This thesis describes some of the problems in providing care for patients with breast cancer. These are then used to motivate the development of an extension to an existing theory of argumentation, which I call the Ontology-based Argumentation Formalism (OAF). The work is assessed in both theoretical and empirical ways. From a clinical perspective, there is a problem with the provision of care. Numerous reports have noted the failure to provide uniformly high quality care, as well as the number of deaths caused by medical care. The medical profession has responded in various ways, but one of these has been the development of Decision Support Systems (DSS). The evidence for the effectiveness of such systems is mixed, and the technical basis of such systems remains open to debate. However, one basis that has been used is argumentation. An important aspect of clinical practice is the use of the evidence from clinical trials, but these trials are based on the results in defined groups of patients. Thus when we use the results of clinical trials to reason about treatments, there are two forms of information we are interested in - the evidence from trials and the relationships between groups of patients and treatments. The relational information can be captured in an ontology about the groups of patients and treatments, and the information from the trials captured as a set of defeasible rules. OAF is an extension of an existing argumentation system, and provides the basis for an argumentation-based Knowledge Representation system which could serve as the basis for future DSS. In OAF, the ontology provides a repository of facts, both asserted and inferred on the basis of formulae in the ontology, as well as defining the language of the defeasible rules. The defeasible rules are used in a process of defeasible reasoning, where monotonic consistent chains of reasoning are used to draw plausible conclusions. This defeasible reasoning is used to generate arguments and counter-arguments. Conflict between arguments is defined in terms of inconsistent formulae in the ontology, and by using existing proposals for ontology languages we are able to make use of existing proposals and technologies for ontological reasoning. There are three substantial areas of novel work: I develop an extension to an existing argumentation formalism, and prove some simple properties of the formalism. I also provide a novel formalism of the practical syllogism and related hypothetical reasoning, and compare my approach to two other proposals in the literature. I conclude with a substantial case study based on a breast cancer guideline, and in order to do so I describe a methodology for comparing formal and informal arguments, and use the results of this to discuss the strengths and weaknesses of OAF. In order to develop the case study, I provide a prototype implementation. The prototype uses a novel incremental algorithm to construct arguments and I give soundness, completeness and time-complexity results. The final chapter of the thesis discusses some general lessons from the development of OAF and gives ideas for future work.

Meningococcal disease (MD) remains a major source of mortality and morbidity in adolescence despite the introduction in some countries of the seroGroup C conjugate vaccine. This study is the first which comprehensively assesses the outcomes of MD in adolescence. In pursuing this aim, a population-based matched cohort study was undertaken and 101 sex and age matched case-control pairs (aged 15-19 years at disease) from 6 regions of England (representing 65% of the population of England) were followed up 18-36 months after MD (46% males). Educational, social and vocational function, mental health, social support, cognitive and quality of life data were collected using standardised questionnaires and neuropsychological tests. In addition, demographic and disease factors associated with outcome were also examined. The results show that 57% (N=58) of cases had physical sequelae ranging from minor scarring to bilateral amputations. Survivors had greater mental fatigue, lower social support, greater reduction in quality of life, and lower educational attainment compared with controls. Cognitive testing revealed no overall change in intellectual ability however, cases had deficits in aspects of memory (short and long-term), attention (selective and sustained), cognitive flexibility and psychomotor speed. Greater cognitive deficit was associated with a younger age at diagnosis. Cases with SeroGroup C disease had greater physical sequelae than those with B disease. MD status increased the risk of depression. Only 53/101 cases reported any medical follow-up after MD. The findings suggest that survivors of MD in adolescence have a disturbing series of deficits including poorer physical and mental health, quality of life and educational achievement. SeroGroup C is associated with poorer outcome. Of concern, medical care is poor after discharge from hospital. Routine follow up of adolescent survivors is essential to address issues and concerns that are important for adolescent MD survivors and to mitigate or prevent physical and psychosocial morbidity after MD.

