Thèses sur le sujet « Biobanca »

The research described in the present PhD Thesis has been conducted in the context of a multicenter FP7 European Project called THALAMOSS (THalassemia MOdular Stratification System), having as major objective the identification of molecular markers for the development of personalized therapies for hemoglobinopathies, in particular ß-thalassemia. The ß-thalassemias are an autosomal recessive genetic disorders caused by the absence or reduction of ß-globin chains of adult hemoglobin, for which targeted and definitive treatments are, at present, not available. In order to sustain project based on stratification of ß-thalassemia patients according to clinical, genetic and molecular features, we established a systematic collection of cellular samples, the cellular Biobank, containing hematopoietic stem cells isolated from the peripheral blood, expanded, freezed and cryopreserved. To this aim, 75 subjects comprising ß-thalassemia patients and healthy donors have been recruited up to now. They were all characterized for the genotype (in order to detect pathogenic mutations) and possible fetal hemoglobin (HbF)-associated polymorphisms. More importantly, new protocols to efficiently isolate, culture, freeze and thaw hematopoietic stem cells were developed. In particular, we demonstrated that freezing, cryopreservation and thawing steps do not affect the erythroid differentiation potential of the cells and the natural erythroid differentiation process, in terms of kinetics and types of hemoglobin produced by the cells of the same patient. Moreover, we found that the cells stored in the Biobank are responsive, once thawed and sub-cultured, to treatments with known HbF inducers, including mithramycin, resveratrol, butyric acid and hydroxyurea, and are therefore suitable for the identification and development of new HbF inducers to be used for experimental therapeutic strategy for ß-thalassemia. In this context, we demonstrated that the induction effects depend on the subject’s genotype, strongly suggesting that this approach could be very useful to develop personalized therapies. In conclusion, this research activity will allow patients stratification taking into account all the phenotypic/genotypic characteristics of the single individual, in association with in vitro HbF induction under treatment with effective inducers, providing an important opportunity for the research and development of novel therapeutic strategies for ß-thalassemia.

Atherosclerosis (also known as Arteriosclerotic Vascular Disease or ASVD) is the condition in which an artery wall thickens as the result of a build-up of fatty materials such as cholesterol. It is a syndrome affecting arterial blood vessels, a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of macrophage white blood cells and promoted by Low-density lipoproteins (plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high density lipoproteins (HDL). It is commonly referred to as a hardening or furring of the arteries. It is caused by the formation of multiple plaques within the arteries. Other arteriosclerotic disease is aortic aneurysm usually affecting the abdominal tract of the vessel. The prevalence of abdominal aortic aneurysm (AAA) varies ranging from 4.1% to 11.5% in European men. This disorder is characterized by localized structural deterioration of the aortic wall, leading to progressive dilatation and eventual aortic rupture. Rupture of AAA is responsible for 1.5% of the total mortality in males over 55 years of age. Both disease seem to share common causes in alteration in lipid metabolism and immune response against host and oxidised lipids, leading to a condition of chronic inflammation affecting all the vascular system, especially the big diameter arteries. There are several factors such as smoking, hypertension, hypercholesterolemia and male sex, which are well known risk factors for the development of AAA and carotid stenosis. However, better understanding of molecular mechanisms is an important step toward clarification of the pathophysiology, identification of genetic and molecular biomarkers and development of new therapeutic strategies for AAA and atherosclerosis in general. Gene expression profiling studies by microarray technologies are particularly appropriate to investigate and create working hypotheses to understand the pathophysiology of complex genetic tracts such as arteriosclerotic diseases. Previous microarray studies focused on AAA utilized RNA derived from aortic tissue samples. The use of tissue samples has several disadvantages, including the difficulty of obtaining control samples and bias introduced by use of normal specimens from non-age-matched cadavers, organ-transplant donors or patients with different diseases. Peripheral blood is a complex fluid with a high cellular turnover rate that provides physiological connectivity between tissues. Environmental or disease perturbations in the body may leave molecular signatures detectable by analyzing blood-derived RNA. Most importantly, since blood samples can be obtained readily and with little discomfort to patients, biomarkers derived from blood RNA provide an easier integration to clinical and imaging data for the diagnosis and prognosis of AAA and carotid stenosis. In this study we investigate the gene expression profile of venous whole peripheral blood obtained from AAA patients by using microarray technology to provide insight into systemic pathophysiological processes involved in this disease. Using the data obtained from the microarray analysis from which we detected 91 genes differentially expressed from patients and positive controls, we selected 10 gene belonging to pathways involved in lipid metabolism and immune response to deep our analysis and eventually confirm the microarray data in order to set up new reliable parameters for arteriosclerosis diseases diagnosis and prognosis. The genes we chosen are Lipid Metabolism: 8. Monoglyceride lipase - MGLL - U67963 - 11343 9. Free fatty acid receptor 2 - FFAR2 - AF024690 – 2867 10. Adiponectin receptor 1 - ADIPOR1 - AK001484 – 51094 11. Phospholipase A2, group IB (pancreas) - PLA2G1B - M21054 – 5319 12. Hydroxysteroid (17-beta) dehydrogenase 14 - HSD17B14 - NM_016246 3738 13. Acyl-Coenzyme A dehydrogenase, C-2 to C-3 short chain - ACADS Z80345 – 682 14. Low density lipoprotein receptor-related protein 5 - LRP5 - AF077820 - 4041 Immune system: 4. Toll-like receptor adaptor molecule 1 - TICAM1 - AF070530 - 7746 5. Interleukin 1 receptor accessory protein-like 1 - IL1RAPL1 - AJ243874 11141 6. Tumor necrosis factor type 1 receptor-associated protein - TRAP1 NM_016292 – 10131 We designed 10 couples of primers to analyze the expression levels of the genes onto 3 groups of subjects: 1. Control: N=40 2. AAA patients: N=40 3. Patients affected from carotid artery stenosis: N=40 We first analyze the expression levels of the control gene GAPDH of each subject and than we check the expression levels of the all ten genes comparing the resulting CT values with the ones gotten from the housekeeping gene. The result is the so-called ∆CT and we got these values for all the 120 subjects for everyone of the 10 genes in duplicates for a total of 1200 ∆CT values. Than we compare the average ∆CT values of the 80 patients (40 AAA + 40 carotid stenosis) with the control values to get the ∆∆CT values from which calculate the fold number (2-∆∆CT =FOLD) that provides a numeric but qualitative value of the expression level of the target gene that allow to compare the values with others present in literature. Our analysis are only semiquantitative for the moment but we first needed to check the reliability of the experimental approach. For the future studies we are going to use Taqman® probes to rise the specificity and sensitivity of the analysis, introducing a quantitative method using titolation commercial kit that allow to quantify the exact numbers of copies of an m-RNA transcript calculating the exact amount of m-RNA by substituting the CT values in a linear equation. We confirmed the microarray data and extended the results to the carotid stenosis patients. We were able to confirm the genes upregulation and hypothesise that PBMCs could be a suitable base for the detection of novel risk and prognostic indicators for the arteriosclerotic diseases. In fact our aim is to identify new easy-to-detect markers to predict the risk of developing an artery stenosis or most important, an aneurismatic lesion that is symptomless until the very late phases and whose success in treating is proportional to well-timed diagnosis. In the end seems that the right direction to look into are the metabolism of lipids and phospholipids, that are involved in eicosanoids production and degradation (via fatty acid metabolism) and cell signalling in the immune system.

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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.

Esta tesis se enfrentó al reto de resolver la cuestión sobre si los derechos de propiedad intelectual creados por los biobancos pueden gestionarse más abiertamente para garantizar la distribución equitativa del conocimiento y las mejoras de la investigación genética. Se propone fomentar que los biobancos usen licencias más abiertas en sus obras protegidas por derechos de autor, bases de datos e inventos patentados. Para facilitar la transferencia de conocimiento entre biobancos y garantizar que la investigación genética mejore, se realiza una reflexión sobre la aplicación de licencias abiertas. La tesis describe el modelo de intercambio colectivo y apoya la posibilidad de usar derechos de propiedad intelectual de forma no restrictiva. La tesis también propone el uso del consentimiento informado amplio en las actividades de los biobancos. Un consentimiento informado amplio garantizaría el equilibrio adecuado entre los derechos individuales y el derecho de los biobancos de compartir la información recogida, especialmente, porque existen incentivos para tratar la genética humana como patrimonio común. El consentimiento abierto puede usarse en las actividades del biobanco para garantizar que los tejidos no permanecen sin uso. Este tipo de consentimiento puede asegurar el máximo valor de los tejidos biológicos recogidos. Si las muestras recogidas no están restringidas a un solo uso o a una sola investigación, podemos esperar que otros estudios lleven a cabo investigaciones sobre las mismas muestras y se presente información científica más amplia y relevante.
This thesis faced the challenge of answering the question if intellectual property rights that are created by the biobanks can be managed more openly to ensure the equitable distribution of knowledge and improvements of the genetic research. The proposal is made to encourage the biobanks to use more broadly open licenses in their copyrighted works, databases and patented inventions. To ease the transfer of knowledge between biobanks and ensure that the genetic research is improving, the reflection to apply open licenses is made. The thesis describes the open sharing model and supports the possibilities to use IP rights in a non-restricting way. The thesis also proposes to use broad informed consent in the biobanks’ activities. Broad informed consent would ensure the right balance between individual rights and biobanks’ need to share collected information, especially, because there are incentives to treat human genetics as a common good. Open consent can be used in the biobank’s activities to ensure that the tissues are not left unutilised. Such form of consent can assure the maximum value of the collected biological tissues. If collected samples are not restricted to the one-time or one-research use, we can expect that other studies perform research on the same samples and the broader scientific information is presented.

