The aim of this thesis is to investigate the relationship between individuals and society in the context of healthcare and medical research, more specifically concerning the rights and duties of individuals in regard to biobank-based research. My starting point is that we all have a strong vested interest in improved healthcare, and therefore the possibilities to conduct important research should be optimized. In the first article, I investigate whether individual results from research using samples in large-scale biobanks should be returned. I conclude that there is good reason not to implement such policies, and instead to allocate available resources to pursuing medical advances. In the second article, I compare consent for using stored samples in research with consent for organ donation, whereby many countries have adopted opt-out strategies in order to increase the number of organs available. I claim that the default position should be changed in biobank research as well, i.e. it should be presumed that individuals want to contribute rather than that they do not. In the third article, I argue that safeguarding autonomy by requiring informed consent for using samples in research not only defeats the interests of society but also runs counter to the interests of the individuals the policy purports to protect. Finally, in the fourth article I suggest that it is reasonable to view participation in medical research from the perspective of a social contract, built on our mutual need for medical advances, and that this implies that there is a moral duty to adhere to the contract by allowing one’s samples to be used in research. A central conclusion in this thesis is that biobank research should be viewed as a natural part of healthcare, like quality control, method development and teaching, and that as such, it ought to be endorsed and facilitated.

Zugl.: Rostock, University, Diss., 2006.

Yes / Cross-sectional and longitudinal studies have consistently reported an association between education and myopia. However, conventional observational studies are at risk of bias due to confounding by factors such as socioeconomic position and parental educational attainment. The current study aimed to estimate the causal effect of education on refractive error using regression discontinuity analysis. Methods: Regression discontinuity analysis was applied to assess the influence on refractive error of the raising of the school leaving age (ROSLA) from 15 to 16 years introduced in England and Wales in 1972. For comparison, a conventional ordinary least squares (OLS) analysis was performed. The analysis sample comprised 21,548 UK Biobank participants born in a nine-year interval centered on September 1957, the date of birth of those first affected by ROSLA. Results: In OLS analysis, the ROSLA 1972 reform was associated with a −0.29 D (95% confidence interval [CI]: −0.36 to −0.21, P < 0.001) more negative refractive error. In other words, the refractive error of the study sample became more negative by −0.29 D during the transition from a minimum school leaving age of 15 to 16 years of age. Regression discontinuity analysis estimated the causal effect of the ROSLA 1972 reform on refractive error as −0.77 D (95% CI: −1.53 to −0.02, P = 0.04). Conclusions: Additional compulsory schooling due to the ROSLA 1972 reform was associated with a more negative refractive error, providing additional support for a causal relationship between education and myopia. / Global Education program of the Russian Federation government (DP) and an NIHR Senior Research Fellowship award SRF-2015-08-005 (CW), The Department for Health through an award made by the NIHR to the Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, and UCL Institute of Ophthalmology, London, United Kingdom (grant no. BRC2_009). Additional support was provided by The Special Trustees of Moorfields Eye Hospital, London, United Kingdom (grant no. ST 12 09)

Background: Community acquired pneumonia (CAP) is a high incidence disease resulting in about 260,000 hospital admissions per year in Germany, more than myocardial infarction or stroke. Worldwide, CAP is the most frequent infectious disease with high lethality ranging from 1.2 % in those 20–29 years old to over 10 % in patients older than 70 years, even in industrial nations. CAP poses numerous medical challenges, which the PROGRESS (Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) network aims to tackle: Operationalization of disease severity throughout the course of disease, outcome prediction for hospitalized patients and prediction of transitions from uncomplicated CAP to severe CAP, and finally, to CAP with sepsis and organ failure as a life-threatening condition. It is a major aim of PROGRESS to understand and predict patient heterogeneity regarding outcome in the hospital and to develop novel treatment concepts. Methods: PROGRESS was designed as a clinical, observational, multi-center study of patients with CAP requiring hospitalization. More than 1600 patients selected for low burden of co-morbidities have been enrolled, aiming at a total of 3000. Course of disease, along with therapy, was closely monitored by daily assessments and long-term follow-up. Daily blood samples allow in depth molecular-genetic characterization of patients. We established a well-organized workflow for sample logistics and a comprehensive data management system to collect and manage data from more than 50 study centers in Germany and Austria. Samples are stored in a central biobank and clinical data are stored in a central data base which also integrates all data from molecular assessments. Discussion: With the PROGRESS study, we established a comprehensive data base of high quality clinical and molecular data allowing investigation of pressing research questions regarding CAP. In-depth molecular characterization will contribute to the discovery of disease mechanisms and establishment of diagnostic and predictive biomarkers. A strength of PROGRESS is the focus on younger patients with low burden of co-morbidities, allowing a more direct look at host biology with less confounding. As a resulting limitation, insights from PROGRESS will require validation in representative patient cohorts to assess clinical utility. Trial registration: The PROGRESS study was retrospectively registered on May 24th, 2016 with ClinicalTrials.gov: NCT02782013

