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Prediction of mortality in septic patients with hypotensionMayaud, Louis January 2014 (has links)
Sepsis remains the second largest killer in the Intensive Care Unit (ICU), giving rise to a significant economic burden ($17b per annum in the US, 0.3% of the gross domestic product). The aim of the work described in this thesis is to improve the estimation of severity in this population, with a view to improving the allocation of resources. A cohort of 2,143 adult patients with sepsis and hypotension was identified from the MIMIC-II database (v2.26). The implementation of state-of-the-art models confirms the superiority of the APACHE-IV model (AUC=73.3%) for mortality prediction using ICU admission data. Using the same subset of features, state-of-the art machine learning techniques (Support Vector Machines and Random Forests) give equivalent results. More recent mortality prediction models are also implemented and offer an improvement in discriminatory power (AUC=76.16%). A shift from expert-driven selection of variables to objective feature selection techniques using all available covariates leads to a major gain in performance (AUC=80.4%). A framework allowing simultaneous feature selection and parameter pruning is developed, using a genetic algorithm, and this offers similar performance. The model derived from the first 24 hours in the ICU is then compared with a “dynamic” model derived over the same time period, and this leads to a significant improvement in performance (AUC=82.7%). The study is then repeated using data surrounding the hypotensive episode in an attempt to capture the physiological response to hypotension and the effects of treatment. A significant increase in performance (AUC=85.3%) is obtained with the static model incorporating data both before and after the hypotensive episode. The equivalent dynamic model does not demonstrate a statistically significant improvement (AUC=85.6%). Testing on other ICU populations with sepsis is needed to validate the findings of this thesis, but the results presented in it highlight the role that data mining will increasingly play in clinical knowledge generation.
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Genes contributing to variation in fear-related behaviourKrohn, Jonathan Jacob Pastushchyn January 2013 (has links)
Anxiety and depression are highly prevalent diseases with common heritable elements, but the particular genetic mechanisms and biological pathways underlying them are poorly understood. Part of the challenge in understanding the genetic basis of these disorders is that they are polygenic and often context-dependent. In my thesis, I apply a series of modern statistical tools to ascertain some of the myriad genetic and environmental factors that underlie fear-related behaviours in nearly two thousand heterogeneous stock mice, which serve as animal models of anxiety and depression. Using a Bayesian method called Sparse Partitioning and a frequentist method called Bagphenotype, I identify gene-by-sex interactions that contribute to variation in fear-related behaviours, such as those displayed in the elevated plus maze and the open field test, although I demonstrate that the contributions are generally small. Also using Bagphenotype, I identify hundreds of gene-by-environment interactions related to these traits. The interacting environmental covariates are diverse, ranging from experimenter to season of the year. With gene expression data from a brain structure associated with anxiety called the hippocampus, I generate modules of co-expressed genes and map them to the genome. Two of these modules were enriched for key nervous system components — one for dendritic spines, another for oligodendrocyte markers — but I was unable to find significant correlations between them and fear-related behaviours. Finally, I employed another Bayesian technique, Sparse Instrumental Variables, which takes advantage of conditional probabilities to identify hippocampus genes whose expression appears not just to be associated with variation in fear-related behaviours, but cause variation in those phenotypes.
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A high order Discontinuous Galerkin - Fourier incompressible 3D Navier-Stokes solver with rotating sliding meshes for simulating cross-flow turbinesFerrer, Esteban January 2012 (has links)
This thesis details the development, verification and validation of an unsteady unstructured high order (≥ 3) h/p Discontinuous Galerkin - Fourier solver for the incompressible Navier-Stokes equations on static and rotating meshes in two and three dimensions. This general purpose solver is used to provide insight into cross-flow (wind or tidal) turbine physical phenomena. Simulation of this type of turbine for renewable energy generation needs to account for the rotational motion of the blades with respect to the fixed environment. This rotational motion implies azimuthal changes in blade aero/hydro-dynamics that result in complex flow phenomena such as stalled flows, vortex shedding and blade-vortex interactions. Simulation of these flow features necessitates the use of a high order code exhibiting low numerical errors. This thesis presents the development of such a high order solver, which has been conceived and implemented from scratch by the author during his doctoral work. To account for the relative mesh motion, the incompressible Navier-Stokes equations are written in arbitrary Lagrangian-Eulerian form and a non-conformal Discontinuous Galerkin (DG) formulation (i.e. Symmetric Interior Penalty Galerkin) is used for spatial discretisation. The DG method, together with a novel sliding mesh technique, allows direct linking of rotating and static meshes through the numerical fluxes. This technique shows spectral accuracy and no degradation of temporal convergence rates if rotational motion is applied to a region of the mesh. In addition, analytical mappings are introduced to account for curved external boundaries representing circular shapes and NACA foils. To simulate 3D flows, the 2D DG solver is parallelised and extended using Fourier series. This extension allows for laminar and turbulent regimes to be simulated through Direct Numerical Simulation and Large Eddy Simulation (LES) type approaches. Two LES methodologies are proposed. Various 2D and 3D cases are presented for laminar and turbulent regimes. Among others, solutions for: Stokes flows, the Taylor vortex problem, flows around square and circular cylinders, flows around static and rotating NACA foils and flows through rotating cross-flow turbines, are presented.
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Exploiting whole-PDB analysis in novel bioinformatics applicationsRamraj, Varun January 2014 (has links)
The Protein Data Bank (PDB) is the definitive electronic repository for experimentally-derived protein structures, composed mainly of those determined by X-ray crystallography. Approximately 200 new structures are added weekly to the PDB, and at the time of writing, it contains approximately 97,000 structures. This represents an expanding wealth of high-quality information but there seem to be few bioinformatics tools that consider and analyse these data as an ensemble. This thesis explores the development of three efficient, fast algorithms and software implementations to study protein structure using the entire PDB. The first project is a crystal-form matching tool that takes a unit cell and quickly (< 1 second) retrieves the most related matches from the PDB. The unit cell matches are combined with sequence alignments using a novel Family Clustering Algorithm to display the results in a user-friendly way. The software tool, Nearest-cell, has been incorporated into the X-ray data collection pipeline at the Diamond Light Source, and is also available as a public web service. The bulk of the thesis is devoted to the study and prediction of protein disorder. Initially, trying to update and extend an existing predictor, RONN, the limitations of the method were exposed and a novel predictor (called MoreRONN) was developed that incorporates a novel sequence-based clustering approach to disorder data inferred from the PDB and DisProt. MoreRONN is now clearly the best-in-class disorder predictor and will soon be offered as a public web service. The third project explores the development of a clustering algorithm for protein structural fragments that can work on the scale of the whole PDB. While protein structures have long been clustered into loose families, there has to date been no comprehensive analytical clustering of short (~6 residue) fragments. A novel fragment clustering tool was built that is now leading to a public database of fragment families and representative structural fragments that should prove extremely helpful for both basic understanding and experimentation. Together, these three projects exemplify how cutting-edge computational approaches applied to extensive protein structure libraries can provide user-friendly tools that address critical everyday issues for structural biologists.
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