Durant la segona meitat del segle passat es van estabilitzar algunes tecnologies i maneres de pensar i generar coneixement entorn del que s’ha vingut a denominar biomedicina, la medicina biologicista posterior a la Segona Guerra Mundial. La criopreservació en glicerol, el desenvolupament de maquinària per a la producció de baixes temperatures, l’estandardització de les anàlisis biològiques, la tècnica PCR o la seqüenciació del genoma humà han estat alguns dels esdeveniments que han propiciat l’auge de les ciències “ómicas” i la molecularització de la vida. Els biobancs, un tipus de biorepositori amb mostres i dades associades d’origen humà, que són l’objecte principal d’aquesta tesi, van començar a establir-se formalment a diferents països al final del segle passat i inici del present mil·lenni. S’estableixen així en un moment en el qual la genòmica havia posat sota escrutini la recerca biomolecular i la ciència en general, donant pas a la problematització i formalització del camp de la bioètica. És en aquest context quan a la fi dels anys 90 els biobancs, són presentats com les condicions de possibilitat per a la medicina i recerca biomèdica esdevenidora, per a la producció de coneixement, tractaments i fàrmacs. A diferència d’altres bancs de mostres biològiques d’origen humà que tenen fins terapèutics o reproductius, el que caracteritza als biobancs són els “fins de recerca biomèdica”. Els biobancs són així un tipus de biorepositori que recull, processa, conserva (majoritàriament a baixa temperatura) i distribueixen mostres biològiques d’origen humà i dades associades amb finalitats de recerca biomèdica. L’objectiu general d’aquesta tesi doctoral és analitzar els biobancs en el context de la biomedicina contemporània, un objectiu que em permet explorar de què està feta (parcialment) la biomedicina. Per a estudiar els biobancs m’he servit dels abordatges analítics, conceptuals i metodològics dels estudis en ciència i tecnologia (STS) i l’antropologia. Es tracta d’una recerca qualitativa (anàlisi documental, treball de camp multisituat i un estudi de cas etnogràfic) on l’abordatge empíric se centra en les perspectives i la quotidianitat del personal que treballa en els biobancs. Al llarg de la tesi he analitzat quina és la posada en escena dels biobancs, tant pel que fa a les polítiques científiques europees en matèria d’infraestructures per a la recerca i la normativa de l’estat espanyol, com per part del personal que treballa en ells. Amb l’estudi dels biobancs indago “problemes antropològics”, els quals tenen a veure amb l’existència humana com a productora de coneixement, intervenció tecnològica i problematitzacions eticopolítiques (Collier and Ong, 2008). Els biobancs són presentats a les polítiques científiques com a infraestructures imprescindibles per a la recerca biomèdica i les seves projeccions futuristes a les polítiques científiques. Aquesta tesi problematitza aquesta lectura a través del seu estudi qualitatiu i adoptant un abordatge criopolític. Mitjançant l’anàlisi qualitatiu aporto una redefinició densa de què és/fa un biobanc, la qual cosa ens condueix a preguntar-nos què estan deixant de ser i fer, cap a on transiten i amb ells la coproducció d’un coneixement biomèdic particular. En aquesta recerca analitzo com la condició de mediadors converteix als biobancs en infraestructures oscil·lants, articulant maneres de biodisponibilitat complexes entre l’altruisme i l’emprenedoria neoliberal. Per a això, en aquesta tesi proposo un abordatge empíric que s’aproximi a les friccions que sorgeixen de la praxi bioclínica i que indagui com ampliar el principalisme ètic per tal d’alterar la inèrcia del pensament i l’acció eticopolítica. Finalment, la tesi conclou assenyalant que les recerques qualitatives empíriques són imprescindibles per a configurar un abordatge eticopolític que tingui en compte el caràcter relacional i distribuït de la recerca biomèdica.
Durante la segunda mitad del siglo pasado se estabilizaron algunas tecnologías y formas de pensar y generar conocimiento en torno a lo que se ha venido a denominar biomedicina, la medicina biologicista posterior a la Segunda Guerra Mundial. La criopreservación en glicerol, el desarrollo de maquinaria para la producción de bajas temperaturas, la estandarización de los análisis biológicos, la técnica PCR o la secuenciación del genoma humano han sido algunos de los acontecimientos que han propiciado el auge de las ciencias ómicas y la molecularización de la vida. Los biobancos, un tipo de biorepositorio con muestras y datos asociados de origen humano, que son el objeto principal de esta tesis, comenzaron a establecerse formalmente a lo largo del globo a finales del siglo pasado comienzo del presente milenio. Se establecen así en un momento en el que la genómica había puesto bajo escrutinio la investigación biomolecular y la ciencia en general, dando paso a la problematización y formalización del campo de la bioética. Es en este contexto, cuando a finales de los años 90, los biobancos son presentados como las condiciones de posibilidad para la medicina e investigación biomédica venidera, para la producción de conocimiento, tratamientos y fármacos. A diferencia de otros bancos de muestras biológicas de origen humano que tienen fines terapéuticos o reproductivos, lo que caracteriza a los biobancos son sus “fines de investigación biomédica”. Los biobancos son así un tipo de biorepositorio que recoge, procesa, conserva (mayoritariamente a baja temperatura) y distribuye muestras biológicas de origen humano y datos asociados con fines de investigación biomédica. El objetivo general de la presente tesis doctoral es analizar los biobancos en el contexto de la biomedicina contemporánea, un objetivo que me permite explorar de qué está hecha (parcialmente) la biomedicina. Para estudiar los biobancos me he servido de los abordajes analíticos, conceptuales y metodológicos de los estudios en ciencia y tecnología (STS) y de la antropología social. Se trata de una investigación cualitativa (análisis documental, trabajo de campo multisituado y un estudio de caso etnográfico) donde el abordaje empírico se centra en las perspectivas y cotidianidad del personal que trabaja en los biobancos. A lo largo de la tesis he analizado cuál es la puesta en escena de los biobancos tanto en las políticas científicas europeas en materia de infraestructuras para la investigación y la normativa del estado español, como por parte del personal que trabaja en ellos. Con el estudio de los biobancos indago “problemas antropológicos”, los cuales tienen que ver con la existencia humana como productora de conocimiento, intervención tecnológica y problematizaciones ético-políticas (Collier and Ong, 2008). Los biobancos son presentados como infraestructuras imprescindibles para la investigación biomédica y sus proyecciones futuristas. Esta tesis complejiza dicha lectura a través de su estudio cualitativo y adoptando un abordaje criopolítico. Mediante el análisis cualitativo aporto una redefinición densa de qué es/hace un biobanco, lo que nos lleva a preguntarnos qué están dejando de ser y hacía dónde transitan y con ellos la coproducción de un conocimiento biomédico particular. Argumento en esta investigación que la condición de mediadores convierte a los biobancos en infraestructuras oscilantes, articulando modos de biodisponibilidad complejos entre altruismo y emprendimiento neoliberal. Para ello, en esta tesis propongo un abordaje empírico que se aproxime a las fricciones que surgen de la praxis bioclínica y que indague cómo ampliar el principialismo ético y disrumpir la inercia del pensamiento y la acción ético-política. Concluyo señalando que las investigaciones cualitativas empíricas son imprescindibles para configurar un abordaje ético-político que tenga en cuenta el carácter relacional y distribuido de la investigación biomédica.
During the second half of the last century, some technologies, ways of thinking, and forms of knowledge production were stabilized around what has come to be called biomedicine, a biologicist medicine of the post-World War II era. Cryopreservation in glycerol, machinery for low-temperature manufacturing, the standardization of biological analyses, the PCR technique, and the sequencing of the human genome are some of the events that have led to the rise of the omics sciences and the molecularization of life. Biobanks, a type of biorepository with samples and associated data of human origin, which are the subject of inquiry of this thesis, began to be formally established around the world at the end of the last century and the beginning of the present millennium, along with the aforementioned events. They were born in a context in which genomics had brought biomolecular research and scientific projects under scrutiny, giving rise to the problematization and formalization of the field of bioethics. In this context, during the late 1990s biobanks started to be presented as the condition of possibility for future biomedical research and medicines, including the production of knowledge, treatments, and drugs. Unlike other banks of biological samples of human origin that have therapeutic or reproductive purposes, what characterizes biobanks are their “biomedical research purposes.” Biobanks are thus a type of biorepository that collects, processes, preserves (mainly at low temperatures), and distributes biological samples of human origin and associated data for biomedical research purposes. Overall, the main objective of this dissertation is to analyze biobanks in the context of contemporary biomedicine, which allows me to explore what biomedicine (partially) consists of. I use the analytical, conceptual, and methodological approaches of science and technology studies and anthropology to study biobanks. This research draws upon qualitative methods (documentary analysis, multi-sited fieldwork, and an ethnographic case study) and an empirical approach that revolves around biobankers’ concerns and daily work. Throughout the thesis, I have analyzed the staging of biobanks in European scientific policies on research infrastructures, Spanish state regulations, and by the staff working in them. This doctoral dissertation is a study about biobanks and the staff working in them. In this approach to biobanks, I investigate “anthropological problems”, which have to do with human existence as a producer of knowledge, technological intervention, and ethico-political problematizations (Collier and Ong, 2008). Biobanks are generally presented as essential infrastructures for biomedical research and its futuristic projections. This thesis complexifies such a reading through its qualitative study and cryopolitical approach. Through qualitative analysis, I provide a grounded redefinition of what a biobank is/does, leading us to consider what they are ceasing to be, what they are transiting into, and the accompanying co-production of particular biomedical knowledge. I argue that as mediators, biobanks are oscillating infrastructures, articulating complex modes of bioavailability between altruism and neoliberal entrepreneurship. To this end, in this thesis, I propose an empirical approach that responds to the frictions arising from bioclinical praxis and asks how to broaden ethical principlism and disrupt the inertia of ethico-political thought and action. I conclude by noting that empirical qualitative inquiries are essential to configure an ethico-political approach that accounts for the relational and distributed character of biomedical research.

