The aim this work was to investigate clinical and metabolic consequences of hypopituitarism and the effects of growth hormone (GH) replacement therapy in adults. At baseline, early changes of atherosclerosis were detected using ultrasonography of the peripheral arteries, echocardiography, Doppler scanning and exercise electrocardiography. Abnormalities of glucose tolerance and plasma lipids were detected. Obesity, increased total-body and central fat mass and reduced bone mass were found. Forty patients (aged 19-67 years) entered a double blind placebo controlled trial of GH treatment (daily dose; 0.02-0.05 lU/kg body weight) for 6 months followed by open trial for 12 months. In the controlled study, lean body mass increased, body fat decreased and exercise tolerance increased on GH treatment. No changes in muscle strength nor plasma lipids were observed. Post-prandial plasma glucose increased, as did fasting and postprandial insulin levels on GH therapy. GH increased bone turn-over but bone mineral mass did not change. To study the long-term effects of GH therapy, data were pooled from the two phases of the trial. Thirty four, 27 and 11 patients were treated with GH for 6, 12 and 18 months respectively. The earlier effects on body composition and exercise tolerance were maintained. Minor but significant increases were observed in muscle strength in certain groups. Plasma total and low density lipoprotein cholesterol decreased on long-term GH treatment. Fasting and post-prandial plasma glucose and insulin levels increased. The increase in markers of bone turnover was sustained with no change in bone mineral mass over 6-18 months of GH treatment. Side effects were mainly due to fluid retention. In conclusion, hypopituitary patients on conventional therapy have premature cardiovascular disease, increased frequency of cardiovascular risk factors, abnormal body composition and reduced bone mass. GH therapy produced desirable effects on body composition, exercise tolerance, muscle strength and circulating lipids but produced minor hyperglycemia and hyperinsulinaemia.

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Methods for sequencing deoxyribonucleic acid (DNA) have improved rapidly in the past decade. Recent methods, termed "next-generation sequencing" (NGS), have made sequencing large quantities of DNA economically viable in molecular diagnostics of genetic diseases. This thesis describes some of the first investigations to use NGS for such a purpose. Several different NGS platforms, each of which differs substantially in terms of sample preparation, chemistry, and sequencing methodology, were tested, in addition to several sequence capture and enrichment technologies that allow sequencing to be targeted, and these combinations were compared to Sanger sequencing. They were each found to have different strengths and weaknesses, which affect their accuracy, reliability, time taken to results, financial cost, and ease of use, but all showed high accuracy and dramatically increased throughput over Sanger sequencing. NGS was used to identify pathogenic mutations in two groups of patients who had either inherited retinal dystrophies (IRD), or severe early onset epilepsies. NGS was able to identify pathogenic variants, demonstrating the ability of the technology to provide medically useful information for genetically heterogeneous conditions. NGS combined with a novel data analysis pipeline was able to make a secure molecular diagnosis in 25% of a cohort of IRD patients who previously did not have a genetic diagnosis. The greatest challenge presented by NGS was found to be filtering the vast amounts of data produced to identify potential pathogenic variants. In silico pathogenicity prediction programs were used, but none were 100% accurate. Other methods were also employed to provide further evidence of pathogenicity. These included family based DNA testing for cosegregation of variants with phenotype, and transcript based analysis. In some patients, despite extensive genetic testing, a secure molecular diagnosis could not be made using DNA sequencing technologies, illustrating that challenges still remain in the field of genetic diagnostics.

Rapidly declining costs and increasing availability of whole-genome analysis means that clinical genetic testing has shifted from a targeted approach to broad analysis that can provide many more clinical predictions than previously possible. This thesis explores ethical issues in the discovery of clinically relevant findings not suspected from signs, symptoms or family history. In particular the consent and disclosure practices pertaining to such incidental findings (IFs) were explored from both health professional (HCP) and patient perspectives. Phase 1 reviewed current practices and explored lay and professional experiences of and views about ethical issues surrounding IFs. 27 clinic observations and 48 in-depth interviews (32 HCP and 16 patient) were analysed thematically. Observations demonstrated that the concept of IFs was often not explained at the point of testing, or if it was, this was rarely recalled by patients. In-depth interviews demonstrated that the concept of IFs was variably understood. Some findings, classed as ‘incidental’ were in fact only potential IFs at the time of reporting. Only a sub-group of these became clear IFs, and then only when other complex investigations, including ones in relatives, had been analysed. Both patients and HCPs thought that seeking explicit consent for IFs was important, often using rights-based language, but both groups also described difficulties in gaining explicit consent for a broad and open ended concept. Some thought that actionable results should be provided regardless of consent but acknowledged that this might result in perceptions of paternalism. Furthermore, there were very different perceptions of what a good definition of actionable would be. Despite these concerns patients who had received an IF without giving specific consent, were pleased to receive them and did not feel their rights had been infringed. The aim of Phase 2 was to design a questionnaire to examine whether key findings from phase 1 resonate with a larger and representative sample of UK HCPs who manage genetic testing. The questionnaire was developed through a process of cognitive interviewing and pre-testing and is now ready for piloting and administration as post-doctoral work. Despite the focus on specific or ‘informed’ consent, this research found support for broad consent for the notion of IFs rather than specific consent to any particular IF or type of IF. This research provides an insight into the gap between the technological advances in genomics and their translation into clinical practice. Infrastructures to support consent and communication of IFs, need to be developed as genetic tests become routine for most medical specialities.

