1,721,115 research outputs found
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
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Unravelling the structural complexity of the human genome using linked-read sequencing and optical mapping technologies
Get PDFElucidating the full spectrum of genetic variations across the human population is a fundamental pursuit in scientific research as it underlies the complex interplay between genotype and phenotype. However, most resequencing studies performed to date rely on short read technologies and the lack of long-range sequence information precludes comprehensive structural variations (SVs) analysis. While numerous SV algorithms can pinpoint deletion breakpoints with high sensitivity, it is much more challenging to detect other types of SVs as they cannot be directly inferred through an alignment-based approach. In this dissertation, we leveraged state-of-the-art technologies that allow for long-range genome sequencing and mapping to comprehensively evaluate SVs in the context of population genetics and genomic medicine. To improve the current representation of the human reference genome, we utilized 10x Genomics (10xG) whole genome linked-read sequencing to generate de novo assemblies of 328 genomes from around the world. We breakpoint-resolved 18Mb of genomic sequences missing from the reference genome—aka Non-reference Unique Insertions (NUIs)—and linearly integrated them into the GRCh38 primary chromosomal assemblies so that these NUIs can be annotated based on the local genomic context. We demonstrated that many of these NUIs can be found in the human transcriptome and hence are likely to have functional significance. Our proof-of-concept reference representation will allow researchers to identify biologically relevant polymorphisms beyond what is currently detected, thus enhancing the interpretability of all existing and future short-read whole genome sequencing datasets.Furthermore, we applied either linked-reads or in conjunction with Bionano optical mapping in two precision medicine projects to identify disease-causal variants that previously evaded detection. In the first project, whole genome linked-read sequencing was performed on two families with homozygous familial hypercholesterolemia to determine the underlying genetic etiology of the disease. In the second project, we applied both technologies on 50 undiagnosed children with suspected genetic diseases along with their parents. Our automated informatics pipeline identified 16 clinical diagnoses, with which 25% of these cases were attributed to cryptic SVs. Our results substantiated the use of long-range sequencing and mapping in patients with genetic diseases, and their applications in genomic medicine provides a path forward for bringing tremendous precision to clinical diagnosis, thereby fulfilling the promise of individualized medicine
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Blood Pressure Polygenic Scores, Target Organ Damage, and Antihypertensive Drug Effects: Insights from longitudinal Real-World Clinical Data
No full textHigh blood pressure is a leading cause of disability-adjusted life years (DALYs) worldwide and a major risk factor for adverse health outcomes, including cardiovascular disease, kidney disease, heart failure, and all-cause mortality. Blood pressure (BP) is highly heritable, with narrow-sense heritability estimates of at least 0.2 for systolic and diastolic blood pressure and over 1,000 genome-wide association study (GWAS) loci identified. Polygenic risk scores (PRS) summarize an individual's genetic predisposition to a trait or disease based on the combined effects of genetic variants. While PRS have potential applications in disease risk prediction and population screening, their performance varies based on the context of evaluation. Factors such as age, sex, medication use, ancestry, and their interactions influence the predictive power of BP PRS, which often perform worse in underrepresented populations. This dissertation utilizes longitudinal, real-world clinical data to examine the prediction accuracy of BP PRS across sex, age, and ancestry groups, assess their associations with target organ damage outcomes such as chronic kidney disease, and evaluate BP response to first line monotherapy antihypertensive medications by ancestry and drug class. In the first chapter of my dissertation, I investigate the associations between multi-ancestry polygenic risk scores (PRSs) for blood pressure (BP) traits in a real-world EHR-based clinical cohort by sex, antihypertension medication use, and ancestry. I then looked at the effect of age on PRS association with BP traits and how variance explained by PRS changes with age across ancestry groups. Summary statistics from the meta-analysis of UKB, ICBP, and BioVU, COGENT and Biobank Japan were used to train multi-ancestry PRSs for diastolic blood pressure (DBP) and systolic blood pressure (SBP), using PRS-CSx. I then tested these PRSs in the Kaiser Permanente (KP) Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, in which individuals had multiple office visit BP measures across their life-course. The primary outcomes were DBP and SBP measurements. I tested the exposures (DBP and SBP PRS) on the outcomes using linear mixed models, stratified by sex (female/ male), ancestry group (African American, East Asian, European, Latino(a)) controlling for relevant covariates. I further stratified analyses by evenly sized age-bins. In a sensitivity analysis using individuals with both treated and untreated measures, I further stratified analyses by antihypertension (AHT) medication use (whether the BP measure was treated or not). I found significant differences in BP PRS prediction accuracy, by ancestry, sex, age across ancestries and antihypertension medication use. The estimated associations and prediction accuracy measured by percent variance explained (PVE) by the PRSs for BP traits varied across strata of ancestry, sex. Generally, females had higher PVE then males. The highest PRS PVE was in Latino(a) ancestry (female) with PVE of 2.27% in SBP and 2.14% DBP, followed by European, 1.92 % SBP and 1.7% DBP, then East Asian at 1.13% SBP and 1.7% DBP, and African American ancestries at 0.42 % SBP, and 0.76% DBP. PVE peaked at midlife and tailed off, except in Afr SBP-PRS where the accuracy dropped off drastically from early age. The PVE was higher in BP outcome measures that were not treated compared to treated across all the ancestry groups.