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As biociências, ao tomarem o corpo humano como objeto de escrutínio e experimentação, mobilizam questões e atores que não são apenas científicos e técnicos, mas também políticos, legais e éticos. A imbricação dessas esferas parece tornar problemáticas as perspectivas que se fundamentam em dualidades, como natureza x cultura, fato x valor. Esse é o caso dos biorrepositórios e biobancos com finalidades de pesquisa, cujas práticas de manusear e colecionar material biológico humano e informações associadas para uso em pesquisas, ao tempo em que gera expectativas para o desenvolvimento da saúde e da medicina, também trazem incertezas e controvérsias sobre a natureza e destino das coleções, bem como sobre as consequências dos experimentos. É um contexto em que as práticas científicas engendram entidades que não se enquadram confortavelmente nas ontologias modernas e, mais especificamente, tornam ambíguas as fronteiras do “humano”, demandando novas regulamentações e ordenações. Assim, sob o referencial da Teoria Ator-Rede, esta tese propõe explorar as controvérsias que tomaram forma nos eventos de construção da regulamentação dos biobancos e biorrepositórios no Brasil, no período de 2009 a 2011, sob condução do Ministério da Saúde (MS) e do Conselho Nacional de Saúde (CNS) e que resultaram na publicação das Diretrizes para Análise Ética de Projetos de Pesquisas que Envolvam Armazenamento de Material Biológico Humano ou Uso de Material Armazenado em Pesquisas (Resolução CNS Nº 441/11) e nas Diretrizes Nacionais para Biorrepositórios e Biobancos com Finalidade de Pesquisa (Portaria do MS nº 2.201/ 11). Dois objetivos principais norteiam a investigação: mapear as controvérsias que envolvem a temática do armazenamento e uso de informações e material biológico humano em pesquisa e apreender a tessitura híbrida que conformaram normas e padrões para estas práticas tecnocientíficas. By adopting the human body as an object of scrutiny and experimentation, the biosciences has mobilized issues and actors who are not only scientific and technical, but also political, legal and ethical. The overlapping of these spheres seems to interfere with prospects that are based on dualities, such as nature vs. culture, fact vs. value. This is the case with regards to biobanks and biorepositories that are intended for research, where the practices of collecting and handling human biological material and associated information for use in research. This also creates expectations for the development of health and medicine, they too bring uncertainties and controversies about the nature and destination of the collections, as well as on the consequences of the experiments. It is a context in which scientific practices create entities that do not fit comfortably in modern ontologies, and more specifically, they make unclear the boundaries of the "human", demanding new regulations and ordinances. Therefore, under the Actor- Network Theory framework, this thesis intends to explore the controversies that took shape in the conception event of the regulation of biobanks and biorrepositórios in Brazil, in the 2009-2011 period, under the guidance of the Ministry of Health (MOH) and the National Health Council (CNS), which resulted in the publication of the Guidelines for ethical analyzing of research projects that involve material storage or utilization of stored materials in prior researches (Ordinance No. 2201) and the Brazilian Resolution on the storage and use of human biological material in research projects (Resolution 441/11). There are two main objectives guiding the research: to map the controversies surrounding the issue of storage and use of information and human biological material in research and to learn the hybrid composition that followed norms and patterns for these techno-scientific practices.

Con la presente trattazione ci si e' posto l' obbiettivo di affrontare la questione relativa alla conservazione degli embrioni prodotti tramite le tecniche di fecondazione artificiale e non immediatamente impiantati. In assenza di specifiche disposizioni normative in grado di regolamentare tale materia, si e' cercato di individuare quali possano essere gli obblighi giuridici ed etici che incombono su un centro che si occupa della conservazione degli embrioni residuali, anche alla luce degli interventi comunitari in materia di biobanche, della legge 40/2004 e delle linee guida adottate dal Ministero della Salute in materia di accesso alle tecniche di procreazione medicalmente assistita. La questione non poteva essere trattata in maniera totalmente avulsa dal contesto piu' ampio che riguarda in generale la conservazione del materiale biologico, di cui si occupano le diverse biobanche, ormai diffuse ampiamente tanto a livello internazionale quanto in quello nazionale, le quali hanno iniziato ad operare in assenza di un preciso quadro normativo di riferimento, ricorrendo a forme di autoorganizzazione, mediante le quali ogni centro ha stabilito una propria governance, dettando i propri canoni, i propri metodi, i propri obiettivi. I successivi interventi comunitari in materia non sono stati in grado di dar luogo ad una disciplina precisa, chiara e coerente per quel che riguarda la conservazione del materiale biologico, lasciando dei grossi spazi di indeterminatezza legislativa, vuoi per l'eccessivo tecnicismo da un lato, vuoi per l'ambiguita' lessicale dall' altro. Una volta analizzate le principali questioni che riguardano le biobanche in generale, ci si e' proposti di guardare alla tematica della conservazione degli embrioni in particolare. In questo campo infatti si aggravano in maniera esponenziale, tanto le questioni etiche, quanto la confusione normativa, data dall'assenza di una precisa regolamentazione in materia. Il problema della conservazione degli embrioni nasce successivamente allo sviluppo delle tecniche di congelamento che hanno permesso di conservare gli embrioni prodotti in eccedenza ed e' rimasto aperto anche dopo l'entrata in vigore della legge 40/04 che, nonostante l'apparente rigore, non si occupa della condizione degli embrioni sovranumerai crioconservati. Una volta individuate le disposizioni normative, comunitarie ed interne, da applicare anche alle biobanche di embrioni, ed analizzate le varie questioni etiche sollevate dalla pratica della crioconservazione di embrioni, si e' tentato di ricostruire una possibile disciplina giuridica in grado di regolamentare in maniera piu' precisa l'attivita' di tali tecno-strutture Si e' tentato, infatti, di ricostruire, a partire dai dati normativi esistenti e ricorrendo poi a tradizionali schemi giuridici, una disciplina piu' precisa che possa regolamentare il rapporto che si svolge tra un centro di PMA che si occupa della produzione e conservazione di embrioni e coppia che accede alle tecniche di fecondazione assistita e a cui fanno capo gli embrioni conservati, individuando gli obblighi che assume la biobanca e le susseguenti responsabilita' che possono derivare da un inadempimento. L'obiettivo fondamentale e', quindi, quello della responsabilizzazione dei centri di conservazione degli embrioni attraverso il ricorso agli strumenti giuridici a nostra disposizione. L'esigenza di fondare spazi di responsabilita' giuridica si avverte fortemente in questo campo in quanto si scorge la sacralita' del soggetto coinvolto, l'embrione, che necessita di una tutela estremamente forte in quanto entita' che racchiude in se tutti i caratteri dell'essenza umana ed e' persona dal momento iniziale del suo ciclo vitale.

Thesis (M. Arch.)--Massachusetts Institute of Technology, Dept. of Architecture, 2011.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 116-120).
More than 300 million biospecimens - blood samples, saliva swabs, excised tumors - are housed in different collections all over the country right now. Meanwhile, biometric data is constantly being compiled by sophisticated security systems, by lifestyle products, and even by ordinary ATMs. Because private companies, hospitals, for-profit testing facilities, and security companies 'own' the information they collect, it can't work for you. Billions of dollars in grants are spent each year on focused medical studies seeking information that is most likely already available, but unobtainable. The availability of biometric information to researchers able to draw real statistical conclusions from it is impeded both by a shaky notion of individuals' privacy and the proprietary funding structure by which much of the information has been gathered. The data is out there - it's not a question of wanting to share personal data or not. Measures like the Genetic Information Nondiscrimination Act treat a symptom of the end of privacy, but by no means secure it. The only productive embrace of this national mine of information is to make it fully transparent, to make it available to the public and researchers alike, to nationally acknowledge the end of an antiquated notion of privacy, and to stave off the flow of research dollars into patented pharmaceuticals. The Biobank for America does just that by making transparent the collection and storage of biometric information on a national scale and finally collating it into a comprehensive, searchable archive.
by Sarah Hirschman.
M.Arch.

The forward march of biobanking creates the need for an alternative approach to biobank governance. Biobanking encourages medical advancement by making the conduct of health-related research more efficient, by minimising physical harms to participants, and by facilitating personalised medicine and greater understandings of disease. Nonetheless, its characteristics that distinguish it from general health-related research often give rise to many ethical and social issues. For example, multiple and unexpected uses of biobank resources can render conventional informed consent inadequate for safeguarding participants and maintaining public trust and confidence. Also, because the size of a biobank cohort is normally large, biobanking usually requires considerable management resources and this can mean that biobanks can likely be financially dependent upon for-profit entities. This dependency can cause concern among participants and publics about commercial exploitation. These issues suggest that a new approach to biobank governance is required to address them. Indeed, their complexity and the sheer longevity of biobanking itself also suggest that it is relatively feasible and coherent to address them by focusing on a relationship between participants and biobankers. This involves many aspects of interaction and reflects an element of continuity, which is crucial to biobanking success, as opposed to one-off measures. Consequently, with the aim of addressing issues that arise from biobanking, this thesis offers an analysis of the participant-biobanker relationship that can deal with these issues. Such a relationship constitutes an authentic research relationship in biobanking (“ARR”). Based on this premise, the main research question of my thesis is to ask: What form of research relationship is appropriate for effective and ethical biobanking practices? Three sub-questions are raised to solve this top-level research question. They start with a normative question of why the ARR proposed in this thesis is desirable for biobanking. The next sub-question asks what this ARR should look like from a conceptual perspective. For a practical respect on my proposals, the last sub-question concerns the ways in which the ARR can be fostered in practice. To address these research questions, my thesis first establishes the main characteristics of the proposed ARR as the fundamental notion thereof. These main characteristics are used to answer the first sub-question. For the second sub-question, the thesis suggests that the ARR should be based on the concept of partnership, as opposed to solidarity, mainly because partnership can exhibit the main characteristics of the ARR – as argued – and can also be prescribed in a governance manner. The thesis then uses partnership as a basis for proposing the key features of the ARR, which are deemed to be a conceptual framework for the ARR. To answer the last sub-question, the thesis uses this conceptual framework to propose a partnership model for biobank governance that can be used to develop the ARR in practice. My original contribution is to propose a novel approach to an ARR, and this ARR is based on the concept of partnership. In other words, my thesis argues that the pursuit of the ARR, which looks like a partnership relationship, is an important element of biobanking success. In this respect, my thesis is about a sociologically informed role for partnership in biobank governance. It also provides a nuanced epistemological grounding for a participant-biobanker relationship in both conceptual and practical ways. From a philosophical perspective, my thesis proposes an ethical framework for biobank governance that perceives partnership as a virtuous trait for biobankers and provides rules for acquiring this trait through biobanking practices. Notably, it is argued that this partnership is not – nor need it be – the legal paradigm of partnership, which fundamentally refers to for-profit business association. While law might have a role to play in facilitating the development of the ARR, it cannot prescribe the ARR nor should it attempt to do so.

