A feature of prion disease and other protein misfolding neurodegenerative disease is the formation of amyloid plaques. Amyloid is commonly found in the brain of individuals who have died from prion disease and Alzheimer’s disease. The formation and purpose of amyloid in such diseases is poorly understood and it is not currently known whether the material is neurotoxic, neuroprotective or an artefact. Several methods are used to investigate the formation of amyloid both in vitro and in vivo. A cell free protein conversion assay has been optimised to gain insight into the protein misfolding pathway and prion infection has been introduced to a newly characterised whole brain organotypic slice culture model. Fibrillar, but not oligomeric, recombinant PrP species induce a seeding effect on amyloid formation in the protein conversion assay. Brain homogenate containing amyloid from a β-amyloid aggregation mouse model is demonstrated to have a similar effect to recombinant fibril seeds with a PrP substrate indicating a cross-seeding effect. A whole brain organotypic slice culture (BOSC) model has been developed and slices maintained in culture for up to 8 months. During this time slices remain viable with low levels of stress and thin down from 400μm to 30-50μm with morphological consequences. A prominent glial scar forms on the surface of the slice as a result of astrocyte activation and proliferation. The neuronal population decreases while the microglia have a consistent presence throughout time in culture. Replication of misfolded prion protein has been successfully demonstrated within whole BOSC following prion infection after 2 months in culture. The BOSC model represents an accessible short term in vitro model of the brain which can offer insights into protein misfolding in a complex multicellular context. Amyloid formation has been investigated in vivo using a β-amyloid misfolding mouse model following seeding with a range of recombinant protein and brain homogenate seeds. No seeding effect was observed in animals which had received intracerebral inoculations compared to control animals within the time frame of the experiment. A lack of overall amyloid within all animals at the final time point investigated suggests later time points are required for observation of seeding. The functional role of amyloid in protein misfolding neurodegenerative diseases remains unclear. From the cell free protein conversion assay oligomers do not form on the direct pathway towards amyloid in prion misfolding. BOSC provide an accessible and useful short term in vitro model which retains multiple characteristics of the brain. BOSC support replication of misfolded protein and amyloid formation therefore this model can now be utilised to investigate plaque growth and the effect of amyloid formation on surrounding cells. Results from these assays provide important information to guide future in vivo studies and aid the search for therapeutic intervention in these devastating diseases.

A long term record of the earth's vegetation is important in studies of global climate change. Over the last three decades, multiple data sets on vegetation have been collected using different satellite-based sensors. There is a need for methods that combine these data into a long term earth system data record. The Advanced Very High Resolution Radiometer (AVHRR) has provided reflectance measures of the entire earth since 1978. Physical and statistical models have been used to improve the consistency and reliability of this record. The Moderated Resolution Imaging Spectroradiometer (MODIS) has provided measurements with superior radiometric properties and geolocation accuracy. However, this record is available only since 2000. In this thesis, we perform statistical calibration of AVHRR to MODIS. We aim to: (1) fill in gaps in the ongoing MODIS record; (2) extend MODIS values back to 1982. We propose Bayesian mixed models to predict MODIS values using snow cover and AVHRR values as covariates. Random effects are used to account for spatiotemporal correlation in the data. We estimate the parameters based on the data after 2000, using Markov chain Monte Carlo methods. We then back-predict MODIS data between 1978 and 1999, using the posterior samples of the parameter estimates. We develop new Conditional Autoregressive (CAR) models for seasonal data. We also develop new sampling methods for CAR models. Our approach enables filling in gaps in the MODIS record and back-predicting these values to construct a consistent historical record. The Bayesian framework incorporates multiple sources of variation in estimating the accuracy of the obtained data. The approach is illustrated using vegetation data over a region in Minnesota.

In this thesis, we discuss some topics in random matrix theory which have applications to probability, statistics and quantum information theory. In Chapter 2, by relying on the spectral properties of an associated adjacency matrix, we find the distribution of the maximum of a Dyck path and show that it has the same distribution function as the unsigned Brownian excursion which was first derived in 1976 by Kennedy. We obtain a large and moderate deviation principle for the law of the maximum of a random Dyck path. Our result extends the results of Chung, Kennedy and Khorunzhiy and Marckert. In Chapter 3, we discuss a method of sampling called the Gibbs-slice sampler. This method is based on Neal's slice sampling combined with Gibbs sampling. In Chapter 4, we discuss several examples which have applications in physics and quantum information theory.

