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Over the past few years, embryo research has been a widely discussed topic. New techniques such as embryo stem cell research or therapeutic cloning are considered by scientists to be very promising. Nevertheless, opponents of these experimentations warn against the commodification of human life forms and argue that the moral status of embryos should protect them from being destroyed purely for research. / Legislations on this topic have been enacted in most Western countries, though they are still much criticised. Is there an adequate way of regulating embryo research? Our argument suggests that consensus can only be procedurally obtained. That is, we believe that only legislative assemblies should have authority to take a position on this controversial topic, which is subject to moral disagreement, and as such, judges should only have a minor role.

Numerous ethical guidelines are referred to when medical research is conducted on human participants. These guidelines include the Nuremberg Code, the Declaration of Helsinki, and the International Ethical Guidelines for Biomedical Research Involving Human Subjects. From a Western viewpoint, these guidelines may seem like well-reasoned, universally applicable codes for conducting medical research on human subjects. Some of the guidelines, however, merely impose Western values on developing countries without giving adequate consideration to their worldviews. I explore the applicability of current codes and guidelines of ethics on medical research with human subjects to the Zulu of South Africa and the Kikuyu of Kenya. Through a study of African traditional religions and philosophy and the community mindset that flows out of them, I have gained insight into the limitations of current universal codes when applied to traditional Kikuyu and Zulu communities.

Paul Ramsey's medical ethics is built from a philosophical antinomy: Premise, the human being is a creature of will; Proposition, the human will is a free will; Contrary Proposition, the human will is a not-free will. General, exceptionless rules of conduct function in Ramsey's thought as moral restraint to human freedom. The moral agent ought always to act in accord with the demands of agape; and not only once but as often as the same features of a decision/action arise. General rules guide and restrain human free will in a necessary way to assure an ordered and moral society. This antinomy-interpretation helps locate Ramsey in the theatre of ethical debate; it also is the key to criticism of Ramsey's rigid rules in medical ethics.

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.

The study was designed to explore the proposition that conduct of and participation in research by general practitioners in British Columbia would be both desirable and feasible. Desirability was defined in terms of benefits for knowledge, for the medical practice, and for society at large. Feasibility was defined in terms of being acceptable for the general practitioner, for the patient, for the practice, and for the requirements of research. To answer specific questions related to desirability and feasibility of research by general practitioners, information was obtained from the literature, from a questionnaire survey of the total general practitioner population of British Columbia, and from a random sample of patients in practices selected at random from respondents to the questionnaire to general practitioners. In the survey of general practitioners, 2,344 questionnaires were mailed. Of the 563 (24%) which were returned, 508 were available for analysis. Five were returned by the post-office undelivered, seven were too late for analysis, and forty-three were returned with information indicating that the respondent was not in general practice. Forty- eight respondents were anonymous, and the remainder identified themselves. The response of general practitioners represented a variety of geographic locations, ages, types of practice, and medical schools. Members of the College of Family Physicians of Canada had a response rate of 39%. In the survey of patients, 15 out of 20 general practitioners who were contacted agreed to submit questionnaires to their patients. Of the patients surveyed, approximately 90% completed the questionnaires. Most were regular patients of the doctors, and represented a full range of ages, and both sexes. General practitioners and their patients agreed that research by general practitioners was desirable, and suggested many areas suitable for research. The benefits of research to the general practitioners, patients, and society were considered to be incentives, encouraging research activity. Important among the benefits were the discovery of new knowledge and the contribution to the academic base of general practice. The feasibility of research was explored in terms of the conditions required for its conduct. Attitudes were receptive to the concept of research, as many of the general practitioners had previously been involved in projects. Major deterrents were heavy workload and lack of time, for the general practitioners, and in their practices the high overhead and pressure of work on the staff were problems. Training for research was variable, with some general practitioners having none and a few having much training. Inadequacy of the usual office records was recognized, so that research would usually require special methods. General practitioners had little awareness of resources available for help, advice or financing, but most were aware of the need for such resources. Patients were willing to cooperate in studies. They suggested that the cost of research should be borne primarily by governments, and to a lesser extent by foundations and the public. Recommendations were made for the support of research, to help overcome the problems which decrease its feasibility. There should be encouragement of training in research methods, at both undergraduate and postgraduate levels. This would include presentation of research findings to scientific meetings of medical societies, and visits to and from eminent research workers in general practice. Some assistance should be given to the general practitioners, such as help in developing office records for research or payment for time spent on research. Resources for help in planning studies and processing results should be readily available, including both consultant advice and the provision of grants. Conclusions from the study were that research by general practitioners in British Columbia is desirable, and that it is feasible but has several major deterrent factors which can inhibit research activity. Because of these factors, the great potential for research in British Columbia is still far from being realized. / Medicine, Faculty of / Population and Public Health (SPPH), School of / Graduate

