Disentangling the impact of seroconversion age and set-point viral load on ART-free HIV survival

Thesis (Master's)--University of Washington, 2016-06

Modeling Depression Progression Dynamics from Electronic Health Record

Thesis (Master's)--University of Washington, 2016-06

Modeling Seasonal and Weather Impacts on Cycling Count

Thesis (Master's)--University of Washington, 2016-06

Impact of ethnicity upon body composition assessment in Sri Lankan Australian children

Objectives: Obesity is a disease with excess body fat where health is adversely affected. Therefore it is prudent to make the diagnosis of obesity based on the measure of percentage body fat. Body composition of a group of Australian children of Sri Lankan origin were studied to evaluate the applicability of some bedside techniques in the measurement of percentage body fat. Methods: Height (H) and weight (W) was measured and BMI (W/H-2) calculated. Bioelectrical impedance analysis (BIA) was measured using tetra polar technique with an 800 mu A current of 50 Hz frequency. Total body water was used as a reference method and was determined by deuterium dilution and fat free mass and hence fat mass (FM) derived using age and gender specific constants. Percentage FM was estimated using four predictive equations, which used BIA and anthropometric measurements. Results: Twenty-seven boys and 15 girls were studied with mean ages being 9.1 years and 9.6 years, respectively. Girls had a significantly higher FM compared to boys. The mean percentage FM of boys (22.9 +/- 8.7%) was higher than the limit for obesity and for girls (29.0 +/- 6.0%) it was just below the cut-off. BMI was comparatively low. All but BIA equation in boys under estimated the percentage FM. The impedance index and weight showed a strong association with total body water (r(2)= 0.96, P < 0.001). Except for BIA in boys all other techniques under diagnosed obesity. Conclusions: Sri Lankan Australian children appear to have a high percentage of fat with a low BMI and some of the available indirect techniques are not helpful in the assessment of body composition. Therefore ethnic and/or population specific predictive equations have to be developed for the assessment of body composition, especially in a multicultural society using indirect methods such as BIA or anthropometry.

Predicting functional capacity outcome 12 months after hospitalized injury

Background: There is a recognized need to move from mortality to morbidity outcome predictions following traumatic injury. However, there are few morbidity outcome prediction scoring methods and these fail to incorporate important comorbidities or cofactors. This study aims to develop and evaluate a method that includes such variables. Methods: This was a consecutive case series registered in the Queensland Trauma Registry that consented to a prospective 12-month telephone conducted follow-up study. A multivariable statistical model was developed relating Trauma Registry data to trichotomized 12-month post-injury outcome (categories: no limitations, minor limitations and major limitations). Cross-validation techniques using successive single hold-out samples were then conducted to evaluate the model's predictive capabilities. Results: In total, 619 participated, with 337 (54%) experiencing no limitations, 101 (16%) experiencing minor limitations and 181 (29%) experiencing major limitations 12 months after injury. The final parsimonious multivariable statistical model included whether the injury was in the lower extremity body region, injury severity, age, length of hospital stay, pulse at admission and whether the participant was admitted to an intensive care unit. This model explained 21% of the variability in post-injury outcome. Predictively, 64% of those with no limitations, 18% of those with minor limitations and 37% of those with major limitations were correctly identified. Conclusion: Although carefully developed, this statistical model lacks the predictive power necessary for its use as a basis of a useful prognostic tool. Further research is required to identify variables other than those routinely used in the Trauma Registry to develop a model with the necessary predictive utility.

Comparison of the reintroduced MEIA (R) assay with HPLC-MS/MS for the determination of whole-blood sirolimus from transplant recipients

Therapeutic monitoring with dosage individualization of sirolimus drug therapy is standard clinical practice for organ transplant recipients. For several years sirolimus monitoring has been restricted as a result of lack of an immunoassay. The recent reintroduction of the microparticle enzyme immunoassay (MEIA (R)) for sirolimus on the IMx (R) analyser has the potential to address this situation. This Study, using patient samples, has compared the MEIA (R) sirolimus method with an established HPLC-tandem mass spectrometry method (HPLC-MS/MS). An established HPLC-UV assay was used for independent cross-validation. For quality control materials (5, 11, 22 mu g/L), the MEIA (R) showed acceptable validation criteria based on intra-and inter-run precision (CV) and accuracy (bias) of < 8% and < 13%, respectively. The lower limit of quantitation was found to be approximately 3 mu g/L. The performance of the immunoassay was compared with HPLC-MS/MS using EDTA whole-blood samples obtained from various types of organ transplant recipients (n = 116). The resultant Deming regression line was: MEIA = 1.3 x HPLC-MS/MS+ 1.3 (r = 0.967, s(y/x) = 1) with a mean bias of 49.2% +/- 23.1 % (range, -2.4% to 128%; P < 0.001). The reason for the large and variable bias was not explored in this study, but the sirolimus-metabolite cross-reactivity with the MEIA (R) antibody could be a substantive contributing factor. Whereas the MEIA (R) sirolimus method may be an adjunct to sirolimus dosage individualization in transplant recipients, users must consider the implications of the substantial and variable bias when interpreting results. In selected patients where difficult clinical issues arise, reference to a specific chromatographic method may be required.

