1,721,008 research outputs found
The development, implementation, and evaluation of a DPYD testing program in British Columbia
No full textA third of patients develop severe or life-threatening toxicities from fluoropyrimidines, a commonly prescribed chemotherapeutic. Fluoropyrimidine toxicity is often due to variation in the gene (DPYD) encoding dihydropyrimidine dehydrogenase (DPD). DPYD genotyping can be used to adjust doses to reduce the likelihood of fluoropyrimidine toxicity while maintaining therapeutically effective drug levels. However, DPYD testing was not routinely available in British Columbia. This study sought to implement an evidence-based pharmacogenetic test and integrate it into routine clinical practice. DPYD testing for six variants was offered for all patients starting on fluoropyrimidines at the BC Cancer Centre in Vancouver and then across British Columbia. In nine months, 186 patients were tested, and 14 were heterozygous variant carriers. Fluoropyrimidine-related toxicity was higher in DPYD variant carriers. Of 127 non-variant carriers who have completed chemotherapy, 18 (14%) experienced severe (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). In eight variant carriers, two (25%) experienced severe toxicity even at reduced doses. For one of these carriers who experienced severe thrombocytopenia within the first week, DPYD testing likely prevented lethal toxicity. DPYD variant carriers who tolerate reduced doses could not tolerate dramatic dose increases. One variant carrier developed toxicity and had to discontinue chemotherapy when the dose was escalated by 25%, leading to updated guidelines for physicians that outlined how they should escalate doses by 10% for variant carriers who have tolerated reduced doses for two cycles. DPYD testing is now routinely offered to all patients in British Columbia.Medicine, Faculty ofMedicine, Department ofGraduat
The development of dose-adjusted pharmacogenetic prediction models in pediatric oncology
No full textAnthracyclines and cisplatin are two widely-used chemotherapeutic agents in the treatment of pediatric cancers. However, their use is limited by severe life-threatening and life-altering adverse drug reactions (ADRs). Anthracyclines cause cardiotoxicity in up to 57% of treated patients, and cisplatin causes permanent hearing loss in 60-70% of patients. Thus, efforts must be made to predict those most susceptible to these ADRs in order to mitigate the risk of toxicity before it occurs. Significant interindividual variability in anthracycline-induced cardiotoxicity and cisplatin-induced ototoxicity has prompted the discovery and replication of several pharmacogenetic variants involved in the development of these ADRs. Clinical practice guidelines have been published outlining the roles of SLC28A3, UGT1A6, and RARG in anthracycline-induced cardiotoxicity, and TPMT in cisplatin-induced ototoxicity. While both anthracycline- and cisplatin-induced toxicities are dose-dependent reactions, no studies have explored the dose-gene relationship in the development of these ADRs. This study seeks to understand how anthracycline/cisplatin dose and pharmacogenetics together contribute to the development of anthracycline- and cisplatin-induced toxicities. In so doing, this work aims to construct dose-adjusted pharmacogenetic prediction models for these ADRs. 595 anthracycline-treated children were stratified into low-dose (≤150mg/m²) and high-dose (>250mg/m²) groups based on cumulative anthracycline dose received, and pharmacogenetic effects in the development of cardiotoxicity were compared. Results revealed that UGT1A6 and RARG risk variants significantly increased cardiotoxicity risk at low-doses (OR 7.18; p=0.0045 and OR 2.76, p=0.057, respectively), while the SLC28A3 protective variant significantly reduced risk at high-doses (OR 0.43, p=0.0093). A separate cohort of 371 cisplatin-treated children were stratified according to cisplatin dose intensity and incidence of ototoxicity was compared. Dose intensity was defined as the amount of cisplatin administered per unit time. Patients receiving cisplatin at high dose intensity experienced significantly higher incidences of ototoxicity (p=9e-07). Further stratification by TPMT-genotype revealed that carriers of ≥1 TPMT variant have increased incidence of ototoxicity compared to their wildtype counterparts, regardless of dose intensity (OR 1.41 per allele, p=0.038). These results may help identify patients able to safely tolerate higher doses of chemotherapy based on their pharmacogenetic profile, as well as those at risk of toxicity even at low exposure-levels.Medicine, Faculty ofMedical Genetics, Department ofGraduat
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe 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
No full text“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
No full textWe 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
Pharmacogenomic and machine learning insights for the prediction of l-asparaginase-induced hypersensitivity in pediatric cancer
No full textHypersensitivity reactions to l-asparaginase pose a major limitation in pediatric acute lymphoblastic leukemia (ALL) therapy, often necessitating treatment modifications that jeopardize remission and survival. This dissertation investigates the genetic underpinnings of these reactions and explores strategies for identifying high-risk patients.
A systematic review of studies examining the genetic associations of l-asparaginase-induced hypersensitivity in human case-control studies confirmed a consistent, albeit modest, effect of HLA-DRB1*07:01 (p = 3.51 x 10⁻¹⁸, OR = 1.96 [1.68–2.28], I² = 18.42%) on hypersensitivity risk. By contrast, genome-wide association studies produced heterogeneous findings. These observations emphasize the importance of robust phenotyping and ancestry-aware study designs.
In a genome-wide associations study of l-asparaginase-induced hypersensitivity in a large discovery cohort (n = 926) of pediatric cancer patients, large effect variants (OR = 3.9-8.5, p < 10⁻⁵) were identified within regulatory regions of genes (CYP1B1, OPLAH, SORCS2, SEC16B) involved in amino acid stress response, endoplasmic reticulum stress, and l-asparaginase clearance. These findings were then validated in an independent replication cohort (n = 180). When top-risk variants were incorporated into a genetic risk score, carriers of two or more risk alleles displayed a 25-fold increased risk of experiencing hypersensitivity (OR = 25.2 [7.4-86.2], p = 1.0 x 10⁻¹⁰), underscoring the power of polygenic models to enhance individual risk stratification.
Predictive modeling revealed that incorporating multiple polygenic risk scores from diverse studies, along with clinical variables and drug usage data, improved risk prediction by 36% over single-variant models. The most comprehensive machine learning frameworks (neural networks, support vector machines, logistic regression) achieved area under the curve (AUC) scores > 0.70 in an independent replication cohort, with significant differences for the prediction of cases of hypersensitivity compared to controls (OR = 3.4 - 4.5, p < 3.86 x 10⁻⁴), demonstrating discrimination between patients who developed hypersensitivity and those who did not.
These findings highlight the complex genetic architecture of l-asparaginase hypersensitivity and the potential of comprehensive risk scores in refining patient stratification. By integrating genetic, clinical, and pharmacological data, this work provides a framework for pharmacogenetic testing to preserve treatment efficacy while minimizing adverse events, advancing precision medicine in pediatric ALL care.Medicine, Faculty ofMedical Genetics, Department ofGraduat
Dispelling the Myths Behind First-author Citation Counts
No full textWe 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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