Copy number variants (CNVs) play an important role in the disease pathogenesis, including epilepsy, diabetes and many others. CNVs, are also known to affect cellular phenotypes through several phenomenon such as gene dosage. Next generation technologies for sequencing (DNA and RNA) and metabolite profiling (metabolomics) has led to the systematic discovery and evaluation of various genomic variants and their relationship to multiple phenotypes. Such approaches often involve application of several statistical and machine learning methods for unravelling new relationships between genomic variants and phenotypes i.e. disease outcomes or quantitative traits characterized at the molecular level. This thesis explores and develops several statistical methods for CNV detection and association with complex human phenotypes, in particular for epilepsy drug-response, epilepsy susceptibility, metabolomics and gene expression. In more detail, chapter 3, describes a genome wide CNV association analysis for two phenotypes including epilepsy susceptibility and epilepsy drug response. I have identified several important candidate genes for these two phenotypes, including the top most associated genes, SLC9A1 (p-value=6.69E-15) for epilepsy susceptibility and WWOX (p-value=1.93E-3) for epilepsy drug response. These associations were replicated in a separate Australian cohort and were further validated in lab and in-silico, leading to some positive and negative confirmation. In chapter 4, I present CNV association with metabolomic data in the exonic regions of the TSPAN8 gene. A strong association signal was detected in the 6th exon and 7th exon of the TSPAN8 gene, where a large proportion of metabonomic lipid phenotypes were found to be associated with univariate (P-value=7.64E-4) and multivariate (P-value=1.33E-6) approaches. These CNVs were also found to be nominally associated with type 2 diabetes (P-value=3.32e-7). In addition, I also carried out advanced multivariate based association analysis to corroborate these results and further reported sequencing based validation results for TSPAN8 exonic CNVs in different human populations from the 1000 genomes project. In chapter 5, I report a genome wide CNV association analysis with gene expression in ten different regions of the human brain. I identified a novel CNV near the DRD5 gene which was found to be strongly associated with gene expression. Further, I have reported on-going efforts to replicate and validate this finding. Each of these different phenotype categories analysed posed its own unique challenges and required specific approaches for analysis and interpretation.

The PhD outlines criteria under which a psychiatric classification merits belief and, as a case study, establishes that autism merits belief. Three chapters respond to anti-realist arguments, three chapters establish conditions under which psychiatric classifications merit belief. Chapter one addresses the pessimistic meta-induction. I historically analyse autism to show there has been sufficient historical continuity to avoid the pessimistic meta induction. Chapter two considers arguments from underdetermination. I consider the strongest candidate for an alternative to autism, classificatory changes which occurred between 1980 and 1985. I argue this does not constitute underdetermination because those changes were methodologically and evidentially flawed. Chapter three considers theory-ladenness. I consider the two strongest candidates for background theories which might have a negative epistemic effect (cognitive psychology and psychoanalysis). I show these have little influence on what symptoms are formulated or how symptoms are grouped together. Chapter four argues against psychiatric classifications as natural kinds and against notions that inductive knowledge of psychiatric classifications requires robust causes. I outline psychiatric classifications as scientific laws. They are high level idealised models which guide construction of lower level, more specific, models. This opens alternative routes to belief for psychiatric classification lacking robust causes. Chapter five shows that psychiatric classifications can set relevant populations for deriving statistically significant symptoms. The same behaviour can count as statistically significant for one psychiatric classification but not another. I argue this process strengthens psychiatric classifications inductively, thus contributing to belief. Chapter six bases belief on theoretical virtues. Unifications and causation are the two main theoretical virtues. Autism strongly exhibits unifications, stringently covering a wide range of otherwise unrelated symptoms. Additionally, emphasising causation may reduce unifications and thus reduce belief. Attributing unifications is reliable because autism is accessible without employing extremely complicated experimental processes and relies upon secure background theories.