Gene expression in human alcoholism: Microarray analysis of frontal cortex

Background: Changes in brain gene expression are thought to be responsible for the tolerance, dependence, and neurotoxicity produced by chronic alcohol abuse, but there has been no large scale study of gene expression in human alcoholism. Methods: RNA was extracted from postmortem samples of superior frontal cortex of alcoholics and nonalcoholics. Relative levels of RNA were determined by array techniques. We used both cDNA and oligonucleotide microarrays to provide coverage of a large number of genes and to allow cross-validation for those genes represented on both types of arrays. Results: Expression levels were determined for over 4000 genes and 163 of these were found to differ by 40% or more between alcoholics and nonalcoholics. Analysis of these changes revealed a selective reprogramming of gene expression in this brain region, particularly for myelin-related genes which were downregulated in the alcoholic samples. In addition, cell cycle genes and several neuronal genes were changed in expression. Conclusions: These gene expression changes suggest a mechanism for the loss of cerebral white matter in alcoholics as well as alterations that may lead to the neurotoxic actions of ethanol.

A comparison of different choices for the regularization parameter in inverse electrocardiography models

Calculating the potentials on the heart’s epicardial surface from the body surface potentials constitutes one form of inverse problems in electrocardiography (ECG). Since these problems are ill-posed, one approach is to use zero-order Tikhonov regularization, where the squared norms of both the residual and the solution are minimized, with a relative weight determined by the regularization parameter. In this paper, we used three different methods to choose the regularization parameter in the inverse solutions of ECG. The three methods include the L-curve, the generalized cross validation (GCV) and the discrepancy principle (DP). Among them, the GCV method has received less attention in solutions to ECG inverse problems than the other methods. Since the DP approach needs knowledge of norm of noises, we used a model function to estimate the noise. The performance of various methods was compared using a concentric sphere model and a real geometry heart-torso model with a distribution of current dipoles placed inside the heart model as the source. Gaussian measurement noises were added to the body surface potentials. The results show that the three methods all produce good inverse solutions with little noise; but, as the noise increases, the DP approach produces better results than the L-curve and GCV methods, particularly in the real geometry model. Both the GCV and L-curve methods perform well in low to medium noise situations.

Splines and vector splines

The thrust of this report concerns spline theory and some of the background to spline theory and follows the development in (Wahba, 1991). We also review methods for determining hyper-parameters, such as the smoothing parameter, by Generalised Cross Validation. Splines have an advantage over Gaussian Process based procedures in that we can readily impose atmospherically sensible smoothness constraints and maintain computational efficiency. Vector splines enable us to penalise gradients of vorticity and divergence in wind fields. Two similar techniques are summarised and improvements based on robust error functions and restricted numbers of basis functions given. A final, brief discussion of the application of vector splines to the problem of scatterometer data assimilation highlights the problems of ambiguous solutions.

A generative probabilistic oriented wavelet model for texture segmentation

This Letter addresses image segmentation via a generative model approach. A Bayesian network (BNT) in the space of dyadic wavelet transform coefficients is introduced to model texture images. The model is similar to a Hidden Markov model (HMM), but with non-stationary transitive conditional probability distributions. It is composed of discrete hidden variables and observable Gaussian outputs for wavelet coefficients. In particular, the Gabor wavelet transform is considered. The introduced model is compared with the simplest joint Gaussian probabilistic model for Gabor wavelet coefficients for several textures from the Brodatz album [1]. The comparison is based on cross-validation and includes probabilistic model ensembles instead of single models. In addition, the robustness of the models to cope with additive Gaussian noise is investigated. We further study the feasibility of the introduced generative model for image segmentation in the novelty detection framework [2]. Two examples are considered: (i) sea surface pollution detection from intensity images and (ii) image segmentation of the still images with varying illumination across the scene.