Surface reconstruction of anatomical structures is an integral part of medical modeling. Contour information is extracted from serial cross-sections of tissue data and is stored as "slice" files. Although there are several reasonably efficient triangulation algorithms that reconstruct surfaces from slice data, the models generated from them have a jagged or faceted appearance due to the large inter-slice distance created by the sectioning process. Moreover, inconsistencies in user input aggravate the problem. So, we created a method that reduces inter-slice distance, as well as ignores the inconsistencies in the user input. Our method called the piecewise weighted implicit functions, is based on the approach of weighting smaller implicit functions. It takes only a few slices at a time to construct the implicit function. This method is based on a technique called variational interpolation. <p> Other approaches based on variational interpolation have the disadvantage of becoming unstable when the model is quite large with more than a few thousand constraint points. Furthermore, tracing the intermediate contours becomes expensive for large models. Even though some fast fitting methods handle such instability problems, there is no apparent improvement in contour tracing time, because, the value of each data point on the contour boundary is evaluated using a single large implicit function that essentially uses all constraint points. Our method handles both these problems using a sliding window approach. As our method uses only a local domain to construct each implicit function, it achieves a considerable run-time saving over the other methods. The resulting software produces interpolated models from large data sets in a few minutes on an ordinary desktop computer.

Markov chain Monte Carlo (MCMC) allows statisticians to sample from a wide variety of multidimensional probability distributions. Unfortunately, MCMC is often difficult to use when components of the target distribution are highly correlated or have disparate variances. This thesis presents three results that attempt to address this problem. First, it demonstrates a means for graphical comparison of MCMC methods, which allows researchers to compare the behavior of a variety of samplers on a variety of distributions. Second, it presents a collection of new slice-sampling MCMC methods. These methods either adapt globally or use the adaptive crumb framework for sampling with multivariate steps. They perform well with minimal tuning on distributions when popular methods do not. Methods in the first group learn an approximation to the covariance of the target distribution and use its eigendecomposition to take non-axis-aligned steps. Methods in the second group use the gradients at rejected proposed moves to approximate the local shape of the target distribution so that subsequent proposals move more efficiently through the state space. Finally, this thesis explores the scaling of slice sampling with multivariate steps with respect to dimension, resulting in a formula for optimally choosing scale tuning parameters. It shows that the scaling of untransformed methods can sometimes be improved by alternating steps from those methods with radial steps based on those of the polar slice sampler.

Markov chain Monte Carlo (MCMC) allows statisticians to sample from a wide variety of multidimensional probability distributions. Unfortunately, MCMC is often difficult to use when components of the target distribution are highly correlated or have disparate variances. This thesis presents three results that attempt to address this problem. First, it demonstrates a means for graphical comparison of MCMC methods, which allows researchers to compare the behavior of a variety of samplers on a variety of distributions. Second, it presents a collection of new slice-sampling MCMC methods. These methods either adapt globally or use the adaptive crumb framework for sampling with multivariate steps. They perform well with minimal tuning on distributions when popular methods do not. Methods in the first group learn an approximation to the covariance of the target distribution and use its eigendecomposition to take non-axis-aligned steps. Methods in the second group use the gradients at rejected proposed moves to approximate the local shape of the target distribution so that subsequent proposals move more efficiently through the state space. Finally, this thesis explores the scaling of slice sampling with multivariate steps with respect to dimension, resulting in a formula for optimally choosing scale tuning parameters. It shows that the scaling of untransformed methods can sometimes be improved by alternating steps from those methods with radial steps based on those of the polar slice sampler.

In this thesis, we discuss some topics in random matrix theory which have applications to probability, statistics and quantum information theory. In Chapter 2, by relying on the spectral properties of an associated adjacency matrix, we find the distribution of the maximum of a Dyck path and show that it has the same distribution function as the unsigned Brownian excursion which was first derived in 1976 by Kennedy. We obtain a large and moderate deviation principle for the law of the maximum of a random Dyck path. Our result extends the results of Chung, Kennedy and Khorunzhiy and Marckert. In Chapter 3, we discuss a method of sampling called the Gibbs-slice sampler. This method is based on Neal's slice sampling combined with Gibbs sampling. In Chapter 4, we discuss several examples which have applications in physics and quantum information theory.

Surface reconstruction of anatomical structures is an integral part of medical modeling. Contour information is extracted from serial cross-sections of tissue data and is stored as "slice" files. Although there are several reasonably efficient triangulation algorithms that reconstruct surfaces from slice data, the models generated from them have a jagged or faceted appearance due to the large inter-slice distance created by the sectioning process. Moreover, inconsistencies in user input aggravate the problem. So, we created a method that reduces inter-slice distance, as well as ignores the inconsistencies in the user input. Our method called the piecewise weighted implicit functions, is based on the approach of weighting smaller implicit functions. It takes only a few slices at a time to construct the implicit function. This method is based on a technique called variational interpolation. <p> Other approaches based on variational interpolation have the disadvantage of becoming unstable when the model is quite large with more than a few thousand constraint points. Furthermore, tracing the intermediate contours becomes expensive for large models. Even though some fast fitting methods handle such instability problems, there is no apparent improvement in contour tracing time, because, the value of each data point on the contour boundary is evaluated using a single large implicit function that essentially uses all constraint points. Our method handles both these problems using a sliding window approach. As our method uses only a local domain to construct each implicit function, it achieves a considerable run-time saving over the other methods. The resulting software produces interpolated models from large data sets in a few minutes on an ordinary desktop computer.

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