As one of the most recommended strategies in decision making of contemporary medicine, evidence-based medicine (EBM) is attracting more and more attention. For EBM, the scientific evidences are obtained mainly from the randomized controlled trials (RCTs), systematic review and meta-analysis. In particular, meta-analysis can help researchers statistically combine several independent studies for a same clinical problem. In meta-analysis, Cohen's d and Hedges' g are among the most commonly used effect size measurements for continuous data. To compute these mean difference criteria, the sample mean and standard deviation are two conventional statistics reported in the literature. However, some other clinical studies may instead report the median, minimum and maximum values, and/or sample quartiles. Such a situation requires researchers to estimate the sample mean and standard deviation from these reported summary statistics. We note, however, that most existing estimators in the literature have some serious limitations. For this, we propose to improve the existing methods and extend them to three frequently encountered scenarios. In this thesis, we developed the optimal sample mean estimators, the normality test statistics and the updated Cohen's d mean difference criterion for three commonly encountered scenarios in meta-analysis. In Chapter 1, we gave a brief introduction on evidence-based medicine, meta-analysis and the summary data. In Chapter 2, we introduced our optimal estimators of the sample mean under the three scenarios, respectively. In Chapter 3, we proposed several methods for testing the normality of the underlying data. And in Chapter 4, we proposed to improve the famous Cohen's d and its relevant parameters. To assess the practical performance of our newly proposed methods, we also chose a few real data at the end of each chapter as illustrating examples. Numerical results of those studies indicated that our proposed methods have satisfactory performance both in theory and in practice. Following our new methodology, we also recommended an improved procedure for medical researchers to conduct meta-analysis. For illustration, we chose a meta-analysis in Chapter 5 on the effect of phytosterols to plasma CRP level (Rocha et al., 2016) to compare the results obtained from our recommended procedure and from the original methods. The results showed that our recommended procedure may lead to distinctly different results for a same clinical problem. To conclude the thesis, we expect that our newly proposed methods can be regarded as "rules of thumb" and will soon be widely applied in meta-analysis and evidence-based medicine.

Conclusions. The sensitivity and positive predictive value are generally more concerned than the specificity and negative predictive value in assessing and adjusting publication bias in meta-analyses. In this sense, Egger's regression can be recommended for its high sensitivity, while any positive result from Tang's method would suggest a probability of bias that should be taken seriously. Given the different patterns of the accuracy with the OR and the P1-P2 combination, a combination of Egger's regression and Tang's regression would be advisable. Further studies are needed to study the accuracy of methods used in combination. / Due to sampling error and true heterogeneity, a single study cannot provide a comprehensive picture and a precise estimate of, say the effectiveness of a treatment. Systematic reviews that identify and integrate relevant studies have become the most important scientific, quantitative method to summarize scientific research. Meta-analysis is the statistical method used in systematic reviews to combine results from individual studies. / However, due to selective submission and publication, not all relevant studies conducted, especially those unpublished studies with an insignificant negative result, are easily accessible to those who conduct reviews. As a result, the truth, say, the effect of a treatment, would be overestimated. This phenomenon is known as publication bias. A few methods for detecting the bias have been developed and used in meta-analyses. Although their accuracy has been studied, some important issues remain to be answered, such as when would a method be good enough for practical use and is it similarly good for different definitions of the odds ratio? / Methods. We conducted a simulation study to examine the accuracy of four commonly used bias-detection methods with various ORs and P1-P2 combinations. In a simulation study, the true bias status can be predetermined and thus be compared with the results of the bias-detection methods. The four methods are Egger's regression, funnel plot regression, rank correlation regression, and Tang's regression. Realistic sample size was used for simulating individual studies and the numbers of studies in a meta-analysis was also varied. Both the sensitivity and specificity are examined against the magnitude of the OR and the P1-P 2 combination to identify the ORs and P1-P 2 combinations for which a method is sufficiently accurate. Predictive values are also examined for the same reason and in the same manner. / Results. The sensitivity and positive predictive value are generally low and in particular when the OR is close to one for which publication bias is of a particular concern. Egger's regression has the highest sensitivity among the four, in particular when the OR is neither close to one nor exceptionally large or small. Due to the relatively lower specificity, the positive predictive value of Egger's regression is not as high as that for Tang's regression and funnel plot regression. Tang's regression and funnel plot regression are very similar in sensitivity, specificity and predictive values, with the former being slightly better. Rank correlation seems the least accurate method overall. Tang's regression has in general the highest positive predictive value among the four methods in particular when the OR is below one. / Chung Chi-keung. / "June 2006." / Adviser: Tang Jin Ling. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1588. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 116-124). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

