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.

Universiẗat, Diss.--Bochum, 2008.

In der vorliegenden Arbeit wurden 16 Parameter analysiert, die im Rahmen der Herzinsuffizienzdiagnostik eine wichtige Rolle spielen. Alle Bioproben waren an den KNHI-Standorten Würzburg und Göttingen gewonnen worden. Ein Teil der so gewonnenen Biomaterialien wurde lokal analysiert und bei -80°C eingelagert (Erstmessung oder Basismessung), ein Teil wurde nach Berlin versandt und dort unter standardisierten Bedingungen in der KNHI-Biobank bei -80°C eingelagert. Nach 6-8 Jahren wurden gezielt Samples aus der KNHI-Biobank angefordert, nach Würzburg versandt, aufgetaut, und zum zweiten Mal gemessen (Nachmessung). Die Messergebnisse aus Pärchen von Serum- und EDTA-Proben aus den lokalen und zentral gelagerten Bioproben wurden verglichen (insgesamt somit 4 Gruppen) und statistisch analysiert (Korrelation, Bestimmtheitsmaß R², Streudiagramme, Bland-Altman-Analysen, Regression, 95%-Übereinstimmungsintervalle, Confounderanalyse). Je nach Parameter wurden zwischen 103 und 322 Probenpaare in die Analyse eingeschlossen. Es konnte gezeigt werden, dass die Lagerung von Biomaterial bei -80°C sinnvoll ist, um in der Zukunft eine genügende Zahl an Patientenwerten für Studien und Analysen bezüglich des Krankheitsbilds Herzinsuffizienz zur Verfügung zu haben. Die Qualität gerade der prognostisch wichtigen Marker hsCRP und NT-proBNP ist als sehr gut zu bewerten, was es dem KNHI ermöglichen dürfte, fast alle eingelagerten Proben zu nutzen. Es wurden verschiedene Akzeptanzbereiche definiert, die sich bei allen Parametern mit Ausnahme von Natrium und Kalium aus den 95%-Übereinstimmungsintervallen der durchgeführten Bland-Altman-Analysen bilden. / In the present study, 16 parameters were analyzed which play an important role in heart failure diagnostics. All biomarkers had been obtained at the KNHI sites in Würzburg and Göttingen. Part of the biomaterial obtained was analyzed locally and stored at -80 ° C (initial measurement or basic measurement), a part was shipped to Berlin and stored there under standardized conditions in the KNHI biobank at -80 ° C. After 6-8 years, samples from the KNHI biobank were requested, sent to Würzburg, thawed, and measured for the second time (final or second measurement). The results from pairs of serum and EDTA samples from the local and centrally stored bioassays were compared (total of 4 groups) and analyzed statistically (correlation, coefficient of determination R², scatterplots, Bland-Altman analyzes, regression, 95% limits of agreement, confounder analyses). Depending on the parameter, between 103 and 322 sample pairs were included in the analyses. It has been shown that the storage of biomaterial at -80 ° C makes sense, in order to have a sufficient number of patient values ​​for studies concerning the disease heart failure available in the future. The quality of the prognostically important markers hsCRP and NT-proBNP is very good, which should allow the KNHI to use almost all stored samples. Various acceptance ranges have been defined for all parameters except sodium and potassium from the 95% limits of agreement of the Bland-Altman analyzes performed.

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.

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.

Zugl.: Mannheim, Universiẗat Diss., 2007.

Yes / Over the next decade the number of humans venturing beyond Earth is projected to rapidly increase in both quantity and diversity. Humans will regularly fly to the International Space Station until it is decommissioned by 2031, will return to the Moon by 2025 via the Artemis programme, and will fly to space via commercial ventures. Spaceflight presents a hazardous environment for human health. To understand spaceflight-associated health risks further and to increase safety via advanced healthcare approaches, including personalised medicine, more data must be collected. Importantly, this data must be derived from a diverse cohort of participants and a range of mission formats. We propose that the UK should start to consider all citizens venturing into space as potential participants from which health and biological data could be consensually collected. Importantly, we believe that this routine data collection programme should adopt a similar strategy to the UK National Health Service and the UK Biobank, by including "omics" data for scientific and healthcare purposes. We consider how such a world-leading programme, kick-started via a pilot study, might be realised through appropriate policy design, including which measures to collect, when to collect them, and unique ethical considerations pertaining to the spacefaring population. / H.C. is supported by the Horizon Centre for Doctoral Training at the University of Nottingham (UKRI grant no. EP/ S023305/1).

No description available.

The quality of biospecimens stored in a biobank depends tremendously on the technical personnel responsible for processing, storage, and release of biospecimens. Adequate training of these biobank employees would allow harmonization of correct sample handling and thus ensure a high and comparable quality of samples across biobank locations. However, in Germany there are no specific training opportunities for technical biobank staff. To understand the educational needs of the technical personnel a web-based survey was sent to all national biobanks via established e-mail registers. In total, 79 biobank employees completed the survey, including 43 technicians. The majority of the participating technical personnel stated that they had worked in a biobank for less than three years and had never participated in an advanced training. Three-quarters of the technicians indicated that they were not able to understand English content instantly. Based on these results and the results of a workshop with 16 biobank technicians, 41 learning objectives were formulated. These learning objectives can be used as a basis for advanced training programs for technical personnel in biobanks. Setting up courses based on the identified learning objectives for this group of biobank staff could contribute to harmonization and sustainability of biospecimen quality.

Glioblastoma multiforme (GBM) is the most common and lethal form of primary brain tumor that mainly affects adults. GBM displays remarkable intra- and inter-tumoral heterogeneity and contains a subpopulation of cells named glioma stem cells that is believed to be responsible for tumor maintenance, progression and recurrence. We have established and characterized a biobank of 48 cell lines derived from GBM patients. The cells were explanted and maintained as adherent cultures in serum-free, defined neural stem cell medium. These GBM cells (GCs) displayed NSC marker expression in vitro, had orthotopic tumor initiating capability in vivo, harboured genomic alterations characteristic of GBM and represented all four TCGA molecular subtypes. Our newly established biobank is also connected with a database (www.hgcc.se) that provides all molecular and clinical data. This resource provides a valuable platform of valid in vitro and in vivo models for basic GBM research and drug discovery. By using RCAS/tv-a mouse models for glioma, we found that GBMs originating from a putative NSC origin caused more tumorigenic GCs that had higher self-renewal abilities than those originating from putative glial precursor cell origin. By transcriptome analysis a mouse cell origin (MCO) gene signature was generated to cluster human GCs and GBM tissue samples and a functional relationship between the differentiation state of the initially transformed cell and the phenotype of GCs was discovered, which provides the basis for a new predictive MCO-based patient classification. LGR5 was found to be highly expressed in the most malignant mouse GC lines of putative NSC origin and also enriched in proneural GBMs characterized by PDGFRA alterations and OLIG2 up-regulation. By overexpressing or depleting LGR5 we discovered that high LGR5 expression in proneural GC lines increased the tumorigenicity, self-renewal and invasive capacities of the cells and could potentiate WNT signalling through its ligand RSPO1. Through transcriptome analysis we identified the candidate genes CCND2, PDGFRA, OLIG2, DKK1 that were found to be regulated by LGR5. In the last study, we found that mouse OPCs could initiate both astrocytic and oligdendroglial gliomas, which indicated that oncogenic signalling is dominant to cell of origin in affecting the histology of gliomas.