1,721,218 research outputs found
Unravelling the genetic basis of hereditary disorders by high-throughput exome sequencing strategies
Get PDFThe research presented in this thesis focuses on using Whole Exome Sequencing (WES) to unravel the genetic basis of human hereditary disorders with different inheritance patterns. We set out to apply WES as a diagnostic approach for establishing a molecular diagnosis in a highly heterogeneous group of patients with microcephaly and varied intellectual disability. Additionally, a family with familial glucocorticoid deficiency (FGD) and a cohort of patients with L1 syndrome were studied. In our microcephaly project, we achieved a diagnostic yield of 29% and found mutations in known disease-genes. Our results confirmed that many microcephaly cases are explained by autosomal recessive inheritance. For FGD, trio-exome sequencing revealed a novel homozygous mutation in the NNT gene. We also reviewed the literature for all reported NNT mutations and their clinical presentation. By application of X-exome sequencing in a cohort of 58 patients with L1 syndrome, an X-linked disorder, we identified 5 possible novel candidate genes, among which three independent mutations in DACH2 suggest this gene as the most promising candidate gene for L1 syndrome. Finally, using an in silico composite biological network analysis, we identified molecular pathomechanisms underlying congenital microcephaly (CM) and predicted further CM-candidate genes. Next to known processes, our analysis suggested, telomere biology and tRNA metabolic process as biological functions underlying CM. Supportive evidence for several selected candidate genes demonstrated the potential of our network approach to facilitate gene discovery in genetically heterogeneous disease
Inflammatory biomarker genomics: From discovery to causality
Get PDFInflammatory biomarkers are a group of proteins circulating in the blood that play key roles in inflammation. The blood levels of these are partially genetically determined, and elevated levels are hallmarks for various types of diseases and sometimes even directly implicated in pathogenesis. In this thesis I aimed to identify previously unknown genetic regions (‘loci’) for well-known inflammatory biomarkers, to understand how they influence molecular levels, and whether they play a causal role in various diseases. After the preface (Chapter 1), I present three large-scale genome-wide association studies (GWASs) that led to the identification of new genetic loci for levels of four inflammatory biomarkers: TNF-α, Interleukin-6, serum albumin and total protein (Chapter 3,4 and 5, respectively). These analyses were supported by a software pipeline that automated data quality checks for these studies (Chapter 2). In Chapter 6, we focussed on disentangling the molecular mechanisms through which genetic determinants influence levels of one of the most widely clinically used inflammatory biomarkers, C-Reactive Protein, followed by an investigation of its involvement in multiple disease classes (Chapter 7). I conclude with a review on GWAS for Coronary Artery Disease (Chapter 8), and argue that we can improve our understanding of the mechanisms by which genetic loci influence traits of interest through the integration with other layers of molecular data, an approach known as systems genetics. This research has increased our biological understanding of genetic determinants of inflammatory biomarkers and provides further leads for investigation of their direct involvement in the pathogenesis of disease
Nutrients and diet quality in gastrointestinal cancers
Get PDFFindings on the role of foods in the risk of gastrointestinal cancers are not consistent. This thesis studied the role of some essential dietary components that are required for normal development and function, as well as that of balanced and healthy patterns of diet intake, on the risk of gastrointestinal cancers. We show that neither synthetic folic acid nor the blood level folate is associated with an increased risk of colorectal cancer (Chapter 2). However, the results of a large study show that supplementing folic acid and iron at higher levels than provided in the original food may increase the risk for colorectal cancer (Chapter 3). The risk of colorectal cancer also seems not to be increased for pregnant women taking synthetic folic acid according to data from smaller study (Chapter 4). As anticipated, healthy and balanced diet intake patterns are associated with lower risks of gastrointestinal cancers, yet the findings are of insufficient quality to develop dietary recommendations for gastrointestinal cancers prevention (Chapters 5, 6, & 7). Moreover, healthy food intake is inadequate among cancer survivors (Chapter 8). The effect of folic acid and iron, as well as that of a healthy and balanced pattern of food and beverage intake, remain unclear regarding gastrointestinal cancer. Future studies will need to assess the role of inherited features on the effect of essential nutrients in diet and on the healthiest patterns of diet intake needed to prevent gastrointestinal cancer
Bioinformatics of genomic association mapping
Get PDFIn this thesis we present an overview of bioinformatics-based approaches for genomic association mapping, with emphasis on human quantitative traits and their contribution to complex diseases. We aim to provide a comprehensive walk-through of the classic steps of genomic association mapping illustrating the application and development of bioinformatics tools along the way. We start with a classic heritability study, continue with providing novel tools for genome-wide association studies (GWASs) of complex traits, and end with an integrated post-GWAS pipeline for translating GWAS findings of any human trait or disease to biological knowledge. Using this A-to-Z approach, we emphasize the importance of following the consecutive steps of genomic association mapping. To show how bioinformatics tools can facilitate and support analysis of high-throughput biological data, in Chapters 2, 3, 5, 6, and 7 we applied a number of already available tools, whereas in Chapters 3, 4, and 7 we developed novel bioinformatics tools supporting appropriate analysis of “big data” for genomic association mapping. Our in-house developed and extensively documented bioinformatics tools are freely available to the scientific community for further use. Furthermore, and as a running example of genomic association mapping of a typical human complex trait, we strictly adhered to serum levels of C-reactive protein (CRP). Using appropriate bioinformatics-based tools, either already available or our in-house developed ones, we succeeded to gain in knowledge of biological mechanisms controlling serum levels of CRP as well as its (causal) contribution to the pathophysiology of human diseases
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Statistical approaches to explore clinical heterogeneity in psychosis
Get PDFPsychotische stoornissen tonen een zeer heterogeen klinisch beeld; iets wat vaak over het hoofd wordt gezien. Doel van dit proefschrift is om inzicht te krijgen in de heterogeniteit, stabiliteit en familiaire kwetsbaarheid van mensen met een psychose en hun broers/zussen. Om deze heterogeniteit en stabiliteit aan te tonen werd gebruikt gemaakt van classical clustering, linear, generalized linear mixed effects en group-based trajectory modeling (GBTM). Wat betref heterogeniteit, lieten we zien dat Duda en Hart de geschikte index is om cluster te identificeren. Daarmee bevestigden wij eerder studie over cognitieve subtypes vanuit het GROUP-project. Vervolgens toonden we de waarde van deze subtypes aan in de loop van de stoornis met behulp van GBTM. Stabiliteit bleek een belangrijk kenmerk bij cognitie te zijn, maar niet bij negatieve symptomen. Familiaire kwetsbaarheid kwam tot uiting in cognitie ( siblings presteerden tussen controles en patiënten), in somatische comorbiditeit (risico voor siblings lag ook tussen beide) en in psychotische belevingen (meer aanwezig bij siblings dan bij controles). Binnen dit proefschrift werd een aantal verschillende predictoren geïdentificeerd. Het cognitieve profiel van de patiënten voorspelden de cognitie van siblings. Bovendien bleek de Theory of Mind bij siblings een voorspeller voor psychotische belevingen, drie jaar later. Negatieve symptomen voorspelden functioneren in de tijd. Bij multimorbiditeit bleek familiaire kwetsbaarheid de belangrijkste voorspeller. Tenslotte was migratie de belangrijkste risicofactor voor duur van de onbehandelde psychose. Concluderend, heterogeniteit bij psychosen is een klinisch relevant concept. Subtypering van patiënten opent nieuwe wegen naar inzicht en behandeling van mensen met een psychose
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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