A web processing service for validating interpolation

An interoperable web processing service (WPS) for the automatic interpolation of environmental data has been developed in the frame of the INTAMAP project. In order to assess the performance of the interpolation method implemented, a validation WPS has also been developed. This validation WPS can be used to perform leave one out and K-fold cross validation: a full dataset is submitted and a range of validation statistics and diagnostic plots (e.g. histograms, variogram of residuals, mean errors) is received in return. This paper presents the architecture of the validation WPS and a case study is used to briefly illustrate its use in practice. We conclude with a discussion on the current limitations of the system and make proposals for further developments.

Consumer evaluations of brand extensions in emerging economies : evidences from China

This project explored how consumers in emerging economies evaluate brand extension by using China as a case. Two separate but related studies were conducted, and university students were used as respondents in both the studies. Study one or replication study tested Aaker and Keller's brand extension model in China. Assuming similar methods to Aaker and Keller's, six well-recognised brands were chosen as parent brand and each was extended to three product categories. Totally, 469 respondents completed the survey questionnaire. As each was to evaluate six extensions, this made the cases 2814. The data was analysed using Optimal Least Square regression approach and "residual centred" approach respectively. The result confirmed most of the findings observed in developed countries. Specifically, consumer's attitude towards the extension is primarily driven by the brand affect, the fit between the two product categories, the difficulty of making the extension and moderated via the interactions between the brand affect and the fit variables. Study two refined and extended Aaker and Keller's model by adding new variables and making methodological adjustments. The same stimuli and data analysis techniques as those in the replication were employed. 252 respondents participated in the survey and each evaluated six extensions, making cases 1512. In addition to re-verifying the findings of the replication and providing cross validation to these findings, the extended study found that the image consistency between the parent brand and the extension, the competition intensity of the extension product market were important in determining the success of the extension. Further, consumer differed in evaluating durable extensions and non-durable extensions. The thesis detailed the two studies above, and discussed the findings and their implications by relating to branding literature, to the general situation of the emerging economies as well as the reality of China. It also presented the limitations of the research and the future research directions.

Quantitative assessment of the pharmacotherapy of biopolar disorder and schizophrenia

The work present in this thesis was aimed at assessing the efficacy of lithium in the acute treatment of mania and for the prophylaxis of bipolar disorder, and investigating the value of plasma haloperidol concentration for predicting response to treatment in schizophrenia. The pharmacogenetics of psychotropic drugs is critically appraised to provide insights into interindividual variability in response to pharmacotherapy, In clinical trials of acute mania, a number of measures have been used to assess the severity of illness and its response to treatment. Rating instruments need to be validated in order for a clinical study to provide reliable and meaningful estimates of treatment effects, Eight symptom-rating scales were identified and critically assessed, The Mania Rating Scale (MRS) was the most commonly used for assessing treatment response, The advantage of the MRS is that there is a relatively extensive database of studies based on it and this will no doubt ensure that it remains a gold standard for the foreseeable future. Other useful rating scales are available for measuring mania but further cross-validation and validation against clinically meaningful global changes are required. A total of 658 patients from 12 trials were included in an evaluation of the efficacy of lithium in the treatment of acute mania. Treatment periods ranged from 3 to 4 weeks. Efficacy was estimated using (i) the differences in the reduction in mania severity scores, and (ii) the ratio and difference in improvement response rates. The response rate ratio for lithium against placebo was 1.95 (95% CI 1.17 to 3.23). The mean number needed to treat was 5 (95% CI 3 to 20). Patients were twice as likely to obtain remission with lithium than with chlorpromazine (rate ratio = 1.96, 95% CI 1.02 to 3.77). The mean number needed to treat (NNT) was 4 (95% CI 3 to 9). Neither carbamazepine nor valproate was more effective than lithium. The response rate ratios were 1.01 (95% CI 0.54 to 1.88) for lithium compared to carbarnazepine and 1.22 (95% CI 0.91 to 1.64) for lithium against valproate. Haloperidol was no better than lithium on the basis of improvement based on assessment of global severity. The differences in effects between lithium and risperidone were -2.79 (95% CI -4.22 to -1.36) in favour of risperidone with respect to symptom severity improvement and -0.76 (95% CI -1.11 to -0,41) on the basis of reduction in global severity of disease. Symptom and global severity was at least as well controlIed with lithium as with verapamil. Lithium caused more side-effects than placebo and verapamil, but no more than carbamazepine or valproate. A total of 554 patients from 13 trials were included in the statistical analysis of lithium's efficacy in the prophylaxis of bipolar disorder. The mean follow-up period was 5-34 months. The relapse risk ratio for lithium versus placebo was 0.47 (95% CI 0.26 to 0.86) and the NNT was 3 (95% CI 2 to 7). The relapse risk ratio for lithium versus imipramine was 0.62 (95% CI 0.46 to 0.84) and the NNT was 4 (951% Cl 3 to 7), The combination of lithium and imipramine was no more effective than lithium alone. The risk of relapse was greater with lithium alone than with the lithium-divalproate combination. A risk difference of 0.60 (95% CI 0.21 to 0.99) and an NNT of 2 (95% CI 1 to 5) were obtained. Lithium was as effective as carbamazepine. Based on individual data concerning plasma haloperidol concentration and percent improvement in psychotic symptoms, our results suggest an acceptable concentration range of 11.20-30.30 ng/mL A minimum of 2 weeks should be allowed before evaluating therapeutic response. Monitoring of drug plasma levels seems not to be necessary unless behavioural toxicity or noncompliance is suspected. Pharmacokinetics and pharmacodynamics, which are mainly determined by genetic factors, contribute to interindividual and interethnic variations in clinical response to drugs. These variations are primarily due to differences in drug metabolism. Variability in pharmacokinetics of a number of drugs is associated with oxidation polymorphism. Debrisoquine/sparteine hydroxylase (CYP2D6) and the S-mephenytoin hydroxylase (CYP2C19) are polymorphic P450 enzymes with particular importance in psychopharmacotherapy. The enzymes are responsible for the metabolism of many commonly used antipsychotic and antidepressant drugs. The incidence of poor metabolisers of debrisoquine and S-mephenytoin varies widely among populations. Ethnic variations in polymorphic isoenzymes may, at least in part, explain ethnic differences in response to pharmacotherapy of antipsychotics and antidepressant drugs.

