1,721,273 research outputs found
Statistical approaches for copy number variation detection and association with complex human phenotypes
Full text linkCopy number variants (CNVs) play an important role in the disease pathogenesis, including epilepsy, diabetes and many others. CNVs, are also known to affect cellular phenotypes through several phenomenon such as gene dosage.
Next generation technologies for sequencing (DNA and RNA) and metabolite profiling (metabolomics) has led to the systematic discovery and evaluation of various genomic variants and their relationship to multiple phenotypes. Such approaches often involve application of several statistical and machine learning methods for unravelling new relationships between genomic variants and phenotypes i.e. disease outcomes or quantitative traits characterized at the molecular level.
This thesis explores and develops several statistical methods for CNV detection and association with complex human phenotypes, in particular for epilepsy drug-response, epilepsy susceptibility, metabolomics and gene expression.
In more detail, chapter 3, describes a genome wide CNV association analysis for two phenotypes including epilepsy susceptibility and epilepsy drug response. I have identified several important candidate genes for these two phenotypes, including the top most associated genes, SLC9A1 (p-value=6.69E-15) for epilepsy susceptibility and WWOX (p-value=1.93E-3) for epilepsy drug response. These associations were replicated in a separate Australian cohort and were further validated in lab and in-silico, leading to some positive and negative confirmation.
In chapter 4, I present CNV association with metabolomic data in the exonic regions of the TSPAN8 gene. A strong association signal was detected in the 6th exon and 7th exon of the TSPAN8 gene, where a large proportion of metabonomic lipid phenotypes were found to be associated with univariate (P-value=7.64E-4) and multivariate (P-value=1.33E-6) approaches. These CNVs were also found to be nominally associated with type 2 diabetes (P-value=3.32e-7). In addition, I also carried out advanced multivariate based association analysis to corroborate these results and further reported sequencing based validation results for TSPAN8 exonic CNVs in different human populations from the 1000 genomes project.
In chapter 5, I report a genome wide CNV association analysis with gene expression in ten different regions of the human brain. I identified a novel CNV near the DRD5 gene which was found to be strongly associated with gene expression. Further, I have reported on-going efforts to replicate and validate this finding.
Each of these different phenotype categories analysed posed its own unique challenges and required specific approaches for analysis and interpretation.Open Acces
Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight
Full text linkTo identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy
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
Disséquer les facteurs génétiques contribuant à la prédisposition partagée à l'obésité et au cancer
No full textL'obésité est une affection courante et complexe qui pose de graves problèmes de santé dans le monde entier. Elle est également un facteur de risque critique connu pour certaines maladies non transmissibles, dont les cancers. Différentes mesures anthropométriques telles que l'indice de masse corporelle (IMC) et le rapport taille hanche (RTH) ont été utilisées pour évaluer l'obésité. Ce dernier est un indice de l'obésité centrale ou abdominale, tandis que le premier représente l'obésité totale ou globale. Des études épidémiologiques fournissent des preuves que les mesures de l'obésité centrale et de l'obésité globale peuvent avoir un rapport différent avec le risque de cancer. Les mécanismes physiologiques exacts qui permettent la comorbidité entre l'obésité et le cancer restent flous. Cependant, certains facteurs tels que les facteurs de croissance analogues à l'insuline, l'hyperglycémie, la dérégulation du profil lipidique et les facteurs adipokines ont fait l'objet d'hypothèses. Les études d'association pangénomique (GWAS) ont identifié de nombreuses variations génétiques communes pour les phénotypes de l'obésité et du cancer. Cependant, cesvariations ne fournissent que de modestes indices sur la comorbidité sous-jacente.Néanmoins, les résultats des études d'association pangénomique peuvent être appliqués à des méthodes statistiques telles que les scores polygéniques et la randomisation Mendélienne (MR) qui aident à démêler les déterminants communs.Dans ce projet de doctorat, j'ai évalué l'impact de l'obésité globale et centrale sur le risque de cancers, notamment le cancer du sein, le cancer du sein postménopausique,le cancer de la prostate, le cancer colorectal, le cancer du poumon et le cancer du pancréas. J'ai défini la corrélation génétique entre l'IMC/l’RTH et les cancers en utilisant l'ensemble des données de la UK Biobank. J'ai ensuite utilisé des loci génomiques établis pour l'IMC et l’RTH afin de créer des scores polygéniques d'obésité dont l'association avec les phénotypes de cancer a ensuite été testée dans la UK Biobank. En outre, à l'aide de variantes génétiques établies associées à ces phénotypes, j'ai effectué une MR entre les deux phénotypes d'obésité et trois cancers(sein, prostate et colorectal) afin d'étudier les relations causales entre eux.Obesity is a common, complex condition that poses serious health problems worldwide.It is also a known critical risk factor for some non-communicable diseases including cancers. Different anthropometric measures such as body mass index (BMI) andwaist-to-hip ratio (WHR) have been used to assess obesity. The latter is an index for central or abdominal obesity while the former represents total or overall obesity. Epidemiological studies provide evidence that central and overall obesity measures mayrelate to cancer risk differently. The exact physiological mechanisms that enable the obesity and cancer co-morbidity remain unclear. However, certain factors such as insulin-like growth factors, hyperglycaemia, dysregulated lipid profile and adipokine factorshave been hypothesised. Genome-wide association studies (GWAS) have identifiednumerous common genetic variations for obesity and cancer phenotypes. However,these variations provide only modest clues as to the underlying comorbidity. Nevertheless,output from GWAS can be applied to statistical methods such as polygenicscores and Mendelian randomization that aid in the unravelling of shared determinants.In this PhD project, I assessed the impact of overall and central obesity on the risk of cancers including overall breast, post-menopausal breast, prostate, colorectal, lungand pancreatic cancers. I defined the genetic correlation between BMI/WHRadjBMIand cancers using the UK Biobank dataset. I then used established BMI and WHRadjBMI genome-wide loci to create obesity polygenic scores which were then tested for association with cancer phenotypes in the UK biobank. Further, using established genetic variants associated with these phenotypes, I performed MR between the two obesity phenotypes and three cancers (breast, prostate and colorectal) to investigate the causal relationships between them
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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe 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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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