This study was conducted by conceptualising, designing and implementing new knowledge at the forefront of body image inflexibility (a construct derived from Acceptance and Commitment Therapy (ACT)) and disordered eating. The study design was adjusted in the light of emergent issues and understandings. The thesis involved a review of the literature which investigated disordered eating and the factors known to influence disordered eating such as body image inflexibility. A critical understanding of the current state of knowledge in this field of theory and practice has been provided. Overall the literature review suggested that body image inflexibility is an important factor to examine when investigating the predictors of disordered eating behaviours. The current study involved the creation and interpretation of new knowledge through original research and advanced scholarship by using a quantitative online survey and latent structural equation modelling (SEM) to test an adapted version of the Tripartite Influence Model with the inclusion of body image inflexibility with 378 adult women. In the method, the range of study design methods and statistical analyses that were considered for this study were outlined. A rationale was provided for the chosen study design and statistical analysis, in order to demonstrate a critical understanding of the methodology of enquiry. The results identified that body image inflexibility represented a single pathway which fully mediated the relationship between women’s body image and their engagement in disordered eating behaviours. Body image inflexibility also fully mediated the relationships between internalisation of the thin ideal and disordered eating and between friend pressure and disordered eating. Perceived pressure to be thin from friends, partners, 15 family and the media also had distinct relationships in the model. Perceived pressure from friends was significantly related to body image inflexibility. Both pressure from partners and pressure from the media had direct relationships with internalisation of the thin ideal and also with disordered eating behaviours. Pressure from family had a direct relationship with body image. Internalisation of the thin ideal and body image had significant mediational roles in the model. Internalisation of the thin ideal fully mediated the relationship from partner pressure to body image inflexibility, from media pressure to body image inflexibility and from partner pressure to body image. Internalisation of the thin ideal partially mediated the relationship between media pressure and body image. Body image fully mediated the relationships between media pressure and body image inflexibility, and between family pressure and body image inflexibility. Body image partially mediated the relationship between internalisation of the thin ideal and body image inflexibility. The results have highlighted the importance of including body image inflexibility as a mediating variable in theoretical models of disordered eating and as a psychological construct to target in treatment interventions for disordered eating. In the discussion, an independent judgement of issues and ideas within the field of disordered eating and psychological flexibility research and practice was provided. Finally a critical reflection on the current study and its strengths and weaknesses was then outlined.

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The importance of the “therapeutic relationship” in the process of therapeutic change has long been recognised in psychotherapy literature and in recent years has also been evidenced in empirical research. Using a social constructionist framework, this study considers relationships formed in a therapeutic intervention for children and young people affected by child sexual abuse. The intervention is based primarily on a psychodynamic model of recovery informed by trauma, attachment and resilience theories. Based on interviews with six children and young people, seven carers and thirteen practitioners, the thesis explores the individual perspectives of children and young people, their carers and practitioners involved in the intervention. In addition, data collected during the evaluation of the intervention from 85 completed Carer Feedback Questionnaires and 148 responses on the Therapeutic Alliance Scale for Children (Shirk and Saiz, 1992) is presented. Perceptions of change within the therapeutic relationship are explored, including participants’ recollections of conversations and events. The thesis examines how children, young people and carers made connections with practitioners, agreed therapeutic goals and activities within the relationship and how they transferred activities and learning beyond the therapy into their everyday spaces. Major themes discussed are confidentiality, trust, safety, choice, power, non-judgemental attitudes and hope for the future. An unanticipated but connected theme links maternal responses to social constructions of “bad” mothers, and highlights the importance for parents of feelings of safety and trust in the practitioner-parent relationship following child sexual abuse. The findings demonstrate the importance for service users of sharing a relational space, and provide insight into the relational processes in therapeutic work with young people and their parents.

