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Haffertyjd 2021.Pdf (5.674Mb) This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Quantifying Psychotropic Treatment and Illness Outcome in Cohort Studies using Record-Linkage to Administrative Health Data Jonathan D. Hafferty MA(Oxon), BA(Hons), BMBCh, MRCPsych Submitted for the degree of Doctor of Philosophy University of Edinburgh 2019 1 This thesis has been submitted in fulfilment of the requirements for the postgraduate degree of Doctor of Philosophy (PhD) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author Jonathan D. Hafferty, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Division of Psychiatry Kennedy Tower Royal Edinburgh Hospital Morningside Edinburgh EH10 5 HF 2 Dedicated to my father Michael T. Hafferty 3 Abstract The advent of powerful information technology and the increasing availability of so- called ‘Big Data’, in a multitude of forms, has had revolutionary impact on many aspects of society, such as commerce and communication. Within healthcare broadly and mental health research specifically, however, the progress of these techniques is considered relatively nascent. This is paradoxical, as the complexity and multi- factorial nature of mental health conditions, such as major depression and self-harm, makes them particularly tractable for more sophisticated data-driven approaches. In this thesis I will apply the transformative potential of data science applications related to record-linkage for mental health research. I will demonstrate that record- linkage of cohort studies to administrative health data enables: (i) improved signal and power for discoveries and the reduction of false associations (ii) validation of research data and the identification of inaccuracies (iii) transformation of cross-sectional studies into longitudinal studies; and (iv) identification of new phenotypes for study. Chapters 1, 2 and 3 provide an introductory overview. In Chapter 1, I will survey the current state of psychiatric research in major depressive disorder (MDD), antidepressant pharmacoepidemiology, self-harm and suicidal ideation. These inter- related aspects of mental illness are common, highly complex and place a high burden on society. They are thus particularly appropriate for the research methods I shall employ herein. In Chapter 2 I will discuss the evolution of data sciences approaches within psychiatry, and specifically of record-linkage techniques and their 4 application in medical epidemiology. In Chapter 3 I will also review the demographics and characteristics of the datasets used in this thesis, namely Generation Scotland (GS:SFHS), UK Biobank (UKB), the Scottish Morbidity Records (SMR) and the Prescribing Information System (PIS) of NHS Scotland. Chapter 4 demonstrates the application of record-linkage to administrative health data for validation in psychiatric research. Using national prescribing data in PIS as the ‘gold standard’, I compare the accuracy of GS:SFHS cohort self-reported psychiatric drug use, which is often thought to be relatively under-reported for reasons such as self-stigma, compared to other commonly prescribed medications. Our study finds that under-reporting is not found for all psychiatric medications, indeed antidepressants show very good agreement between self-report and prescribing data (k=0.85,(95% Confidence Interval(CI)0.84-0.87)), similar to antihypertensives (k=0.90, (CI 0.89-0.91)) which are another commonly prescribed medicine. However, for mood stabilizers the agreement is relatively poor (k=0.42, CI 0.33-0.50). A number of medication-related and patient-level factors are analysed, with relevant past medical history being the strongest predictor of self-report sensitivity. By contrast, general intelligence is not found to be predictive. The chapter concludes that there is no simple relationship between psychiatric medication use and medication under- reporting. In addition, that no patient-level factor produces greater accuracy of self- report across all medications studied, although history of indicated illness – where this could be defined - predicted more accurate self-report. In Chapter 5 the potential of record-linkage to transform cross-sectional research studies into longitudinal studies, is investigated using the problem of quantifying antidepressant prevalence. antidepressants are the most commonly prescribed 5 psychiatric medication, but concerns have been raised about significant increases in their usage. By linking PIS prescribing data with the phenotypic data in a subset of GS:SFHS, the study is able to determine new measures of antidepressant prevalence, incidence, adherence, prescribing patterns with other medications, and patient-level predictors of usage. an antidepressant prevalence of almost one third of the cohort (28%, 95% CI 26.9-29.1), defined as dispensing of at least one PIS antidepressant prescription in the five-year period 2012-16, is described. This is a 36.2% increase in annual prevalence between 2010 and 2016. Incidence is calculated as 2.4(2.1-2.7)% per year, which is not significantly changed from previous estimates. The majority of antidepressant episodes (57.6%) are found to be greater than 9 months duration and adherence, using the Proportion of Days Covered (PDC) measure, is found to be generally high(69%). In time-to-antidepressant-use Cox regression analysis of the 5 years following individual GS:SFHS enrolment, predictors of new antidepressant use included: history of affective disorder; being female; physical comorbidities; higher neuroticism scores; and lower cognitive function scores. The chapter finds that this research supports the hypothesis that increased long-term use among existing (and returning) users, along with wider range of indications of antidepressants, has significantly increased the prevalence of these medications. In Chapter 6 the potential of record-linkage to identify new phenotypes for study within psychiatric cohorts is examined using the example of self-harm. Self-harm is a common and debilitating behaviour but often difficult to research as there may be unwillingness in sufferers to disclose. Using record-linkage to hospital morbidity data(SMR), I identified individuals with hospital-treated self-harm in GS:SFHS and compared these to a replication cohort drawn from UK Biobank, with self-reported 6 hospital-treated self-harm. I further demonstrated that neuroticism, a stable personality trait associated with depression, is independently positively associated with self-harm (per Eysenck Personality Questionnaire Short-Form(EPQ-SF) unit Odds Ratio 1.2 95% Credible Interval 1.1-1.2, PFDR <0.001), even when adjusted for a range of relevant covariates. I further replicated this finding in UK Biobank (per EPQ-SF unit Odds Ratio 1.1, 1.1-1.2, pFDR <0.001). In a follow-up recontact study of GS:SFHS, STRaDL, where self-reported suicidal ideation was recorded, I find that neuroticism, and the neuroticism-correlated coping style, emotion-oriented coping (EoC), were also associated with suicidal ideation in multivariable models. Therefore the chapter concludes that neuroticism is an independent predictor of hospital-treated self-harm risk, and is therefore independent of major depressive disorder in this respect, and is also (along with emotion-oriented coping), an independent predictor of suicidal ideation. Chapter 7 summarises the empirical findings presented in Chapters 4 to 6. The Chapter will also recapitulate the strengths and limitations of the record-linkage approaches used in this thesis. Finally, suggestions for future research avenues for record-linkage studies using psychiatric cohorts, and psychiatric data science as an evolving field, are discussed. 7 Lay Summary We know that modern computer technology has changed many aspects of how we work, learn, communicate and trade. It also has enormous potential to improve how we understand our health, in particular research into the complex world of our mental health (how we think, feel, behave and relate to each other). We have learned a lot from previous studies of mental health, which often involve recruiting large groups of volunteers followed by collecting detailed
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