Genotypic and environmentally derived variation in the cell wall composition of Miscanthus in relation to its use as a biomass feedstock

Fifteen Miscanthus genotypes grown in five locations across Europe were analysed to investigate the influence of genetic and environmental factors on cell wall composition. Chemometric techniques combining near infrared reflectance spectroscopy (NIRS) and conventional chemical analyses were used to construct calibration models for determination of acid detergent lignin (ADL), acid detergent fibre (ADF), and neutral detergent fibre (NDF) from sample spectra. Results generated were subsequently converted to lignin, cellulose and hemicellulose content and used to assess the genetic and environmental variation in cell wall composition of Miscanthus and to identify genotypes which display quality traits suitable for exploitation in a range of energy conversion systems. The NIRS calibration models developed were found to predict concentrations with a good degree of accuracy based on the coefficient of determination (R2), standard error of calibration (SEC), and standard error of cross-validation (SECV) values. Across all sites mean lignin, cellulose and hemicellulose values in the winter harvest ranged from 76–115 g kg-1, 412–529 g kg-1, and 235–338 g kg-1 respectively. Overall, of the 15 genotypes Miscanthus x giganteus and Miscanthus sacchariflorus contained higher lignin and cellulose concentrations in the winter harvest. The degree of observed genotypic variation in cell wall composition indicates good potential for plant breeding and matching feedstocks to be optimised to different energy conversion processes.

Relaxation procedures for an iterative MFS algorithm for the stable reconstruction of elastic fields from Cauchy data in two-dimensional isotropic linear elasticity

We investigate two numerical procedures for the Cauchy problem in linear elasticity, involving the relaxation of either the given boundary displacements (Dirichlet data) or the prescribed boundary tractions (Neumann data) on the over-specified boundary, in the alternating iterative algorithm of Kozlov et al. (1991). The two mixed direct (well-posed) problems associated with each iteration are solved using the method of fundamental solutions (MFS), in conjunction with the Tikhonov regularization method, while the optimal value of the regularization parameter is chosen via the generalized cross-validation (GCV) criterion. An efficient regularizing stopping criterion which ceases the iterative procedure at the point where the accumulation of noise becomes dominant and the errors in predicting the exact solutions increase, is also presented. The MFS-based iterative algorithms with relaxation are tested for Cauchy problems for isotropic linear elastic materials in various geometries to confirm the numerical convergence, stability, accuracy and computational efficiency of the proposed method.