1,721,721 research outputs found
A Principal Component Informed Approach to Address Polygenic Risk Score Transferability Across European Cohorts
Full text linkOne important confounder in genome-wide association studies (GWASs) is population genetic structure, which may generate spurious associations if not properly accounted for. This may ultimately result in a biased polygenic risk score (PRS) prediction, especially when applied to another population. To explore this matter, we focused on principal component analysis (PCA) and asked whether a population genetics informed strategy focused on PCs derived from an external reference population helps in mitigating this PRS transferability issue. Throughout the study, we used two complex model traits, height and body mass index, and samples from UK and Estonian Biobanks. We aimed to investigate 1) whether using a reference population (1000G) for computation of the PCs adjusted for in the discovery cohort improves the resulting PRS performance in a target set from another population and 2) whether adjusting the validation model for PCs is required at all. Our results showed that any other set of PCs performed worse than the one computed on samples from the same population as the discovery dataset. Furthermore, we show that PC correction in GWAS cannot prevent residual population structure information in the PRS, also for non-structured traits. Therefore, we confirm the utility of PC correction in the validation model when the investigated trait shows an actual correlation with population genetic structure, to account for the residual confounding effect when evaluating the predictive value of PRS
Genetic influence on age at first birth of female twins born in the UK, 1919-68
No full textUsing a sample of monozygotic (945, 42 per cent) and dizygotic (1,329, 58 per cent) twin pairs born 1919–68 in the UK, we applied innovative tobit models to investigate genetic and environmental influences on age at first birth (AFB). We found that a substantial part (40 per cent) of the variation in AFB is caused by latent family characteristics. Genetic dispositions (26 per cent) play a more important role than the shared environment of siblings (14 per cent), with the non-shared environment/measurement error having the strongest influence (60 per cent). Like previous studies, this study reveals marked changes in estimates over time, and supports the idea that environmental constraints (war or economic crisis) suppress and normative freedom (sexual revolution) promotes the activation of genetic predispositions that affect fertility. We show that the exclusion of censored information (i.e., on the childless) by previous studies biased their results
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Personalized pharmacotherapy of psychosis : clinical and pharmacogenetic approaches
Full text linkDespite 60 years of antipsychotic drugs, the pharmacotherapy of psychosis is still far from ideal. In particular side-effects, such as weight gain and therapy induced movement disorders, are major problems. The aim of this thesis is to contribute to the development of personalised medicine for the treatment of psychosis through the study of clinical factors in the use of oral and depot antipsychotic drugs, and the pharmacogenetics of antipsychotic response and drug-induced side effects. Several clinical factors were determined that predict which patients switch form oral to depot treatment, including the presence of movement disorders, lack of compliance, and lack of psychiatric co-morbidity. New associations were found between various polymorphisms in receptor genes and metabolic disturbances and movement disorders in patients on antipsychotic medication. The researchers were not able to replicate several associations of polymorphisms that were found in earlier studies. Negative results and lack of replication are common in pharmcogenetic studies of antipsychotic drugs. There is growing evidence that environmental, ethnic and many other factors affect the link between genetic variation and the efficacy of antipsychotic drugs.
Inflammatory biomarker genomics: From discovery to causality
Full text linkInflammatory 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
The genetics of heart rate variability
Full text linkHartslagvariabiliteit (HRV) is de slag-tot-slag variatie tussen opeenvolgende hartslagen gedurende een bepaalde periode en is een betrouwbare, niet-invasieve, economische maat die duidt op veranderingen in cardiale regulatie door het autonome zenuwstelsel in reactie op fysiologische en psychologische problemen. Afwijkingen van autonome activiteit gereflecteerd door een verlaagde HRV worden sterk geassocieerd met een verhoogd risico op cardiale gebeurtenissen, plotselinge hartdood en mortaliteit. Het was al bekend dat genetische factoren betrokken zijn bij HRV, maar er zijn nog geen genen voor gevonden. Daarom richt dit proefschrift zich op het ontrafelen van de genetische achtergrond van HRV. Ik heb laten zien dat 10seconden electrocardiogrammen (ECGs) al valide metingen geven om HRV maten in het tijdsdomein te bepalen, wat impliceert dat met routinematig verzamelde ECGs de steekproefgrootte van (genetisch) epidemiologische studies enorm vergroot kan worden. In een erfelijkheidsstudie heb ik aangetoond dat HRV zowel in rust als in stress erfelijk is en dat het merendeel van de genen die HRV in deze condities beïnvloeden, dezelfde zijn met enkele genen die specifiek zijn voor de stresscondities. In een kandidaatgenstudie heb ik de associatie bekeken van acht genen die betrokken zijn bij acetylcholine transport en afbraak, met HRV, maar dit leverde geen significante resultaten. In een meta-analyses van genoom-brede associatiestudies met meer dan 50.000 Caucasische personen werden 11 genetische varianten gevonden in acht regio’s die geassocieerd zijn met HRV. De meeste werden ook teruggevonden in Spaanse/Latijnse of Afrikaans-Amerikaanse mensen. In deze acht regio’s konden we negen genen aanwijzen die mogelijk causaal gerelateerd zijn met HRV
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