In a real-world clinical multi ancestry cohort of ~100 000 US adults (GERA) within the same healthcare system, I show significant differences in multi-ancestry BP PRS prediction accuracy (measured by PVE) by ancestry, sex, age and antihypertension treatment status within Afr, Eas, Eur, Lat ancestry groups. This highlights the challenges of using multi-ancestry BP-PRS in real-world clinical settings, even though the PRS is constructed using multiple ancestry GWAS with large samples sizes.
In the second chapter of my dissertation, I investigated the association between multi-ancestry PRSs BP and the incidence of target organ damage (TOD) clinical phenotypes at any age: chronic kidney disease (CKD), and cardiovascular disease (CVD) outcomes: Ischemic stroke (IS), heart failure (HF), atrial fibrillation (Afib), cardiomyopathy (CMP), coronary artery disease (CAD) and myocardial infarction (MI) in a real-world clinical cohort across African (Afr), East Asian (Eas), European (Eur), and Latino(a) (Lat) ancestry groups. I constructed multi-ancestry PRSs for SBP and DBP using summary statistics from genome-wide association studies (GWAS) of the UKB, ICBP, BioVU meta-analysis, the COGENT collaboration, and Biobank Japan. I then used these PRSs to test their association with TOD incidence in the Kaiser Permanente (KP) Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. The primary outcome was incidence of each TOD, with age as the time scale in the analysis. Individuals entered the risk set at their age of entry into the cohort and were followed until the age at which they experienced the TOD or were censored, excluding those with prevalent disease at their age of entry. I used Cox proportional hazard models, stratified by ancestry group (Afr, Eas, Eur, Lat) and adjusted for sex, genetic principal components, diabetes, and respective PRS of the target organ damage phenotype obtained from the polygenic score catalogue (PGS catalogue, which is an open database of published polygenic scores that provides consistently annotated metadata for each score). An increase of 1 SD of the SBP PRS resulted in a 22%, 21%, 13%, 11% higher risk in incidence of CKD at any age in Lat, Afr, Eur, Eas ancestries respectively. This was statistically significant associated. However, the BP PRS association with the incidence of the CVD related TOD phenotypes was weaker, and not consistently statistically significant across ancestries. The effect of SBP PRS was found to be largely independent of PRS of the target organ damage phenotypes and diabetes status at start of follow up for CKD as the association only slightly deteriorated when added to the models. However, for ischemic stroke, the HRadj became statistically insignificant after addition of stroke TOD PRS. The correlation coefficient between SBP PRS and stroke TOD PRS was observed to be high across all ancestries. BP-PRS is associated with increased risk in incident CKD TOD at any age across ancestries, independent of TOD PRS and diabetes status at start of follow up. This association was less apparent in CVD related TOD outcomes.