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Scientific research involving human beings, carried out in the biomedical and genetic areas, generates data from activities developed in biobank, among which genetic data, which should be protected not only in the ethical scope, but also in the legal sphere. Genetic data are information related to hereditary characteristics obtained from samples of human biological sources (eg: cells, hair, tissues, blood, bone, tumors and organs, among other materials derived from human body). These samples can be stored, processed and accessed on biobank - nonprofit structure, organized and systematized in universities and research institutions that provides technologies and/or equipment necessary for scientific investigation. The purpose of this study is to verify whether current Brazilian regulation is sufficient or not regarding the ethical-legal protection of human genetic data in biobank activities, considering the rights of the participants, as far as safeguarding their personal data and to sensitive data, fundamentals of genetic identify. Genetic identify understood as the projection of personal identify. In view of this, it is essential to review the national literature in the light of the constitutional principle of human dignity and fundamental rights, such as the right to life, health, intimacy, privacy and the free development of personality. In turn, a review and analysis of current Brazilian legislation, as well as the identification of guidelines, recommendations and international regulations, are constructs that support and contribute to the understanding of the relevance and pertinence of the subject of personal data protection, particularly human genetic data, demanding the legal support from the principles of the democratic State based on the rule of law. Finally, it is concluded that the protection of human genetic data in biobank activities is deserving of specific legislation, which includes measures of coherence in case of violation of the principle of human dignity and of the fundamental rights implied, that guarantees the integrity of the participant of the research and their personal rights, that imposes to the researchers, the participants, the research institutions and universities and the State, the duties and limits of action in relation to human life and health. Therefore, a specific infraconstitutional legislation, effective in the legal and effective protection in its implementation.
Las investigaciones cient?ficas que involucran seres humanos, realizadas en las ?reas biom?dica y gen?tica, generan datos a partir de actividades desarrolladas en biobanco - entre los cuales datos gen?ticos - debiendo los mismos ser protegidos, no s?lo en el ?mbito ?tico, sino tambi?n en el ?mbito jur?dico. Los datos gen?ticos son informaciones sobre las caracter?sticas hereditarias obtenidas de muestras de material biol?gico humano (por ejemplo, c?lulas, pelo, tejidos, sangre, huesos, tumores y ?rganos, entre otros ejemplares derivados del cuerpo humano). Estas muestras pueden ser almacenadas, procesadas y accesadas en biobanco - estructura sin fines de lucro, organizada y sistematizada en universidades e instituciones de investigaci?n que ofrece tecnolog?as y / o recursos necesarios para la investigaci?n cient?fica. El prop?sito de este estudio es verificar si la regulaci?n brasile?a actual es suficiente - o no - cuanto a la protecci?n ?tico-jur?dica de los datos gen?ticos humanos en actividades de biobanco, garantizando los derechos de los participantes, con la salvaguardia de sus datos personales y datos sensibles, fundamentales para la identidad gen?tica. Identidad gen?tica entendida como proyecci?n de la identidad personal. En este prisma, es imprescindible una revisi?n de la literatura nacional, a la luz del principio constitucional de la dignidad humana y de los derechos fundamentales, tales como el derecho a la vida, a la salud, a la intimidad, a la privacidad y al libre desarrollo de la personalidad. Por su parte, una revisi?n y an?lisis de la legislaci?n brasile?a actual, as? como la identificaci?n de directrices, recomendaciones y regulaciones internacionales, son constructos que fundamentan y contribuyen a la comprensi?n de la relevancia y pertenencia de la tem?tica acerca de la protecci?n de datos personales, particularmente datos gen?ticos humanos, lo que exije del Estado Democr?tico de Derecho el debido apoyo legal. Por ?ltimo, se concluye que la protecci?n de los datos gen?ticos humanos en las actividades de biobanco est? merced a una legislaci?n espec?fica, que contemple medidas de cohesi?n para el caso de afrenta al principio de la dignidad humana y de los derechos fundamentales implicados, que garantice la integridad del producto, que participa en la investigaci?n y sus derechos personales, que imponga a los investigadores, a los participantes, a las instituciones de investigaci?n y universidades y al Estado, los deberes y l?mites de actuaci?n en relaci?n con la vida humana y la salud. Por lo tanto, una legislaci?n infraconstitucional espec?fica, eficaz en la protecci?n jur?dica y efectiva en su implementaci?n.
As pesquisas cient?ficas envolvendo seres humanos, realizadas nas ?reas biom?dica e gen?tica, geram dados a partir de atividades desenvolvidas em biobanco, dentre os quais dados gen?ticos, devendo os mesmos serem protegidos, n?o apenas no ?mbito ?tico, como tamb?m no ?mbito jur?dico. Dados gen?ticos s?o informa??es referentes ?s caracter?sticas heredit?rias obtidas de amostras de material biol?gico humano (por exemplo: c?lulas, cabelo, tecidos, sangue, ossos, tumores e ?rg?os, entre outros exemplares derivados do corpo humano). Essas amostras podem ser armazenadas, processadas e acessadas em biobanco - estrutura sem fins lucrativos, organizada e sistematizada em universidades e institui??es de pesquisa que oferece tecnologias e/ou equipamentos necess?rios ? pesquisa cient?fica. O prop?sito deste estudo ? verificar se a regula??o brasileira atual ? suficiente ou n?o quanto ? prote??o ?tico-jur?dica dos dados gen?ticos humanos em atividades de biobanco, considerando os direitos dos participantes, na medida da salvaguarda dos seus dados pessoais e dados sens?veis, fundamentos da identidade gen?tica. Identidade gen?tica entendida como proje??o da identidade pessoal. Sob este prisma, ? imprescind?vel uma revis?o da literatura nacional e internacional, ? luz de princ?pio constitucional da dignidade humana e dos direitos fundamentais, tais como o direito ? vida, ? sa?de, ? intimidade, ? privacidade e ao livre desenvolvimento da personalidade. Por sua vez, uma revis?o e an?lise da legisla??o brasileira atual, assim como a identifica??o de diretrizes, recomenda??es e regulamenta??es internacionais, s?o construtos que fundamentam e contribuem para a compreens?o da relev?ncia e pertin?ncia da tem?tica da prote??o de dados pessoais, particularmente dados gen?ticos humanos, exigindo do Estado Democr?tico de Direito o devido respaldo legal. Por fim, conclui-se que a prote??o dos dados gen?ticos humanos em atividades de biobanco est? a merecer uma legisla??o espec?fica, que contemple medidas de coers?o para o caso de afronta ao princ?pio da dignidade humana e dos direitos fundamentais implicados, que garanta a integridade do participante da pesquisa e seus direitos pessoais, que imponha aos pesquisadores, aos participantes, ?s institui??es de pesquisa e universidades e ao Estado, os deveres e limites de atua??o em rela??o vida humana e ? sa?de. Portanto, uma legisla??o infraconstitucional espec?fica, eficaz na prote??o jur?dica e efetiva na sua implementa??o.

Biobanks pose unique challenges to legal and bioethical frameworks, and raise many as yet unanswered questions, including how these collections of biological samples and information should be governed and for whose benefit. While some commentators have suggested that biobanks should be regulated through specific legislation, I focus on exploring alternative models of governance. I examine, in particular, the interrelationship between benefit-sharing and public engagement, arguing that public engagement is a benefit in itself, valuable both in its own right and as an essential component of good governance, and critically examine proposals for more direct 'representative‘ forms of participant involvement and 'power-sharing‘ arrangements in the biobanking context. Central to my arguments is the concept of the "common heritage", which has been invoked by UNESCO and HUGO in relation to the human genome. From its early beginnings in the law of the sea, this concept has been linked to notions of solidarity, reciprocity and equitable access and sharing. Applied in the context of biobanks, the "common heritage" highlights the value of genetic collections and research for the benefit of present and future generations. Viewed as a third generation human right, the "common heritage" also links to notions of citizenship, civic involvement in policy processes and, ultimately, to participatory or deliberative democracy. From this, I suggest that robust biobank governance mechanisms require not only effective benefit-sharing arrangements but that these must necessarily involve provision for effective public engagement. Drawing on democratic and business management theory, I argue for a 'stakeholder' model of governance. This model draws its basic ideology from communitarian philosophy and regards any organisation (whether it be a corporation or a charity) as a 'social entity', accountable to a broad range of stakeholders. It is my contention that a stakeholder model is the most appropriate model of governance for large-scale population biobanks, such as UK Biobank, which are designed for public benefit, to enhance the health of all, including future generations. In sum, it is a model through which the common interest vested in biobank research might materialise.

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.

This thesis investigates the governance of biobanks in Mexico, exploring elements of legislative reform for the improvement of current legal and ethical guidance. It argues that the great benefits to be obtained from research using biobanks (e.g. personalised or stratified medicine) are at risk of being undermined by the absence of clear legal pathways. A number of legal and ethical issues have emerged from the different aspects of biobanks. Diverse theoretical approaches are reflected in academic literature and heterogeneous legislation of biobanks around the world. Specific binding rules have worked for some, whereas self-regulation has proven suitable for others. Social solidarity has played a key role in innovative biobanking law and decision making, in which traditional governance approaches have become more reflexive, involving not only law and policymakers, but also the public. A detailed legal analysis revealed significant gaps within the complex Mexican laws governing biobanks; this has caused confusion. Areas of concern were identified in relation to the ethical management of research samples and the protection of donors’ rights. This is concerning in Mexico where economic interests influence legal reform, giving way to opportunistic actions by the international pharmaceutical industry and leaving vulnerable populations unprotected. The greatest challenges for Mexican legislators are finding ways to respond to legal gaps with new laws and improving the effectiveness of existing rules. Due to the scarcity of literature on the topic, interviews were conducted with representative actors in strategic areas. Participation in the European Union research network BTCure enabled the inclusion of a study investigating how European experiences can be valuable examples for Mexico to follow. The results of this research indicate ways forward for Mexican governance, which are expected to influence further legislative reforms of biobanks.