none

Pancreatic islet beta cell failure causes type 2 diabetes in humans. To identify transcriptomic changes in type 2 diabetic islets, the Innovative Medicines Initiative for Diabetes: Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in Diabetes (IMIDIA) consortium (www.imidia.org) established a comprehensive, unique multicentre biobank of human islets and pancreas tissues from organ donors and metabolically phenotyped pancreatectomised patients (PPP).

Background: Age-standardised mortality rates for cardiovascular disease (CVD) are generally higher among men than women, prompting suggestions that reproductive factors may be partly responsible. Moreover, there have been major changes in women’s reproductive patterns and CVD rates in China over the last few decades, but the association between them is still poorly understood. Objectives: To start addressing these issues, this thesis examines the secular trends and correlates of age at menarche and menopause (the major physiological events defining a woman’s reproductive window), as well as their association with blood pressure and anthropometry in 302,180 women born in 1930-74 from 10 areas across China using cross-sectional demographic, behavioural, physical and reproductive data from the China Kadoorie Biobank. Results: Mean age at menarche decreased by 2 years over a 44-year period (1930-1974), with the exception of an increase of about 1 year for women exposed to the Great Chinese Famine in early adolescence. No other factor showed as large an effect on age at menarche. Among women aged >57 years at the baseline, mean age at menopause increased by 1.4 years over a 21-year period (1930-1951) and was significantly associated with several reproductive and behavioural factors, notably gravidity (2 years later menopause) and smoking (6 months earlier menopause). Blood pressure and anthropometry were weakly inversely associated with age at menarche (0.2mmHg and 0.2kg/m² lower per year later menarche) and even more weakly positively associated with age at menopause (0.06mmHg and 0.04kg/m² higher per year later menopause). These trends and associations all varied to some extent by area and socioeconomic status. (All p-values <0.0001) Conclusion: This study adds new information on the secular trends and correlates of age at menarche and menopause in a large Chinese population born around the mid-20th century and provides a basis for further prospective work on the association of reproductive history with the incidence of CVD in China.