The first part of this thesis is a systematic review and narrative synthesis of healthcare professionals’ experiences of working with people with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). A total of 15 qualitative studies met the inclusion criteria. There was significant overlap of themes across the 15 studies. Themes were organised into four categories: Contesting the Legitimacy of CFS/ME, Emotional Burden, Stereotyping the CFS/ME Patient, and Tension in Clinician-Patient Communication and Relationships. The review identified a need for further research to better understand differences in understandings of CFS/ME, including the understandings and experiences of specialist CFS/ME healthcare professionals. The second part of this thesis is an empirical paper describing a study that used Interpretative Phenomenological Analysis (IPA) to explore the lived experiences of healthcare professionals working in specialist CFS/ME services. Interviews were conducted with eight clinicians from a range of healthcare professions. Four superordinate themes were identified: Safe Haven, Challenges of Understanding, Person-Centredness, and Recovery Road. Some of these findings support issues identified by previous research, but novel themes were also discovered. Clinical implications and suggestions for further research are discussed.

Chronic Fatigue Syndrome (CFS) is characterised by severe fatigue, endured for at least six months, together with symptoms including impaired cognitive function, sleep disturbance, and musculoskeletal pain. The pathogenesis is still unknown, resulting in a lack of treatment options and the stigmatization of patients. Both psychological and biological factors have been implicated in the development of CFS. To date, evidence has come largely from cross-sectional studies, and there have been a paucity of longitudinal studies. The aim of this study was to explore interferon-alpha (IFN-α) induced persistent fatigue as a proxy model of CFS. IFN-α is an immunotherapy for chronic Hepatitis C Virus (HCV) infection. It induces a range of side effects including fatigue, which in some patients persists post-treatment. This model allows for the identification of risk factors and monitoring of biological and behavioural changes from the perspective of the trigger, to determine factors relevant to the persistence of fatigue after the original stimulus is no longer present. Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during treatment, and six-months post-treatment. Clinical, inflammatory and cortisol measures were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment measures from HCV persistent and resolved fatigue patients. IFN-α induced persistent fatigue was associated with an exaggerated response to IFN-α, with increased fatigue, depressive symptoms, and perceived stress, a greater decline in health status, and higher inflammation. This higher symptomatology during treatment put these patients at a disadvantage for their subsequent recovery. Neither IFN-α induced persistent fatigue nor CFS was associated with continued peripheral inflammation, emphasising the importance of the response to the initial trigger. Future studies are needed to elucidate the mechanisms behind the exaggerated response, and the ‘conversion’ to chronic illness in the absence of peripheral immune activation.

“Evidence Based Medicine” (EBM) urges that medical recommendations be based on the best research evidence, rather than on clinical judgement. While I strongly endorse attention to relevant research evidence, I argue that the related downplaying of clinical judgement is a step backwards. This is because actual models of EBM encourage physicians to focus exclusively on research probabilities and so to neglect relevant information about patients. I call this feature of EBM the “Problem of Extra Information” (PEI), and contend that it leads to predictions and prescriptions based on the wrong probabilities. The PEI has been largely neglected by EBM, which has construed the challenge of clinical care as a matter of developing better research evidence, and of reminding physicians to attend to patients’ preferences and values. And although meritorious attempts have been made to connect research with individuals through sophisticated methodological improvements, these only address the PEI partially, and do not eliminate the need for clinical discretion. In this dissertation I contend that, in response to the PEI, clinical medicine requires a more Discretionary Approach (DA). This approach recognizes that the objective probabilities that matter for clinical recommendations are those in the reference class defined by everything the physician knows about the patient, and argues that the central role for judgment in clinical practice is to estimate these probabilities. So understood, the DA has two main advantages over the EBM approach: prudential adequacy and evidential flexibility. My defence of the DA consists of addressing criticisms of the role ascribed to judgment and clinical experience within this approach. The final two chapters of this doctoral dissertation complement my arguments with two meta-analytical empirical studies: one which compares “therapeutic guidelines based on evidence” with “usual care” with respect to patients’ outcomes, and another which examines the relative predictive performance of statistical models and physicians’ judgment in the context of diagnosis and prognosis. These studies refute previous evidence cited against judgment and vindicate the plausibility of the Discretionary Approach to clinical care.

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