What role should trust have in biobank research? Is it a scarce resource to be cultivated, or does its moral significance lie elsewhere? How does it relate to the researcher’s individual responsibility? In this thesis I draw four general conclusions. First, trust is still very much present in at least some biobanking settings, notably in Sweden, but possibly also internationally. Second, a morally relevant conception of trust entails that to be trustworthy, researchers must consider the normative expectations that people have of them, and renegotiate expectations that are mistaken. Third, this conception differs from “public trust” assessed through surveys. The main use of the latter is to legitimate policy, not to identify moral duties. Fourth, in spite of ethics review, guidelines and informed consent procedures, ethical issues will always arise during the course of a research project. Researchers can therefore never avoid their individual moral responsibility. Ensuring that one is adequately trusted is one step towards conducting morally acceptable research. Study I indicates that few Swedes refuse storage of samples in healthcare-associated biobanks and their use in research. Study II suggests that people are somewhat more willing to donate samples than surveys indicate, especially when approached face-to-face by health care personnel. Relationships of trust might thus be important in people’s decision-making. Study III investigates trust as a moral concept. The trustee is often in a unique position to determine what the other’s trust amounts to. When it is mistaken, the trustee has an obligation to counteract it, compensate for it, or renegotiate the expectations that cannot be met. In Study IV, I critique the feasibility of guaranteeing the trustworthiness of the research apparatus through formal measures such as ethics review and guidelines. Not only are there limitations of such measures to consider. They also risk blinding researchers to ethical issues that are not covered by the rules, fostering moral complacency, and alienating researchers to ethics.

Background: 1985 saw the beginnings of a population-based biobank in Västerbotten County, Sweden. In 1999, a start-up genomics company, UmanGenomics, obtained ‘all commercial rights’ to the biobank. The company introduced an ethics policy, which was well received in prestigious journals, focusing on public oversight and informed consent. Aims: To explore how social anthropology can aid understanding of the challenges posed by the new role of the biobank in Västerbotten, and thus complement more established traditions in the field of medical ethics. An anthropological study of the ethics policy was executed. Theoretical perspective: Inspired by the anthropology of policy and social science perspectives on ethics and morality, the policy was studied at three analytical levels: policymakers (who formulate the policy), policy workers (who implement the policy, primarily nurses who obtain informed consent) and target group (for whom and on whom the policy is supposed to work: the potential donors to the biobank). Methods: Policymakers, nurses, and potential donors were interviewed, donations observed, and official documents analysed to mirror the moral problematizations made at the three levels in each other and to study the practical implications of the policy. To extend the reliability of the findings two surveys were executed: one among the general population, one among donors. Results: The qualitative studies show that policymakers distinguish between blood and data differently to potential donors. Informed consent seems more important to policymakers than potential donors, who are more concerned about political implications at a societal level. Among the respondents from the survey in the general public, a majority (66.8%) accepted surrogate decisions by Research Ethics Committees; a minority (4 %) stated informed consent as a principal concern; and genetic research based on biobank material was generally accepted (71%). Among the respondents to the survey in donors, 65% knew they had consented to donate a blood sample, and 32% knew they could withdraw their consent; 6% were dissatisfied with the information they had received; and 85% accepted surrogate decisions by Research Ethics Committees. Discussion: The ethics policy constitutes a particular naming and framing of moral problems in biobank-based research which overemphasises the need for informed consent, and underemphasises other concerns of potential donors. This embodies a political transformation where access to stored blood and medical information is negotiated in ethical terms, while it also has unacknowledged political implications. In particular, the relations between authorities and citizens in the Swedish welfare state are apparently transforming: from mutual obligation to individual contracts. Conclusion: Anthropology contributes to medical ethics with increased awareness of the practical implications of particular research ethical initiatives. This awareness promotes appreciation of the political implications of ethics policies and raises new issues for further consideration.

Background: Blood pressure is one of the most important modifiable risk factors for stroke. Although the influence of an individual’s average blood pressure (BP) on their overall stroke risk is well established, visit-to-visit blood pressure variability (BPV) - variation in blood pressure from one clinic visit to the next - may be an independent risk factor for stroke. The influence of BPV on stroke risk in the general population is not fully understood, nor is it known whether associations with BPV vary by pathological stroke type. Very large prospective studies, including exposure measurements of BP and BPV as well as accurate identification, confirmation and sub-classification of large numbers of stroke cases during follow-up, are needed to test the associations between BP parameters, stroke and its main pathological types. UK Biobank (UKB) is a very large prospective cohort study of ~500,000 middle aged adults recruited from England, Scotland, and Wales between 2006 and 2010. Participants completed a detailed baseline assessment at recruitment (which included self-report of prior stroke and BP measurement). Follow up for health-related outcomes (including new occurrences of stroke) in UKB relies on linkages to routine coded datasets for hospital admissions, death registrations and primary care data. Coded primary care data could also be used to capture novel exposures, like blood pressure variability (BPV). In this thesis, I aimed to investigate how large prospective epidemiological studies such as UK Biobank might be used to investigate the influence of BP, and in particular BPV, on stroke and its types and subtypes. I did this through advancing understanding of the identification and characterisation of stroke cases in large prospective studies, and of obtaining measures of BPV from linked primary care data. Specifically, I aimed: (1) to evaluate the accuracy of patient self-report of stroke, the accuracy of routinely available coded healthcare data for stroke, and the reliability and feasibility of ischaemic stroke classification systems for large epidemiological studies such as UKB; (2) to identify prevalent and early incident stroke cases in UKB using multiple overlapping sources of coded data, and determine the proportions of cases classified into main pathological types of stroke; (3) to explore the feasibility of using coded primary care data to obtain measures of BPV in UKB. Methods: (1) I performed a series of systematic reviews of published data on (i) the accuracy of patient self-report of stroke, (ii) the accuracy for stroke and its main pathological types (ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage) of International Classification of Diseases (ICD) coded hospital admissions and death certificates, and Read coded primary care records, and 3) the inter-rater reliability of ischaemic stroke classification systems. (2) Informed by this work I identified prevalent and early incident stroke cases in UKB using linked coded hospital and death registration data as well as self-report data. In a sub cohort of participants, I was able to assess the additional role in case identification of linked coded primary care data. I compared the numbers of potential stroke cases ascertained by multiple overlapping combinations of these data and examined the proportions classified into the main pathological stroke types. (3) Finally, I analysed data from about 10,000 Welsh UKB participants with linked coded primary care data to identify those in whom visit-to-visit BPV could be measured using coded systolic blood pressure values (BP). I explored the association between frequency of visits with coded BP values and: participant characteristics; time between visits; mean BPV; standard deviation of BPV (SD BPV). I also calculated within-individual agreement between coded BP and UKB baseline assessment BP. Results: (1) From my systematic reviews I found that self-report accuracy was strongly influenced by characteristics of the study population. In populations with low stroke prevalence up to 75% of self-reported strokes were false positives. ICD codes for cerebrovascular diseases had a broad range of accuracy for stroke and its main pathological types, but appropriately selected, ‘stroke specific’ ICD codes were consistently >70% accurate when compared to an independent reference standard for stroke. Few studies assessed the accuracy of either primary care data or combinations of data sources for stroke. The overall inter-observer reliability of ischaemic stroke classification systems ranged from moderate to almost perfect. Study characteristics other than classification system accounted for much of the variation in reliability. Additional features which enhanced reliability included use of clear rules, data abstraction protocols, computerised assignment, and reduced number of subtype categories. (2) The prevalence of stroke in UK Biobank based on linked ICD coded hospital admissions data and participant self-report was ~1.7%. The majority of these prevalent stroke cases were of ‘unspecified’ stroke type. Incident strokes captured by ICD codes were mostly hospital admitted cases, but a smaller additional proportion were fatal cases not detected in hospital admissions data. The majority (~89%) of ICD coded incident strokes were a specified pathological type. In the sub-cohort of UKB participants with additional primary care data linkage ~20% of potential incident stroke cases were detected by coded primary care data alone. (3) Among Welsh UKB participants with linked primary care data, around two thirds had sufficient coded data to estimate visit-to-visit BPV any time before recruitment, and just under half had sufficient coded data to estimate BPV during the 5 years before recruitment. Selecting participants with more visits reduced generalizability, but there was good variability in BPV amongst those selected (standard deviation in BPV range ~5mmHg to ~7mmHg), and reasonable agreement between coded BP and BP recorded at the UKB baseline assessment (intra class correlation coefficient 0.53, 95% CI 0.52 to 0.55). Conclusions: This work will inform the approaches to stroke outcomes ascertainment and the measurement of a novel exposure, blood pressure variability, in UK Biobank. This will enable future exploration of the associations between blood pressure parameters, stroke, and its main types and sub-types in UK Biobank. Investigating these associations will improve our understanding of causal pathways for the different pathological types and sub-types of stroke and underpin increasingly targeted strategies to modify BP for stroke prevention.