Introduction Vitamin D status is an important public health issue due to the high prevalence of vitamin D insufficiency and deficiency, especially in high latitude areas. Furthermore, it has been reported to be associated with a number of diseases. In a previous umbrella review of meta-analyses of randomized clinical trials (RCTs) and of observational studies, it was found that plasma/ serum 25-hydroxyvitamin D (25(OH)D) or supplemental vitamin D has been linked to more than 130 unique health outcomes. However, the majority of the studies yielded conflicting results and no association was convincing. Aim and Objectives The aim of my PhD was to comprehensively explore the association between vitamin D and multiple outcomes. The specific objectives were to: 1) update the umbrella review of meta-analysis of observational studies or randomized controlled trials on associations between vitamin D and health outcomes published between 2014 and 2018; 2) conduct a systematic literature review of previous Mendelian Randomization studies on causal associations between vitamin D and all outcomes; 3) conduct a systematic literature review of published phenome wide association studies, summarizing the methods, results and predictors; 4) create a polygenic risk score of vitamin D related genetic variants, weighted by their effect estimates from the most recent genome wide association study; 5) encode phenotype groups based on electronic medical records of participants; 6) study the associations between vitamin D related SNPs and the whole spectrum of health outcomes, defined by electronic medical records utilising the UK Biobank study; 7) explore the causal effect of 25- hydroxyvitamin D level on health outcomes by applying novel instrumental variable methods. Methods First I updated the vitamin D umbrella review published in 2015, by summarizing the evidence from meta-analyses of observational studies and meta-analyses of RCTs published between 2014 and 2018. I also performed a systematic literature review of all previous Mendelian Randomizations studies on the effect of vitamin D on all health outcomes, as well as a systematic review of all published PheWAS studies and the methodology they applied. Then I conducted original data analysis in a large prospective population-based cohort, the UK Biobank, which includes more than 500,000 participants. A 25(OH)D genetic risk score (weighted sum score of 6 serum 25(OH)D-related SNPs: rs3755967, rs12785878, rs10741657, rs17216707, rs10745742 and rs8018720, as identified by the largest genome wide association study of 25(OH)D levels) was constructed to be used as the instrumental variable. I used a phenotyping algorithm to code the electronic medical records (EMR) of UK Biobank participants into 1853 distinct disease categories and I then ran the PheWAS analysis to test the associations between the 25(OH)D genetic risk score and 950 disease outcome groups (i.e. outcomes with more than 200 cases). For phenotypes found to show a statistically significant association with 25(OH)D levels in the PheWAS or phenotypes which were found to be convincing or highly suggestive in previous studies, I developed an extended case definition by incorporating self-reported data collected by UK Biobank baseline questionnaire and interview. The possible causal effect of vitamin D on those outcomes was then explored by the MR two-stage method, inverse variance weighted MR and Egger's regression, followed by sensitivity analyses. Results In the updated systematic literature review of meta-analyses of observational studies or RCTs, only studies on new outcomes which had not been covered by the previous umbrella review were included. A total of 95 meta-analyses met the inclusion criteria. Among the included studies there were 66 meta-analyses of observational studies, and 29 meta-analyses of RCTs. Eighty-five new outcomes were explored by meta-analyses of observational studies, and 59 new outcomes were covered by meta-analyses of RCTs. In the systematic review of published Mendelian Randomization studies on vitamin D, a total of 29 studies were included. A causal role of 25(OH)D level was supported by MR analysis for the following outcomes: type 2 diabetes, total adiponectin, diastolic blood pressure, risk of hypertension, multiple sclerosis, Alzheimer's disease, all-cause mortality, cancer mortality, mortality excluding cancer and cardiovascular events, ovarian cancer, HDL-cholesterol, triglycerides and cognitive functions. For the systematic literature review of published PheWAS studies and their methodology, a total of 45 studies were included. The processes for implementing a PheWAS study include the following steps: sample selection, predictor selection, phenotyping, statistical analysis and result interpretation. One of the main challenges is the definitions of the phenotypes (i.e., the method of binning participants into different phenotype groups). In the phenotyping step, an ICD curated phenotyping was widely used by previous PheWAS, which I also used in my own analysis. By applying the ICD curated phenotyping, 1853 phenotype groups were defined in the participants I used. In PheWAS, only phenotype groups with more than 200 cases were analysed (920 phenotypes). In the PheWAS, only associations between rs17216707 (CYP24A1) and "calculus of ureter" (beta = -0.219, se = 0.045, P = 1.14*10-6), "urinary calculus" (beta = -0.129, se = 0.027, P = 1.31*10-6), "alveolar and parietoalveolar pneumonopathy" (beta = 0.418, se = 0.101, P = 3.53*10-5) survived Bonferroni correction. Nine outcomes, including systolic blood pressure, diastolic blood pressure, body mass index, risk of hypertension, type 2 diabetes, ischemic heart disease, depression, non-vertebral fracture and all-cause mortality were explored in MR analyses. The MR analysis had more than 80% power for detecting a true odds ratio of 1.2 or larger for binary outcomes. None of explored outcomes were statistically significant. Results from multiple MR methods and sensitivity analyses were consistent. Discussion Vitamin D and its association with multiple outcomes has been widely studied. More than 230 outcomes have been linked with vitamin D by meta-analyses of observational studies and RCTs. On the contrary, evidence from Mendelian Randomization studies is lacking. In particular I identified only 20 existing MR studies and only 13 outcomes were suggested to be causally related to vitamin D. In the systematic literature review of previous PheWAS studies, I summarized the applied methods, predictors and results. Although phenotyping based on ICD codes provided good performance and was widely applied by previous PheWAS studies, phenotyping can be improved if lab data, imaging data and medical notes can be incorporated. Alternative algorithms, which takes advantage of deep learning and thus enable high precision phenotyping, needs to be developed. From the PheWAS analysis, the score of vitamin D related genetic variants was not statistically significantly associated with any of the 920 phenotypes tested. In the single variant analysis, only rs17216707 (CYP24A1) was shown to be associated with calculus outcomes statistically significantly. Previous studies reported associations between vitamin D and hypercalcemia, hypercalciuria, nephrolithiasis and nephrocalcinosis, may be due to the role of vitamin D in calcium homeostasis. In the MR analysis, I found no evidence of large to moderate (OR > 1.2) causal associations of vitamin D on a very wide range of health outcomes. These included SBP, DBP, hypertension, T2D, IHD, BMI, depression, non-vertebral fracture and allcause mortality which have previously been proposed to be influenced by low vitamin D levels. Further, even larger studies, probably involving the joint analysis of data from several large biobanks with future IVs that explain a higher proportion of the trait variance, will be required to exclude smaller causal effects which could have public health importance because of the high population prevalence of low vitamin D levels in some populations.

