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HIGH-THROUGHPUT DATA ANALYSIS OF HEARING PHENOTYPES ON 9000 SUBJECTS FROM TEN COHORTS AND IN 200.000 INDIVIDUALS FROM UK BIOBANK
No full textLa funzione uditiva (Normal Hearing Function - NHF) e il suo declino dovuto all’età (la presbiacusia, o Age-Related Hearing Loss - ARHL) sono influenzati sia da fattori ambientali che da fattori genetici, ma quali siano esattamente i geni coinvolti è una questione ancora aperta. Con l’invecchiamento della popolazione mondiale, e il pesante impatto socioeconomico dell’ARHL, sta diventando sempre più importante acquisire una conoscenza dettagliata delle basi genetiche che stanno dietro a questi tratti.
Questa tesi ha due obiettivi: 1) l’identificazione di nuovi geni coinvolti nella NHF e nell’ARHL mediante l’uso della metodologia GWAS su coorti con un diverso approccio alla raccolta del fenotipo uditivo (audiometria e test speech-in-noise); 2) la valutazione della possibilità di una replica incrociata dei risultati ottenuti.
La NHF è stata descritta a partire dai dati audiometrici facendo uso delle singole soglie uditive o del loro valore medio su specifiche frequenze [Medie di toni puri (Pure Tone Averages) alle basse, medie ed alte frequenze (PTA Low: 250, 500, 1KHz; PTA Medium: 500, 1K, 2KHz; PTA High: 4K, 8KHz)]; l’ARHL è stata rappresentata nei soggetti di almeno 50 anni di età mediante una definizione basata sul loro valore di PTAH.
Facendo uso dei dati provenienti dal test speech-in-noise, dopo aver calcolato la soglia di ricezione del parlato (speech reception threshold – SRT), la NHF è stata rappresentata con la variazione totale dell’SRT (fenotipo A), e l’ARHL con gli estremi della distribuzione dell’SRT nei soggetti di almeno 50 anni di età.
L’individuazione di geni per la NHF e l’ARHL mediante dati audiometrici è stata effettuata mediante una meta-analisi GWAS su dieci coorti facenti parte del consorzio G-EAR e provenienti da Italia, Nord Europa, Nord America, Caucaso e Asia Centrale. Per lo scopo erano disponibili complessivamente 9000 soggetti di almeno 18 anni di età con una dettagliata caratterizzazione clinica e audiometrica. Un sottoinsieme di 5745 individui è stato utilizzato nelle meta-analisi sull’ARHL.
I circa 200.000 volontari campionati da UK Biobank sono stati usati per l’individuazione di geni per la NHF e ARHL mediante dati provenienti dal test speech-in-noise. A causa di limitazioni tecniche, solo il fenotipo B è stato impiegato.
La replica dei risultati su NHF e ARHL provenienti dalle analisi su G-EAR è stata ricercata in UK Biobank nei fenotipi A e B rispettivamente. La replica dei risultati ottenuti usando il fenotipo B è stata ricercata nelle analisi effettuate in G-EAR sull’ARHL.
Segnali di associazione fortemente indicativi (p < 10-6 e la stessa direzione degli effetti in tutte le coorti) con i tratti della NHF sono stati individuati nelle analisi G-EAR vicino o entro CADM2 (250Hz), SLC7A2, CALB1, LRRC4C, CAAP1, PLXDC2 (1KHz), e ROBO2 (PTAL). Per CADM2, CALB1, LRRC4C and ROBO2 in particolare, la letteratura fornisce una robusta evidenza a supporto del loro coinvolgimento nel sistema uditivo. In aggiunta, un’associazione significativa genome-wide (p <5*10-8) è stata individuata tra PTAM e geni della regione dell’HLA. Per quanto riguarda l’ARHL, segnali di associazione sono stati individuati con i geni CHD13 e CTIF, già collegati in letteratura ad altri tratti uditivi.
Nel GWAS sul fenotipo B eseguito sui dati di UK Biobank, un’associazione significativa genome-wide è emersa con il gene D2HGDH mentre un’associazione indicative con PDE1A.
Dal momento che la replica incrociata dei segnali ottenuti non ha avuto successo, i risultati seguiranno una replica tradizionale in coorti indipendenti con gli stessi fenotipi. Ulteriori studi In vitro/in vivo chiariranno il ruolo dei geni identificati nella modulazione della funzione uditiva e nell'eziopatogenesi della presbiacusia.Normal hearing function (NHF) and its decline with age (Age-Related Hearing Loss, or ARHL) are influenced by both environmental and genetic factors, but which exactly the involved genes are is still unclear. With the ageing of world population, and the heavy socioeconomic impact of ARHL, the relevance of a detailed knowledge of the genetic inner workings behind these traits is rising.
This thesis has two aims: 1) the identification of new genes playing a role in NHF and in ARHL by using GWAS methodology on cohorts with a different phenotyping approach to hearing (pure-tone audiometry and speech-in-noise test); 2) the assessment of the possibility of cross-replication of the results.
NHF was described with audiometric data with single hearing thresholds or their average value across specific frequencies [Pure-Tone Averages (PTA Low: 250, 500, 1KHz; PTA Medium: 500, 1K, 2KHz; PTA High: 4K, 8KHz)]; ARHL was represented in subjects aged 50+ with a case-control definition based on PTAH.
Using speech-in-noise test data, after the calculation of the speech reception threshold (SRT), NHF was represented by the full variation of SRT (phenotype A), and ARHL by the extremes of SRT distribution in subjects aged 50+ (phenotype B).
Gene discovery on NHF and ARHL with audiometric data was performed through GWAS meta-analyses on ten cohorts belonging to G-EAR consortium and coming from Italy, Northern Europe, North America, Caucasus and Central Asia. Overall 9000 subjects aged 18+ with detailed clinical characterisation and full audiometric data were available. A subset of 5745 individuals was suitable for ARHL meta-analyses.
The ~200,000 volunteers sampled by UK Biobank were used for gene discovery on NHF and ARHL with speech-in-noise data. Due to technical limitations, only phenotype B was tested genome-wide.
Replication of the results on NHF and ARHL from G-EAR analyses was sought in UK Biobank in phenotypes A and B respectively. Replication of the results from phenotype B was sought in G-EAR’s analyses on ARHL.
Strongly suggestive association signals (p <10-6 and same direction of effect in all cohorts) with NHF traits were detected in G-EAR analyses near or within CADM2 (250Hz), SLC7A2, CALB1, LRRC4C, CAAP1, PLXDC2 (1KHz), and ROBO2 (PTAL). For CADM2, CALB1, LRRC4C and ROBO2 in particular, literature provides strong evidence supporting their involvement in the hearing system. Furthermore, a genome-wide significant association (p <5*10-8) was found between PTAM and HLA genes. As regards ARHL, association signals were detected with CHD13 and CTIF genes, linked in literature to other hearing traits.
In the GWAS performed on phenotype B in UK Biobank data, a genome-wide significant signal was detected with D2HGDH gene and a suggestive association with PDE1A gene.
As the cross-replication of signals between studies was not successful, results will follow traditional replication in independent cohorts with identical phenotypes. In vitro/in vivo studies will clarify the role of the identified genes in the modulation of the hearing function and in the etiopathogenesis of age-related hearing loss
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
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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