Introdução: O Estudo Longitudinal de Saúde do Adulto é um estudo de coorte multicêntrico com o objetivo de identificar os fatores de risco associados ao diabetes tipo 2 e à doença cardiovascular na população brasileira. Nosso principal objetivo é explicar a concepção e implementação das rotinas do laboratório central e biobanco do Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil); destacando as forças e limitações do protocolo. O segundo objetivo é descrever os pré-testes usados para validar o protocolo de antes do início do estudo. Métodos: O estudo optou pela centralização dos exames em um laboratório central no Hospital Universitário da Universidade de São Paulo (USP), Com base em dados recentes que confirma a estabilidade da glicose em amostras congeladas, até os testes de glicose no sangue foram centralizadas. Porém o processamento das amostras foi realizado nos laboratórios locais o que reduziu os custos do transporte das amostras para o laboratório central. A estratégia implicou na necessidade de implementação de equipes nos laboratórios em cada Centro de Investigação para coletar e processar as amostras antes do transporte. O estudo incluiu exames para a avaliação do metabolismo da glicose, resistência à insulina, perfil lipídico, eletrólitos, ácido úrico, hormônios da tireóide, função hepática e contagem total de células do sangue. Além disso, as amostras de DNA, urina plasma, e de soro foram colhidas e Além desses exames, o estudo também extraiu DNA de leucócitos, colheu e estocou amostras de urina, plasma e soro. Para garantir a homogeneidade do protocolo todos os membros das equipes locais passaram por treinamento e certificação centralizado, com visitas cruzadas entre os centros durante o campo para controle de qualidade. Resultados: A opção por um laboratório central garantiu a uniformidade da metodologia utilizada para a realização dos exames, evitando as variações inevitáveis entre laboratórios. Durante 26 meses, cerca de 375.000 testes foram realizados no laboratório central. Não houve perda de amostras biológicas durante o estudo. A implementação do biobanco usando palhetas armazenados em repositórios de nitrogênio foi realizada sem problemas importantes desde 2008 até agora. Conclusão: O ELSA-Brasil mostrou a exequibilidade de exames multicêntricos no Brasil com todos os exames realizados em um laboratório central, de uma maneira custo-efetiva. A logística de armazenamento de amostras biológicas foi feito com custos aceitáveis e de qualidade, sendo um modelo para estudos futuros
Background: The Longitudinal Study of Adult Health is a multicenter cohort study aimed to identify risk factors associated with type 2 diabetes and cardiovascular disease in Brazilian population. Our main objective is to explain the conception and implementation of the routines of the central laboratory and biobank of the Longitudinal Study of Adult Health (ELSA-Brasil) highlighting the strength and the limitations of the protocol The second objective is to describe the pre-tests used to validate the protocol before the start of the study. Methods: The study made an option to centralize the exams in one central laboratory at the University Hospital, São Paulo University (\"USP\"). Based on recent data that confirms the stability of glucose in freeze samples, even blood glucose tests were centralized. However, biological samples were processed in the local laboratories, reducing the weight of the material to be transported, and diminishing costs of transportation to the central lab. Especially trained local teams collected and processed biological samples before transportation. The study included tests for glucose metabolism, insulin resistance, lipid profile, electrolytes, uric acid, thyroid hormones, hepatic function, and total blood cell count. In addition, DNA, urine, plasma and serum samples were collected and stored. In order to guarantee protocol homogeneity, all team members underwent centralized training and certification, and cross-visits in each research center were done. Results: The choice of a central laboratory assured uniformity of the methodology used for the exams, avoiding the variations between laboratories During 26 months, approximately 375,000 tests were done in the central- laboratory. There was no loss of biological samples during the study. The implementation of the biobank using straws stored in nitrogen repositories was performed without important problems since 2008 until now. Conclusion: The ELSA-Brazil showed the feasibility of a multicenter study in Brazil with all the analyses performed in a central laboratory, in a cost-effective way. The logistic of storage of biological samples was done with acceptable costs and quality being a model for future studies

Rare diseases (RDs) are a global priority yet are still under researched. When combined, RDs are common, with individual diseases numbering approximately 5,000-8,000, equating to approximately 7% of the population in Europe. Extrapolating this figure for Australia suggests that about 1.2 million people are affected by RDs, with about 400,000 of those being children. The WA Rare Diseases Strategic Framework 2015-2018, the first strategy for rare diseases in Australia, recognises that in order to alleviate the significant burden of rare diseases, innovative translational tools that facilitate research into new diagnostic and therapeutic strategies should be given priority. Registries facilitate clinical, epidemiological, and post-marketing surveillance research for RD, collecting information from individuals with a particular disease, and storing these data in an organised system. Registries can lead to a greater understanding of the natural history of disease, consensus-driven treatment protocols, informed policy making and, in turn, improved patient outcomes. Despite these benefits, registries are limited in their capacity to conduct basic research, attributed to the fact that most registries do not collect and store patient and donor specimens appropriately to capture or preserve important biological information (such as DNA, RNA and proteins) for basic research, a prerequisite for translating scientific discoveries into diagnostic tools and therapies for clinical practice. Biobanks (BB) are gradually becoming more recognised as invaluable tools to drive basic and translational research for RDs. BBs collect and store biological specimens with matched clinical data and patient metadata in an organised system, distributing samples and data to the scientific community, enabling “omics” studies. This is especially important considering the field of drug innovation for RDs has, in recent years, become progressively focused on ‘omics-type research, and that more than 80% of RDs have a genetic component RDs have recently been referred to as “fundamental diseases”, highlighting their unique capacity in providing opportunities to investigate the “extremes of human pathology”. For example, research of LDL-receptors in familial hypercholesterolemia, a rare disease, led to the discovery of statins, a drug therapy that is now also routinely used to prevent heart disease. This Masters research thesis examined the research outcomes of two specific research strategies: registries linked to BBs and registries without BBs, and found that whilst registries without BBs had the capacity to uncover the natural history of disease, develop best practice, replace clinical trials, and improve patient outcomes, they were limited in their capacity to conduct basic research. Registries, when annexed to BBs, had the key infrastructure required to make novel Omics discoveries, identify and validate biomarkers, uncover novel genes, and develop new therapeutic strategies. The results of this Masters research thesis suggest that the role of basic research in RD research is vital; scientists must first understand the pathways of disease before they can develop appropriate interventions. Linkage of BBs to RD registries will provide the enhanced resources required for the effective translation of basic research into clinical practice.

Tatt for meg flere runder med forsøk og analyser. Tørking av muselever,-hjerte,-lunge,-nyre og -skjelett muskulatur ved +5ºC og -10ºC. Samt lagring ved +4ºC og -20ºC i fem måneder. Resultatene viste en sammenheng mellom lave temperaturer og høye verdier av RIN. De viste også en motsetning til tidligere resultater, med lavere RIN på prøver tørket ved +5ºC, samt uakseptable lave verdier ved lagring i kjøleskap. Dessuten var det en viss forskjell avhengig hvilket organ vi tørket og lagret.

Although the concept of ownership of human tissue as well as the question of the rights of the tissue source to excised tissue have not been fully developed in law either in Nigeria or in England, recent developments in genetic science and biobank research have made this a contemporary controversy in the sense that biobank research has become an integral part of the process of developing diagnoses and therapies for complex diseases. Biobanks can be used not only for basic research aimed at developing therapeutic products or understanding fundamental biological principles such as molecular mechanisms etc., but also for clinical and epidemiological research. They are now a prerequisite for conducting Genome Wide Association Studies (GWAS) that explore connections between genotypes and phenotypes in order to identify genetic risk factors for common diseases such as heart disease, autoimmune diseases and psychiatric disorders. In spite of the growing importance of biobank research and the attendant significance of the role of the tissue source to the development of science, the law has not developed clear-cut principles that protect the interests of a tissue source who contributes valuable samples or data to biobank research. In the context of biobank research, this discussion engages two intersecting interests: the individual interest of the tissue source, and the communitarian interests of the overall public good that the prospect of biobank research brings. Within this discussion, the thesis discusses protecting the tissue source, his entitlement to privacy of his data; as well as his entitlement to choosing when and if he wants his data or samples used in future research. The thesis also proceeds from a supposition that the tissue source should be given a say in the decisions relating to secondary uses of the samples and data. By this position, the thesis is not advancing a case for an abolition of biobank research, but that the autonomous choice of the tissue source in relation to future research be recognised and protected.

Biobanks are key infrastructures in data-driven biomedical research. The counterpoint of this optimistic vision is the reality of biobank governance, which must address various ethical, legal and social issues, especially in terms of open consent, privacy and secondary uses which, if not sufficiently resolved, may undermine participants’ and society’s trust in biobanking. The effect of the digital paradigm on biomedical research has only accentuated these issues by adding new pressure for the data protection of biobank participants against the risks of covert discrimination, abuse of power against individuals and groups, and critical commercial uses. Moreover, the traditional research-ethics framework has been unable to keep pace with the transformative developments of the digital era, and has proven inadequate in protecting biobank participants and providing guidance for ethical practices. To this must be added the challenge of an increased tendency towards exploitation and the commercialisation of personal data in the field of biomedical research, which may undermine the altruistic and solidaristic values associated with biobank participation and risk losing alignment with societal interests in biobanking. My research critically analyses, from a bioethical perspective, the challenges and the goals of biobank governance in data-driven biomedical research in order to understand the conditions for the implementation of a governance model that can foster biomedical research and innovation, while ensuring adequate protection for biobank participants and an alignment of biobank procedures and policies with society’s interests and expectations. The main outcome is a conceptualisation of a socially-oriented and participatory model of biobanks by proposing a new ethical framework that relies on the principles of transparency, data protection and participation to tackle the key challenges of biobanks in the digital age and that is well-suited to foster these goals.

Human preclinical and translational research frequently relies upon quality human biospecimens and associated data, usually obtained from biobanks. Despite the importance of human biospecimens in research, biobanks have reported sustainability challenges. We highlight the dearth of publications that discuss biobank outputs, and propose that reported sustainability challenges may partly arise from a lack of information about the value of biobank outputs. For a cohort of n=12 cancer biobanks in New South Wales, we performed an in-depth analysis of the annual monetary and in-kind costs and publications supported by each biobank. There were few identified differences between biobank costs and supported publications supported for open-access versus restricted-access biobanks, whereas greater investments in biobanking were associated with supported publications in more prestigious journals that gained more on-line attention. To understand the perspectives of Australian biobank users, we separately conducted a survey of n=137 Australian biomedical researchers. While survey respondents were generally satisfied with biobank services, a proportion reported a lack of sample availability, with the majority of respondents reporting having created their own collection to access the biospecimens that they required. Respondents also highlighted the need for greater availability of annotated data. The results from our studies provide a more evidence-based approach to individual biobank management and planning. Furthermore, external stakeholders can use these results to make more informed decisions that more effectively support the discipline of biobanking. Ultimately, these combined approaches may improve both biobank sustainability, and the capacity of human biobanks to support biomedical research.