Causal inference -- the process of drawing a conclusion about the impact of an exposure on an outcome -- is foundational to biomedicine, where it is used to guide intervention. The current gold-standard approach for causal inference is randomized experimentation, such as randomized controlled trials (RCTs). Yet, randomized experiments, including RCTs, often enforce strict eligibility criteria that impede the generalizability of causal knowledge to the real world. Observational data, such as the electronic health record (EHR), is often regarded as a more representative source from which to generate causal knowledge. However, observational data is non-randomized, and therefore causal estimates from this source are susceptible to bias from confounders. This weakness complicates two central tasks of causal inference: the replication or evaluation of existing causal knowledge and the generation of new causal knowledge. In this dissertation I (i) address the feasibility of observational data to replicate existing causal knowledge and (ii) present new methods for the generation of causal knowledge with observational data, with a focus on the causal tasks of comparing an outcome between two cohorts and the estimation of attributable risks of exposures in a causal system.

Indiana University-Purdue University Indianapolis (IUPUI) / With the availability of electronic medical records, medication dispensing data offers an unprecedented opportunity for researchers to explore complex relationships among longterm medication use, disease progression and potential side-effects in large patient populations. However, these data also pose challenges to existing statistical models because both medication exposure status and its intensity vary over time. This dissertation focused on flexible models to investigate the association between time-varying exposures and different types of outcomes. First, a penalized functional regression model was developed to estimate the effect of time-varying exposures on multivariate longitudinal outcomes. Second, for survival outcomes, a regression spline based model was proposed in the Cox proportional hazards (PH) framework to compare disease risk among different types of time-varying exposures. Finally, a penalized spline based Cox PH model with functional interaction terms was developed to estimate interaction effect between multiple medication classes. Data from a primary care patient cohort are used to illustrate the proposed approaches in determining the association between antidepressant use and various outcomes. / NIH grants, R01 AG019181 and P30 AG10133.

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Indiana University-Purdue University Indianapolis (IUPUI) / Biomedical research has produced vast amounts of new information in the last decade but has been slow to find its use in clinical applications. Data from disparate sources such as genetic studies and summary data from published literature have been amassed, but there is a significant gap, primarily due to a lack of normative methods, in combining such information for inference and knowledge discovery. In this research using Bayesian Networks (BN), a probabilistic framework is built to address this gap. BN are a relatively new method of representing uncertain relationships among variables using probabilities and graph theory. Despite their computational complexity of inference, BN represent domain knowledge concisely. In this work, strategies using BN have been developed to incorporate a range of available information from both raw data sources and statistical and summary measures in a coherent framework. As an example of this framework, a prototype model (In-silico Bayesian Integration of GWAS or IsBIG) has been developed. IsBIG integrates summary and statistical measures from the NIH catalog of genome wide association studies (GWAS) and the database of human genome variations from the international HapMap project. IsBIG produces a map of disease to disease associations as inferred by genetic linkages in the population. Quantitative evaluation of the IsBIG model shows correlation with empiric results from our Electronic Medical Record (EMR) – The Regenstrief Medical Record System (RMRS). Only a small fraction of disease to disease associations in the population can be explained by the linking of a genetic variation to a disease association as studied in the GWAS. None the less, the model appears to have found novel associations among some diseases that are not described in the literature but are confirmed in our EMR. Thus, in conclusion, our results demonstrate the potential use of a probabilistic modeling approach for combining data from disparate sources for inference and knowledge discovery purposes in biomedical research.