The relationship between emotion dysregulation and Generalised Anxiety Disorder (GAD) has been demonstrated in research for the past ten years, with the positing of the Emotion Dysregulation Model of GAD (Mennin et al., 2005). The role of resilience in buffering against mood disorders has also been investigated and resilience training has been successfully utilised as an adjunct to therapy for GAD (Fava et al., 2004). This research considers whether resilience mediates between emotion dysregulation and GAD. One hundred and eighty seven participants were recruited from online social media platforms and self-help forums and completed online questionnaires. These questionnaires included a measure of resilience, two measures of emotion regulation, a measure of worry, a measure of GAD symptoms, a depression measure and brief demographic questions. Participants were split into high and low GAD symptoms groups dependent on their score on the Generalised Anxiety Disorder-7 item questionnaire using a cut-off of 10 (Spitzer, Kroenke, William & Lowe, 2006). The results showed that participants in the high GAD symptoms group had significantly higher emotion dysregulation scores, lower resilience scores and were less likely to engage in adaptive emotion regulation strategies. Emotion dysregulation was also found to be a significant predictor of GAD symptoms. Resilience was not found to be a mediator between emotion dysregulation and GAD, however the relationship between emotion dysregulation and worry was partially mediated by resilience. This highlights potentially different mechanisms behind the pervasive worry experienced by those with GAD and GAD symptoms in general. This has important implications for future research and clinical interventions for GAD.

Aphasia is a communication disorder affecting all language modalities to varying degrees of severity, and impacting on the person’s overall quality of life, place in society and interpersonal relationships. Early post-stroke, healthcare professionals (HCPs) are often the main communication partners of people with aphasia (PWA), yet there are apparently few opportunities for communication practice in the course of rehabilitation. Practice is key to (re)learning, with other processes such as intensity, context, and the therapeutic alliance also shown to impact on outcomes of (re)learning. Currently, PWA in the UK receive stroke rehabilitation in a variety of care settings. Rehabilitation in the home through Early Supported Discharge (ESD) is the focus of this study. A systematic review using adapted Cochrane methodology examined how learning processes are reported in speech and language therapies for post-stroke aphasia with a functional outcome. The 34 included studies were reported with variable degrees of adherence to the Template for Intervention Description and Replication (TIDieR) checklist. More specific and comprehensive articulation of the learning processes entailed in rehabilitation and (re)learning is needed in such aphasia therapies. An exploratory study was conducted to understand how conditions for (re)learning are produced during routine rehabilitation for PWA in the ESD context. Observational and interview methods were used to collect data on perceptions and practices of routine rehabilitation with 10 PWA and 22 HCPs (observation study) and 9 PWA and 8 HCPs (interview study). Interview data were analysed using thematic analysis; observational data explored the structure and ecology of the rehabilitation session and how the interview themes were enacted in interactions. Interview and observation data were analysed and combined within an Activity-based Communication Analysis (ACA) approach. Opportunities to enhance (re)learning of functional communication during routine rehabilitation were identified, but not consistently realised. The home environment, rapport, emotions, the structure of sessions and HCP training all influence PWA’s (re)learning. These findings have clinical implications and warrant further research.

Using data from the China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE) Consortium study of major depressive disorder (MDD)on 11,670 Han Chinese women, this thesis describes an investigation on the etiology of MDD, a psychiatric disease that has eluded previous genetic studies as well as investigations of its mechanistic underpinnings. It asks: what happens during stress, how may it contribute to the risk of developing MDD, and why does it increase the risk of MDD in some people but not others. It presents three main findings. First, a GWAS on MDD conducted on 10,640 samples (5,303 cases and 5,337 controls) in the CONVERGE dataset found two genome wide significant associations with MDD, one lying at the 5' side of SIRT1, and the other in an intron of LHPP. Both signals have been replicated in a completely independent cohort of severe MDD cases and matched controls from Northern China, making them the first replicated association loci for MDD to date. Second, I found there are more copies of mtDNA in cases of MDD than controls and while the increase can be induced by stress, it is contingent on the depressed state. Further analyses of results from animal experiments showed stress increases mtDNA levels in a dose-dependent, reversible and tissue specific way that is mediated partly by stress steroids. Third, the total amount of heteroplasmy was found to increase with increasing mtDNA levels, and therefore is higher in cases of MDD than controls, consistent with a change in mitochondrial function observed in animal models of chronic stress. All three findings suggest stress causes changes in mtDNA, and this change may be larger in cases of MDD than controls. This difference between cases and controls may be due to differences in their regulation of mtDNA levels and sequence mutation during stress, and this may be genetically determined. This study provides a new perspective to the etiology of depression, suggesting it may have origins in metabolic regulation.

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