Submitted by Priscilla Araujo (priscilla@ibict.br) on 2016-10-10T17:10:18Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) RODRIGO PORTO BOZZETTI mestrado 2016.pdf: 883197 bytes, checksum: 050ebfc1523b4008448c5a32d7a953cc (MD5) / Made available in DSpace on 2016-10-10T17:10:18Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) RODRIGO PORTO BOZZETTI mestrado 2016.pdf: 883197 bytes, checksum: 050ebfc1523b4008448c5a32d7a953cc (MD5) Previous issue date: 2016-04-29 / Investiga as dimensões informacionais e documentais dos dispositivos infocomunicacionais biobancos. Apresenta breve histórico sobre os processos de formação da genética como um campo de estudos. Realiza uma apresentação do conceito de biobanco demonstrando os propósitos e principais atividades realizadas. Discute sobre Eugenia e sobre potenciais usos sensíveis de informações genéticas. Discute o conceito de documento, tendo por base os trabalhos de Otlet, Briet, Meyriat, Frohmann entre outros autores da Ciência da Informação, no intuito de defender que amostras biológicas de seres humanos podem ser consideradas como documentos. Discute o conceito de dispositivo infocomunicacional na Ciência da Informação. Aponta o UK Biobank como unidade de análise para se estudar os biobancos a nível mundial e investiga o funcionamento, a estrutura, os documentos e os mecanismos de proteção de informações sigilosas desse biobanco tendo por principal fonte de informação o seu portal. Apresenta os biobancos como dispositivos que tem o potencial de classificar e criar taxonomias de seres humanos, potencializando a capacidade de gerar problemas de cunho ético aos envolvidos nas pesquisas. / Investigates the informational and documentary dimensions of infocommunicative devices biobanks. Presents brief history about the genetics as a field of study. Performs a presentation of the concept of biobank demonstrating the purpose and main activities. Discusses Eugenics and potential sesitive uses of genetic information. Discusses the concept of document, based on the work of Otlet, Briet, Meyriat, Frohmann among other authors of Information Science, in order to argue that biological samples from humans can be considered as documents. Discusses the concept of infocomunicacional device in Information Science. Pointing UK Biobank as units of analysis to study biobanks worldwide and investigates the operation, structure, documents and mechanisms of protection of sensitive information of this biobank usings it’s website as main source of information. It presents biobanks as devices that have the potential to classify and create taxonomies of humans, increasing the capacity to generate ethical problems to the people involved in the research.

UK Biobank is a British clinical study containing over 40 000 Magnetic Resonance Images (MRI) with 100 000 MRI planned of participants aged 44-82 as well as a large amount of related medical data. Analyzing these images with a neural network to find relations between the information in an MRI image and various medical data could lead to interesting medical revelations. While other studies usually focus on improving the network architecture, we instead propose a method to get targeted information out of full body MRI images. This is done by sampling various sub-volumes of the full body images and making a collage specifically tailored to the problem at hand before feeding them to a ResNet50 based network. The images are further analyzed using saliency analysis in order to gain information on what regions the network found important. This method was attempted on a variety of medical data including age, kidney volume, liver fat percentage, and heart volume. The method is used both as a way to increase information density in the input images as well as restricting information, such that we can see how well the network can predict about some medical data point from only some part of the body.The collages are able to increase the information in the images while the more complex representation and non-continuous representation does not cause problems for the network. These collages are also conducive to getting clearer and sharper saliency maps, which may give interesting medical information by showing what regions the network considers relevant. This may reveal otherwise difficult to notice relations between the information in the MRI images and medical information.