The introduction of combination antiretroviral therapy (cART) into clinical practice for the treatment of HIV in 1995-1996 has led to dramatic reductions in mortality and morbidity. Factors linked to a positive response to therapy include a potent and tolerable regimen, good adherence and low levels of HIV drug resistance. The aims of this thesis were to investigate factors potentially associated with different responses to cART measured using virological and immunological predictive markers, and also to look at the development of toxicities to a specific regimen. The analyses were based on data from the EuroSIDA study, which is an observational cohort of 14,310 HIV-1 infected patients from Europe, Israel and Argentina. Data collected includes demographic history, CD4 cell counts, viral loads and details of all drugs taken. EuroSIDA also collects viral sequence data for its resistance database. Investigation into virological response to first-line cART across geographical regions found evidence of variation, which was most apparent in early-cART years. Virological response improved over calendar time in all regions, especially in East Europe. Neither HIV-1 subtype nor transmitted drug resistance (TDR) were found to be associated with virological response to cART, however statistical power was limited. A significantly decreased risk of virological failure was found in patients starting efavirenz compared with nevirapine, which did not appear to be explained by baseline drug resistance. Finally, incidence of abacavir discontinuation due to a hypersensitivity reaction side effect of the drug appeared to be higher in patients starting abacavir as part of first-line therapy but decreased in recent years. In conclusion, this thesis has compared a variety of different responses to antiretroviral therapy across subsets of a large heterogeneous population. It is hoped that these findings will contribute to research in monitoring trends in response to therapy and provide insight into association with the genetic variability of the virus.

This thesis explores clinical outcomes with respect to ethnicity in black, white and lndo-Asian patients with systemic lupus erythematosus (SLE) in the UCH cohort followed-up between 1978-2004 using cross-sectional studies involving retrospective analyses of patient records. It examines adherence to medications in SLE patients in the UCH cohort, and in Jamaica in the West Indies. Study number 1 which examined outcomes in patients with renal lupus showed that black patients were more likely to develop end stage renal failure (ESRF). High dsDNA antibody and low C3 levels were associated with progression to ESRF. Treatment adherence was poor in the majority of patients with ESRF (physician assessment). Study number 2 assessed the prevalence and chronology of development of additional autoimmune diseases (AID) in patients with SLE. A third of patients developed another AID. The total number of AID did not vary by ethnic group; however differences in the frequencies of some AID were noted. Mortality and damage scores were worse at 5 years in the study cases than the controls. Study number 3 assessed damage accrual and mortality in patients who had at least ten years of follow up over a 25 year period. Damage scores increased with time and were associated with a higher risk of mortality. Blacks had higher mortality than other ethnic groups. Sepsis was the main cause of death. Studies 4 and 5 determined self-reported adherence to medications in 220 patients in the UCH cohort and 75 in Jamaica. Interviews were conducted to determine why study participants did/did not take their medications regularly. Adherence did not differ between ethnic groups in the UCH cohort (assessed using the Morisky Medication Adherence Scale and a visual analogue scale). Beliefs and experiences with the drugs, SLE and physicians influenced adherence. Black patients reported feeling discriminated against by their white physicians. Fifty-two percent of the Jamaican patients took their medications regularly. High cost and poor availability of medications were important barriers to adherence. Perceived health benefits of drugs and good doctor: patient communication promoted high adherence. In conclusion, clinical outcomes in patients with SLE vary with respect to ethnicity. These differences may not necessarily relate to differences in treatment adherence.

By 2005 one person in every five UK households suffered with asthma. Research has shown that episodes of poor air quality can have a negative effect on respiratory health and is a growing concern for the asthmatic. To better inform clinical staff and patients to the contribution of poor air quality on patient health, this thesis defines an IT architecture that can be used by systems to identify environmental predictors leading to a decline in respiratory health of an individual patient. Personal environmental predictors of asthma exacerbation are identified by validating the delay between environmental predictors and decline in respiratory health. The concept is demonstrated using prototype software, and indicates that the analytical methods provide a mechanism to produce an early warning of impending asthma exacerbation due to poor air quality. The author has introduced the term enviromedics to describe this new field of research. Pattern recognition techniques are used to analyse patient-specific environments, and extract meaningful health predictors from the large quantities of data involved (often in the region of '/o million data points). This research proposes a suitable architecture that defines processes and techniques that enable the validation of patient-specific environmental predictors of respiratory decline. The design of the architecture was validated by implementing prototype applications that demonstrate, through hospital admissions data and personal lung function monitoring, that air quality can be used as a predictor of patient-specific health. The refined techniques developed during the research (such as Feature Detection Analysis) were also validated by the application prototypes. This thesis makes several contributions to knowledge, including: the process architecture; Feature Detection Analysis (FDA) that automates the detection of trend reversals within time series data; validation of the delay characteristic using a Self-organising Map (SOM) that is used as an unsupervised method of pattern recognition; Frequency, Boundary and Cluster Analysis (FBCA), an additional technique developed by this research to refine the SOM.

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