Finally, in the final chapter of my dissertation, I investigated ancestry differences in individual level response to monotherapy blood pressure medication treatment in a real-world clinical cohort with longitudinal EHR data by drug class type and dose in individuals of African, East Asian, European and Latino(a) ancestry with hypertension. I used prescription data from the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, linking it with BP measurements where individuals had multiple internal medicine office visit BP measures across their life-course. We investigated drug classes—Angiotensin-Converting enzyme (ACE) inhibitors, hydrochlorothiazide (HCTZ), and dihydropyridine calcium channel blockers (CCBs)—and calculated the average change in systolic (SBP) and diastolic blood pressure (DBP) due to treatment by monotherapy AHT. I used ANOVA and Tukey’s Post hoc tests to test the differences in average change by ancestry group. I found that estimated average BP reductions varied depending on ancestry, drug class. Generally, estimated SBP reductions were more modest compared to those seen in clinical trials. The largest average reduction in SBP was seen with HCTZ in individuals of African ancestry, while the smallest was with ACE inhibitors in the same group. African ancestry individuals showed larger SBP reductions with HCTZ, but statistically significant smaller reductions with ACE inhibitors compared to other ancestry groups. The findings suggest that estimated BP reduction from antihypertensive medications vary by ancestry, drug class, in real-world clinical cohort settings. This challenges the common assumption in GWAS studies that BP medication effects are uniform (e.g., a 15 mm Hg reduction in SBP) across all ancestry populations and drug types, highlighting the need for more tailored approaches in clinical and genetic research e.g. in genome-wide association studies (GWAS) studies correcting for BP medication use
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
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Quantitative Genetics in the Postmodern Family of the Donor Sibling Registry
Get PDFQuantitative genetics is primarily concerned with two subjects: the correlation between relatives and the response to selection. The correlation between relatives is used to determine the heritability of a trait — the key quantity that addresses the question of nature vs. nurture. Heritability, in turn, is used to predict the response to selection — the main driver of improvements in crops and livestock. The theory of quantitative genetics has been thoroughly tested and applied in plants and animals, but heritability and selection remain open questions in humans due to limited natural experimental designs. The Donor Sibling Registry (DSR) is an organization that helps individuals conceived as a result of sperm, egg, or embryo donation make contact with genetically related individuals. Families who conceived children via anonymous sperm donation join the DSR and match with other families who used the same donor ID at the same sperm bank. The resulting donor pedigree consists of heterosexual, lesbian, and single mother families who are connected through the common anonymous sperm donor used to conceive their children. Here, we introduce a new quantitative genetic study design based on the unprecedented family relationships found in the donor pedigree. We surveyed 945 individual families constituting 159 donor pedigrees from the Donor Sibling Registry and used their demographic, physical, and behavioral characteristics to conduct a quantitative genetic study of selection and heritability. A direct measurement of phenotypic assortment showed mothers actively selected mates for height, eye color, and religion. Artificial selection for donor height increased mean child height in a manner consistent with the selection differential. Reared-apart donor-conceived paternal half-siblings provided unbiased heritability estimates for traits influenced by maternal and contrast effects. Maternal effects were important in determining the variance of birth weight while eliminating contrast effects revealed sociability to be a highly heritable childhood temperament. Thus, the unprecedented family relationships in the donor pedigree enable a universal model for quantitative genetics
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Using Human Genetic Variation to Predict Functional Elements in Non-Coding Genomic Regions
Get PDFThe annotation of the human genome has been a daunting task requiring the creation of innovative methods to characterize its diverse elements. Given that previous studies have successfully used human polymorphism data to characterize functional elements within coding regions, the objective of this thesis is to use human polymorphism data to improve the identification of functional elements in both coding and non-coding regions. This study relies on using the combination of genetic variation from ethnically diverse human populations and several bioinformatics approaches to discriminate and identify several elements of functional importance within genomic regions.Human polymorphism data within genes was acquired from three different publicly available datasets. We then demonstrated that positions within introns that correspond to known functional elements involved in pre-mRNA splicing, including the branch site, splice sites, and polypyrimidine tract showed reduced levels of genetic variation. These precise sites of reduced polymorphism levels also coincide with the positions known for base pairing and interacting with their corresponding ligand. Furthermore, we observed regions of reduced genetic variation that were candidates for distance dependent localization sites of functional elements. Using several computational approaches, we provided additional evidence that suggests these regions correspond to intronic splicing enhancers in both the 5' and 3' splice site regions.We conclude that studies of genetic variation can successfully discriminate and identify functional elements in non-coding regions. Although current polymorphism data is only available for small gene subsets, as more non-coding sequence data becomes available, the methods employed here can be utilized to identify additional functional elements in the human genome and provide possible explanations for phenotypic associations
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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