Population biobanks hold promise for improving the health of future generations by providing researchers with a resource of both human samples and data to investigate the linkages between genes, lifestyle and environment in population health. Widespread concern has been expressed in academic and policy literature as to the ongoing ethical, legal and social challenges that are raised by population biobanks, by virtue of their longitudinal nature and broadly set research aims. To address these challenges, and to balance private interests of the individuals who donate to biobanks, with the public benefit that is believed to derive from the establishment of biobanks, some countries have specifically legislated to establish national biobanks. Alternatively, UK Biobank has been incorporated as a charitable corporation. Potentially, this private legal structure diminishes the public accountability of the project, as well as the protection of donors from personal harm. This thesis analyses the multi-layered nexus of laws within which UK Biobank is embedded and shows the tensions that are associated with using a private legal structure to secure public objectives. UK Biobank is in unchartered legal territory on a number of levels, and this thesis posits UK Biobank as a timely example of a large-scale organisation whose model straddles the public/private divide in law and invites an eclectic mix of corporate, public, charity, contract and tort lawyers into a conversation with ethicists, scientists, policy experts and the public to consider how to effectively progress population health via biobanking. As such, the experience of UK Biobank raises questions as to how best to balance public and private interests in large-scale, public mission organisations in general.

Dissertação para obtenção do grau de Mestre em Biologia Molecular em Saúde
No Biobanco-IMM as amostras são colhidas e armazenadas por longos períodos de tempo sendo de extrema importância que estas sejam de elevada qualidade. Para cumprir este requisito, os procedimentos do biobanco efetuam-se de acordo com diretrizes internacionais para a avaliação da qualidade das amostras que armazena.
No Biobanco-IMM, as amostras de DNA são extraídas e avaliadas em relação à sua concentração, pureza (razão A260/A280) e integridade. Por vezes, uma pequena percentagem das amostras pode não cumprir estes parâmetros de qualidade e uma vez que estas amostras são muitas vezes irrecuperáveis, surge a necessidade de testar a funcionalidade do DNA. O PCR é uma técnica largamente utilizada, pelo que outros biobancos internacionais, com os quais o Biobanco-IMM mantém estreita relação, aplicam esta técnica para complementar o procedimento de controlo de qualidade. Assim, este trabalho teve por objetivo implementar um método que comprove a funcionalidade das amostras de DNA armazenadas no Biobanco-IMM. Foram selecionadas amostras de cinco coleções representativas do Biobanco-IMM e amostras que não cumpriam os parâmetros de qualidade atualmente implementados. Segundo os resultados, as amostras pertencentes às cinco coleções apresentam boa amplificação do gene ACVR2B por PCR. Foi também observado que mesmo as amostras que se situavam fora do controlo de qualidade (87,8%) apresentaram amplificação, o que sugere que, mesmo que algumas amostras não cumpram os parâmetros de controlo de qualidade já aplicado no biobanco, poderão ser utilizadas, desde que se revelem funcionais. Segundo estes resultados, sugere-se que a adaptação do procedimento de CQ das amostras de DNA passe por acrescentar a técnica de PCR quando as amostras traduzam uma razão A260/280 < 1,7 ou > 2,0 e/ou não apresentem uma banda íntegra em gel de agarose.

Cognitive impairment is a major cause of disability for a large number of working-age adults living with chronic psychiatric and neurological conditions. Although well recognised in schizophrenia spectrum disorders and in neurological diseases such as multiple sclerosis (MS), cognitive impairment has historically received less attention in mood disorders. The relative prevalence of cognitive impairment in bipolar disorder (BD) and major depression compared with other conditions has not been clearly established, and the risk factors that drive cognitive variation within and across conditions are not well understood. The primary focus of this thesis was on BD, and the objectives were: (1) to investigate the prevalence of cognitive impairment in BD, compared with major depression, schizophrenia, MS and Parkinson’s disease (PD); and (2) to develop causal models to quantify and explain variation in cognitive function in BD and in other conditions. The methods encompassed a systematic literature review, a prevalence study using cross-sectional data from the UK Biobank cohort, and a series of multivariable analyses of UK Biobank data using graphical methods, regression- and matching-based estimation, and mediation models. The systematic review indicated that between 5% and 58% of adults with euthymic BD showed cognitive impairment. Prevalence was lower in the mania/BD group identified within the UK Biobank cohort, at around 7-10%, which was similar to rates seen in the MS and PD groups within the cohort. When causal models of cognitive performance in the mania/BD group took account of multiple potential confounders, performance on a short-term visuospatial memory test showed a small but reliable decrement. Mediation models provided evidence of indirect negative effects on cognitive performance via psychotropic medication, but not via cardiometabolic disease. A similar pattern of results was seen in the major depression group, though with smaller effect sizes. This thesis emphasises the importance of cognitive function as a fundamental phenotype in psychiatric and epidemiological research. There is scope to build on this work in future follow-up waves in UK Biobank, as well as in other UK and international cohort studies and through linkage with routine healthcare data.

Biobank-based genomic research is considered instrumental to realize Personalised Medicine and considerable benefits for diagnosis and therapy of many common complex diseases. It raises manifold ethical and regulatory challenges which are discussed extensively, the main focus being on adaptations of Informed Consent to the emerging research context. This study highlights challenges to the strongly individualistic focus of classical research ethics in confrontation with biobank development. The debate on adequate protections for individual donor-participants tends towards deflationary accounts of participant rights, in which in particular the dimension of potential property in human tissue and genomic information is undervalued. Criticizing the common bioethical and legal stance that there can and should be no property in the human body and its parts, the close conceptual connections between privacy, property and consent underlying the protection of a more substantive version of participant integrity are emphasized. While ultimately the framework of traditional, in particular individual property rights is ill-suited to safeguard participant and public interests in research, property discourse is fundamental to advance discussion on the direction biobank ethics and governance should take by 1) taking serious the reordering of individual, group and societal interests in biobank research, 2) clarifying strength and limits of claims to “autonomy” and 3) refocusing to public or common goods biobank research should provide. These foundational insights are applied to an emerging normative model beneath biobank governance in which implications for the future role of consent and participant involvement in large-scale digitalized research projects are outlined.

Thesis (Ph.D.) - University of Glasgow, 2007.
Ph.D. thesis submitted to the MRC Social and Public Health Sciences Unit, University of Glasgow, 2007. Includes bibliographical references. Print version also available.

Background: This thesis examines the origins and early development of UK Biobank. This is a resource funded in 2002 by the Medical Research Council, the Wellcome Trust, the Department of Health and the Scottish Executive to gather genetic and lifestyle information from half a million participants aged 4069 years old in the UK and monitor their health for up to thirty years in order to improve the prevention, diagnosis and treatment of major diseases. UK Biobank was set up following the completion of the Human Genome Project in 2001, and was one of many established at around the same time with the goal of translating the knowledge of the human genome sequence into practical benefits for human health. (National genetic databases were also set up or proposed in Iceland, Estonia, Latvia, Sweden, Singapore, Tonga, Spain, and the United States). They, and the Human Genome Project, had raised a number of important issues about access to and ownership of genetic information. Aims: The original aim of my PhD was to examine lay and professional understandings and responses to Biobank in the light of this background. However, UK Biobank took longer than expected to reach the stage of data collection, in part because of negotiations about its organisational structure. The aim therefore changed to address the question of how and why was UK Biobank initially configured in the manner it was. Organisational structure: UK Biobank was originally set up by the funders with a ‘hub’ and ‘spoke’ model, with calls for bids from UK Universities for a central ‘hub’ charged with financial management and overall control of data and samples, and ‘spokes’ who were responsible for recruitment and data collection through primary care. The selection of both was made through the procurement rules of the EU. The hub (Manchester), six regional spokes, and the CEO (from Oxford) were all appointed simultaneously in 2003 and subsequently a Board of Directors and a number of committees were appointed. The CEO resigned in late 2004, and a new CEO and Principal Investigator was appointed in 2005, after which there were significant changes to the organisational structure. Methods: I conducted 76 oral history interviews with academic scientists directly and indirectly involved in UK Biobank, representatives of all four funding bodies, and representatives of UK Biobank Limited (the company set up to manage UK Biobank). I also conducted archival analysis of the MRC’s official documents concerning the origins and development of UK Biobank. Findings: From its beginning UK Biobank was marked by tension between academic scientists on the one hand and representatives of the funding bodies and UK Biobank Limited on the other. Academic scientists criticised the funding bodies for establishing UK Biobank in a way that departed from what I have termed ‘standard academic scientific practice’. Spokes felt they should receive some privileged access to data they would contribute to collecting, and felt that the set up did not recognise the performance indicators driving scientists and universities. Lack of clarity over who was in control of UK Biobank contributed to these tensions as both spokes and funders felt that the other exerted undue influence. Some mistrust developed between academic scientists and representatives of the funding bodies and UK Biobank Limited. Discussion: The configuration of UK Biobank was difficult for academic scientists and representatives of both the funding bodies and UK Biobank alike. Organisational issues, typical of those confronting Big Science initiatives, were largely responsible for this difficult legacy. Issues of leadership, the hub and spoke model, the sequencing of funding decisions, appointment of groups and committees and protocol development, uncertainties about who was in control, and ambiguities within the organisational structure as a whole were the most significant issues in the origins and development of UK Biobank, as the organisational changes in 2005 testify.

