a small island around Northland. The prolonged period of isolation is expected to have generated deep phylogenetic splits within taxa present on both islands, and an important current aim should be to identify such signals in surviving endemics to start building a picture of the historical phylogeography, and inferred ecology of both islands through the Cenozoic. Given the potential differences in founding terrestrial species and climatic conditions, it seems likely that the ecology may have been very diferent between the North and South Islands. New genetic data from the 10 or so species of extinct moa suggest that the radiation of moa was much more recent than previously suggested, and reveals a complex pattern that is inferred to result from the interplay of the Cenozoic biogeography, marine barriers, and glacial cycles.

Concept combination and the origins of complex cognition

At the core of our uniquely human cognitive abilities is the capacity to see things from different perspectives, or to place them in a new context. We propose that this was made possible by two cognitive transitions. First, the large brain of Homo erectus facilitated the onset of recursive recall: the ability to string thoughts together into a stream of potentially abstract or imaginative thought. This hypothesis is sup-ported by a set of computational models where an artificial society of agents evolved to generate more diverse and valuable cultural outputs under conditions of recursive recall. We propose that the capacity to see things in context arose much later, following the appearance of anatomically modern humans. This second transition was brought on by the onset of contextual focus: the capacity to shift between a minimally contextual analytic mode of thought, and a highly contextual associative mode of thought, conducive to combining concepts in new ways and ‘breaking out of a rut’. When contextual focus is implemented in an art-generating computer program, the resulting artworks are seen as more creative and appealing. We summarize how both transitions can be modeled using a theory of concepts which high-lights the manner in which different contexts can lead to modern humans attributing very different meanings to the interpretation of one concept.

Developing tools to support complex infrastructure decision-making

Purpose – The rapidly changing role of capital city airports has placed demands on surrounding infrastructure. The need for infrastructure management and coordination is increasing as airports and cities grow and share common infrastructure frameworks. The purpose of this paper is to document the changing context in Australia, where the privatisation of airports has stimulated considerable land development with resulting pressures on surrounding infrastructure provision. It aims to describe a tool that is being developed to support decision-making between various stakeholders in the airport region. The use of planning support systems improves both communication and data transfer between stakeholders and provides a foundation for complex decisions on infrastructure. Design/methodology/approach – The research uses a case study approach and focuses on Brisbane International Airport and Brisbane City Council. The research is primarily descriptive and provides an empirical assessment of the challenges of developing and implementing planning support systems as a tool for governance and decision-making. Findings – The research assesses the challenges in implementing a common data platform for stakeholders. Agency data platforms and models, traditional roles in infrastructure planning, and integrating similar data platforms all provide barriers to sharing a common language. The use of a decision support system has to be shared by all stakeholders with a common platform that can be versatile enough to support scenarios and changing conditions. The use of iPadss for scenario modelling provides stakeholders the opportunity to interact, compare scenarios and views, and react with the modellers to explore other options. Originality/value – The research confirms that planning support systems have to be accessible and interactive by their users. The Airport City concept is a new and evolving focus for airport development and will place continuing pressure on infrastructure servicing. A coordinated and efficient approach to infrastructure decision-making is critical, and an interactive planning support system that can model infrastructure scenarios provides a sound tool for governance.

Development of a 3D culture system to study the skeletal metastasis of prostate cancer

In the cancer research field, most in vitro studies still rely on two-dimensional (2D) cultures. However, the trend is rapidly shifting towards using a three-dimensional (3D) culture system. This is because 3D models better recapitulate the microenvironment of cells, and therefore, yield cellular and molecular responses that more accurately describe the pathophysiology of cancer. By adopting technology platforms established by the tissue engineering discipline, it is now possible to grow cancer cells in extracellular matrix (ECM)-like environments and dictate the biophysical and biochemical properties of the matrix. In addition, 3D models can be modified to recapitulate different stages of cancer progression for instance from the initial development of tumor to metastasis. Inevitably, to recapitulate a heterotypic condition, comprising more than one cell type, it requires a more complex 3D model. To date, 3D models that are available for studying the prostate cancer (CaP)-bone interactions are still lacking. Therefore, the aim of this study is to establish a co-culture model that allows investigation of direct and indirect CaP-bone interactions. Prior to that, 3D polyethylene glycol (PEG)-based hydrogel cultures for CaP cells were first developed and growth conditions were optimised. Characterization of the 3D hydrogel cultures show that LNCaP cells form a multicellular mass that resembles avascular tumor. In comparison to 2D cultures, besides the difference in cell morphology, the response of LNCaP cells to the androgen analogue (R1881) stimulation is different compared to the cells in 2D cultures. This discrepancy between 2D and 3D cultures is likely associated with the cell-cell contact, density and ligand-receptor interactions. Following the 3D monoculture study, a 3D direct co-culture model of CaP cells and the human tissue engineered bone (hTEBC) construct was developed. Interactions between the CaP cells and human osteoblasts (hOBs) resulted in elevation of Matrix Metalloproteinase 9 (MMP9) for PC-3 cells and Prostate Specific Antigen (PSA) for LNCaP cells. To further investigate the paracrine interaction of CaP cells and (hOBs), a 3D indirect co-culture model was developed, where LNCaP cells embedded within PEG hydrogels were co-cultured with hTEBC. It was found that the cellular changes observed reflect the early event of CaP colonizing the bone site. In the absence of androgens, interestingly, up-regulation of PSA and other kallikreins is also detected in the co-culture compared to the LNCaP monoculture. This non androgenic stimulation could be triggered by the soluble factors secreted by the hOB such as Interleukin-6. There are also decrease in alkaline phosphatase (ALP) activity and down-regulation of genes of the hOB when co-cultured with LNCaP cells that have not been previously described. These genes include transforming growth factor β1 (TGFβ1), osteocalcin and Vimentin. However, no changes to epithelial markers (e.g E-cadherin, Cytokeratin 8) were observed in both cell types from the co-culture. Some of these intriguing changes observed in the co-cultures that had not been previously described have enriched the basic knowledge of the CaP cell-bone interaction. From this study, we have shown evidence of the feasibility and versatility of our established 3D models. These models can be adapted to test various hypotheses for studies pertaining to underlying mechanisms of bone metastasis and could provide a vehicle for anticancer drug screening purposes in the future.