This thesis reports on two aspects of interpersonal meaning in peer reviewer reports for eleven researchers in the Animal and Veterinary Sciences awarded NRF ratings in A1, B1, C1 and Y1 rating categories. These aspects are the evaluation of the researcher applying for a rating, and the instruction to the NRF as to the rating the researcher ought to receive. A full APPRAISAL Analysis (Martin & White 2005) complemented by an investigation of politeness strategies (Myers 1989) is used to analyse the reports and show how the various systems of interpersonal meaning co-function and to what effect. The analysis reveals that there are clear differences between the evaluative and instructive language used in the reports. Those for the A1 rated researchers are characterised by only positive evaluations of the applicant, frequently strengthened in terms of Graduation and contracted in terms of Engagement. Overall there is less Engagement and politeness in these reports rendering them more ‘factual’ than the reports for the other rating categories. The A1 rated researcher is therefore construed as being, incontestably, a leader in his/her field of research, worthy of a top rating. The reports for the B1 and C1 rated researchers are characterised by the increasing presence of negative evaluations. In addition, there are more instances of softened/downscaled Graduation, dialogic expansion and deference politeness, showing that there is more perceived contention about the evaluations made. The reports for the Y1 rated researchers (a category for young researchers) focus on the applicant’s demonstrated potential to become a leader in the field. In addition to a high incidence of negative evaluations, downscaled Graduation, dialogic expansion and deference politeness, the Y1 reports are also characterised by a high incidence of advice and suggestions from the reviewers concerning the applicant’s work and standing. At a broader level, the analysis reveals that the language used in the reports has a profound influence on the outcome of the rating process. The reports are crucial, not only for evaluating the applicant but, also, more subtly, in directing the NRF towards a specific rating category. It offers insights into what is valued in the scientific community, what is considered quality research, and what leads to international recognition. The research also adds uniquely to current thinking about the language of science and, more particularly, highlights the nuanced understanding of evaluative and instructive language in the reports that is possible if one draws on the full APPRAISAL framework, and insights into politeness behaviour.

Indiana University-Purdue University Indianapolis (IUPUI) / The sympathetic nervous system strongly modulates the contractile and electrical function of the heart. The anatomical underpinnings that enable a spatially and temporally coordinated dissemination of sympathetic signals within the cardiac tissue are only incompletely characterized. In this work we took the first step of unraveling the in situ 3D microarchitecture of the cardiac sympathetic nervous system. Using a combination of two-photon excitation fluorescence microscopy and computer-assisted image analyses, we reconstructed the sympathetic network in a portion of the left ventricular epicardium from adult transgenic mice expressing a fluorescent reporter protein in all peripheral sympathetic neurons. The reconstruction revealed several organizational principles of the local sympathetic tree that synergize to enable a coordinated and efficient signal transfer to the target tissue. First, synaptic boutons are aligned with high density along much of axon-cell contacts. Second, axon segments are oriented parallel to the main, i.e., longitudinal, axes of their apposed cardiomyocytes, optimizing the frequency of transmitter release sites per axon/per cardiomyocyte. Third, the local network was partitioned into branched and/or looped sub-trees which extended both radially and tangentially through the image volume. Fourth, sub-trees arrange to not much overlap, giving rise to multiple annexed innervation domains of variable complexity and configuration. The sympathetic network in the epicardial border zone of a chronic myocardial infarction was observed to undergo substantive remodeling, which included almost complete loss of fibers at depths >10 µm from the surface, spatially heterogeneous gain of axons, irregularly shaped synaptic boutons, and formation of axonal plexuses composed of nested loops of variable length. In conclusion, we provide, to the best of our knowledge, the first in situ 3D reconstruction of the local cardiac sympathetic network in normal and injured mammalian myocardium. Mapping the sympathetic network connectivity will aid in elucidating its role in sympathetic signal transmisson and processing.

Indiana University-Purdue University Indianapolis (IUPUI) / Advancements in human genomics have simultaneously enhanced our basic understanding of the human body and ability to combat debilitating diseases. Historically, research has shown that there have been many hindrances to realizing this medicinal revolution. One hindrance, with particular regard to the kidney, has been our inability to effectively and routinely delivery genes to various loci, without inducing significant injury. However, we have recently developed a method using hydrodynamic fluid delivery that has shown substantial promise in addressing aforesaid issues. We optimized our approach and designed a method that utilizes retrograde renal vein injections to facilitate widespread and persistent plasmid and adenoviral based transgene expression in rat kidneys. Exogenous gene expression extended throughout the cortex and medulla, lasting over 1 month within comparable expression profiles, in various renal cell types without considerably impacting normal organ function. As a proof of its utility we by attempted to prevent ischemic acute kidney injury (AKI), which is a leading cause of morbidity and mortality across among global populations, by altering the mitochondrial proteome. Specifically, our hydrodynamic delivery process facilitated an upregulated expression of mitochondrial enzymes that have been suggested to provide mediation from renal ischemic injury. Remarkably, this protein upregulation significantly enhanced mitochondrial membrane potential activity, comparable to that observed from ischemic preconditioning, and provided protection against moderate ischemia-reperfusion injury, based on serum creatinine and histology analyses. Strikingly, we also determined that hydrodynamic delivery of isotonic fluid alone, given as long as 24 hours after AKI is induced, is similarly capable of blunting the extent of injury. Altogether, these results indicate the development of novel and exciting platform for the future study and management of renal injury.