Background: Prior studies regarding the risk factors of mild cognitive impairment (MCI), such as physical activity (PA) and sleep related factors in older Chinese populations are scarce, and the findings have not been consistent. Objectives: 1. To cross-sectionally and longitudinally examine the dose-response association between PA and cognitive function by Delayed Word Recall Test (DWRT) or Mini-mental State Examination (MMSE). 2. To cross-sectionally and prospectively examine the association of sleep related factors, including sleep duration, daytime napping, morning tiredness and insomnia, with cognitive function. Design: Cross-sectional and longitudinal analysis using both baseline and follow-up data from the GBCS. Methods Baseline data from 8,451 men and 22,067 women aged 50 years or above were used for the cross-sectional analysis. Among them, 4,214 men and 11,284 women participating in the second examination were included in the longitudinal analysis. Information on demographic, socioeconomic and lifestyle factors, and personal disease history was collected. Cognitive function was assessed by MMSE and DWRT under standardized protocols. Results 1. Significant dose-response relations across quintiles of metabolic equivalent value (METs) with DWRT score in participants with or without good self-rated health were found in cross-sectional analysis (all P for trend <0.001). 2. Prospectively, compared to those who were physically active, those with moderate activity or inactivity had increased risk for MCI. Regarding daily walking time, subjects with walking of 0.5 to 1 h, or ≥1 h had significantly reduced risk of MCI by 25% and 31% respectively compared with those who walked < 0.5 h per day. Subjects with low PA level at both baseline and follow-up had a significantly higher risk of MCI than those reporting PA at both baseline and follow-up. 3. Cross-sectionally, after adjustment for a range of potential confounders, an inverted U-shaped association between sleep duration and DWRT score was found, with 7 to 8 h of habitual sleep duration showing the highest score (P-values for trend from 3 to 7 h and from 7 to ≥10 h were all ≤0.001). Subjects with daily napping, morning tiredness, or insomnia had lower DWRT score than those without (P ranged from <0.001 to 0.01). 4. Prospectively, after adjustment for multiple risk factors, compared to sleep duration of 7 hours per day, those with sleep duration of 5 hours or less had increased risk for MCI by 43%. The adjusted P value for the linear trend from sleep duration of 3 hours to 7 hours per day was 0.01. The association remained after excluding those with poor health status. No significant associations of daytime napping, morning tiredness and insomnia with MCI were found. Conclusions In summary, we found a significant dose response association between PA and cognitive function in both cross-sectional and longitudinal analysis. One hour of daily walking is recommended for older Chinese people to delay or prevent cognitive decline. Short or long sleep duration may also be an important predictor of mild cognitive impairment. Sleep duration of less than 6 hours per day may indicate an increase risk of cognitive impairment in older people.
published_or_final_version
Community Medicine
Doctoral
Doctor of Philosophy

Myocardial infarction (MI) and stroke are the major causes of cardiovascular related morbidities and mortalities around the world. The prevalence of cardiovascular diseases has been increased in last decades and it is vital need of time to investigate this global problem with focus on risk population stratification. The aim of the present study is to investigate the association between individualized personality trait that is neuroticism and risk of MI and stroke has been investigated in a large population-based cohort of UK biobank.375,713 individuals (mean age: 56.24 ± 8.06) were investigated in this longitudinal study and were followed up for seven years to assess the association between neuroticism and risk of MI and stroke incidence. The neuroticism score was assessed by a 12-item questionnaire at baseline, while information related to MI and stroke events was either collected from hospital records and death registries or was self-reported by the participants. Cox proportional hazard regression adjusted for age, gender, BMI, socioeconomic status, lifestyle factors and medical histories for hypertension, diabetes and depression was used. All statistical analyses were performed using R software. In fully adjusted model, a one standard deviation increase in neuroticism score was associated with 1.05-fold increased risk for MI. (HR=1.047(1.009-1.087), p=0.015). However, no significant association was observed between neuroticism score and incident stroke as well as between neuroticism score and overall cardiovascular disease (MI and stroke combined). Results from the present study indicate that neuroticism is a risk factor for MI but not for stroke. These findings suggest that personality traits such as neuroticism may prove to be helpful in efficient risk stratification and pre-clinical diagnosis of individuals at risk for MI.

La bioetica è il luogo ideale per cercare risposte ai grandi interrogativi concernenti la vita, la morte e la cura dell'essere umano. I recenti dibattiti sull'uso, ed il temuto abuso, del corpo umano in medicina hanno messo in evidenza la necessità di una discussione approfondita sul potere di scelta che l'individuo può esercitare sulla propria mente e sul proprio corpo. Spinta dal desidero di indagare l'estensione di tale potere di scelta ho voluto analizzare le tematiche riguardanti “il corpo”, “l'individuo”, “la proprietà” e “l'autodeterminazione”. L'analisi è stata condotta individuando alcuni dei differenti significati che questi termini assumono nei diversi ambiti che la bioetica lambisce e mostrando, in particolare, la visione di tale realtà attraverso le lenti del giurista. A chi appartiene il corpo? Chi ha il potere di decidere su di esso? Il potere di scelta valica gli antichi i confini legati al corpo del paziente e coinvolge tessuti, organi e cellule staccati dal corpo umano, parti che un tempo erano considerati scarti operatori sono oggi divenuti tesori inestimabili per la ricerca. L'importanza assunta dai campioni biologici ha portato alla creazione di biobanche nelle quali sono raccolti, catalogati e il DNA studiato in campioni biologici Le biobanche riflettono le tensioni della bioetica e del biodititto. Lo studio delle biobanche riguarda, tra l'altro, la riceca dell'equilibrio tra le diverse esigenze meritevoli di tutela: in primo luogo il diritto alla privacy, diritto a che le “proprie informazioni” non vengano divulgate ed il diritto a non essere discriminato ed in secondo luogo le necessità dettate dalla ricerca e dalla scienza medica. Nel 2009 la rivista Times messo biobanche tra le 10 idee in grado di cambiare il mondo anche in considarazione della medicina personalizzata e del fatto che costituiscono una la speranza per la ricerca contro le malattie attuali e future.
Bioethics is the perfect field to look for answers concerning life, death and medical care. Bioethics starts from the interaction among 3 mains points of view: medical, ethical and legal. Recent debates about uses and abuses of human body in medicine have highlighted the need for a thorough discussion of the uses of bodies. New forms of intervention on the body pose an alternative to the legal status of the person and its body property, commodity or gift. Who belongs my body? The power of choice belong to whom? The power of choice overcomes the old boundaries related to the patient's body. Self determination expresses individual freedom of choice; in healthcare decision-making power is part of the process of sharing treatment decisions between the doctor and the patient. Now bioethics involves the organ tissues and cells stored outside a given person, previously considered unuseful left-overs, which today have become invaluable treasures for researchers. From a physical dimension the focus has now been shifted also to an informational dimension. The extensive role of shared biological samples has led to the creation of biobanks in which they are collected, cataloged and the DNA studied in tissue samples and stem cells from umbilical cord blood. Biobanks are, in fact, at the same time an example of bio-ethical tension and a bio-law early hour representative. The priority regarding biobanks is thoughtful balance concerning the different needs deserving protection: firstly the right to privacy, right to self-disclosure, non-discrimination law and secondly, the requirements dictated by the research and diagnostic - medical science. In 2009 Times magazine put biobanks among the 10 ideas changing the world right now. Biobanks are the key for our future because they involve personalized medicine, hope against current and future disease, particularly in rare disease research.

La bioetica è il luogo ideale per cercare risposte ai grandi interrogativi concernenti la vita, la morte e la cura dell'essere umano. I recenti dibattiti sull'uso, ed il temuto abuso, del corpo umano in medicina hanno messo in evidenza la necessità di una discussione approfondita sul potere di scelta che l'individuo può esercitare sulla propria mente e sul proprio corpo. Spinta dal desidero di indagare l'estensione di tale potere di scelta ho voluto analizzare le tematiche riguardanti “il corpo”, “l'individuo”, “la proprietà” e “l'autodeterminazione”. L'analisi è stata condotta individuando alcuni dei differenti significati che questi termini assumono nei diversi ambiti che la bioetica lambisce e mostrando, in particolare, la visione di tale realtà attraverso le lenti del giurista. A chi appartiene il corpo? Chi ha il potere di decidere su di esso? Il potere di scelta valica gli antichi i confini legati al corpo del paziente e coinvolge tessuti, organi e cellule staccati dal corpo umano, parti che un tempo erano considerati scarti operatori sono oggi divenuti tesori inestimabili per la ricerca. L'importanza assunta dai campioni biologici ha portato alla creazione di biobanche nelle quali sono raccolti, catalogati e il DNA studiato in campioni biologici Le biobanche riflettono le tensioni della bioetica e del biodititto. Lo studio delle biobanche riguarda, tra l'altro, la riceca dell'equilibrio tra le diverse esigenze meritevoli di tutela: in primo luogo il diritto alla privacy, diritto a che le “proprie informazioni” non vengano divulgate ed il diritto a non essere discriminato ed in secondo luogo le necessità dettate dalla ricerca e dalla scienza medica. Nel 2009 la rivista Times messo biobanche tra le 10 idee in grado di cambiare il mondo anche in considarazione della medicina personalizzata e del fatto che costituiscono una la speranza per la ricerca contro le malattie attuali e future.
Bioethics is the perfect field to look for answers concerning life, death and medical care. Bioethics starts from the interaction among 3 mains points of view: medical, ethical and legal. Recent debates about uses and abuses of human body in medicine have highlighted the need for a thorough discussion of the uses of bodies. New forms of intervention on the body pose an alternative to the legal status of the person and its body property, commodity or gift. Who belongs my body? The power of choice belong to whom? The power of choice overcomes the old boundaries related to the patient's body. Self determination expresses individual freedom of choice; in healthcare decision-making power is part of the process of sharing treatment decisions between the doctor and the patient. Now bioethics involves the organ tissues and cells stored outside a given person, previously considered unuseful left-overs, which today have become invaluable treasures for researchers. From a physical dimension the focus has now been shifted also to an informational dimension. The extensive role of shared biological samples has led to the creation of biobanks in which they are collected, cataloged and the DNA studied in tissue samples and stem cells from umbilical cord blood. Biobanks are, in fact, at the same time an example of bio-ethical tension and a bio-law early hour representative. The priority regarding biobanks is thoughtful balance concerning the different needs deserving protection: firstly the right to privacy, right to self-disclosure, non-discrimination law and secondly, the requirements dictated by the research and diagnostic - medical science. In 2009 Times magazine put biobanks among the 10 ideas changing the world right now. Biobanks are the key for our future because they involve personalized medicine, hope against current and future disease, particularly in rare disease research.

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.