| 1. |
- Campbell, Brittany B., et al.
(författare)
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Comprehensive Analysis of Hypermutation in Human Cancer
- 2017
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 171:5
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 Elsevier Inc. We present an extensive assessment of mutation burden through sequencing analysis of > 81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.
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| 2. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 3. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 4. |
- Clark, Leigh, et al.
(författare)
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Mapping Theoretical and Methodological Perspectives for Understanding Speech Interface Interactions
- 2019
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Ingår i: CHI EA '19 EXTENDED ABSTRACTS. - New York, NY, USA : ASSOC COMPUTING MACHINERY.
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Konferensbidrag (refereegranskat)abstract
- The use of speech as an interaction modality has grown considerably through the integration of Intelligent Personal Assistants (IPAs- e.g. Siri, Google Assistant) into smartphones and voice based devices (e.g. Amazon Echo). However, there remain significant gaps in using theoretical frameworks to understand user behaviours and choices and how they may applied to specific speech interface interactions. This part-day multidisciplinary workshop aims to critically map out and evaluate theoretical frameworks and methodological approaches across a number of disciplines and establish directions for new paradigms in understanding speech interface user behaviour. In doing so, we will bring together participants from HCI and other speech related domains to establish a cohesive, diverse and collaborative community of researchers from academia and industry with interest in exploring theoretical and methodological issues in the field.
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| 5. |
- Clark, Leigh, et al.
(författare)
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The State of Speech in HCI : Trends, Themes and Challenges
- 2019
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Ingår i: Interacting with computers. - : Oxford University Press. - 0953-5438 .- 1873-7951. ; 31:4, s. 349-371
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Tidskriftsartikel (refereegranskat)abstract
- Speech interfaces are growing in popularity. Through a review of 99 research papers this work maps the trends, themes, findings and methods of empirical research on speech interfaces in the field of human-computer interaction (HCI). We find that studies are usability/theory-focused or explore wider system experiences, evaluating Wizard of Oz, prototypes or developed systems. Measuring task and interaction was common, as was using self-report questionnaires to measure concepts like usability and user attitudes. A thematic analysis of the research found that speech HCI work focuses on nine key topics: system speech production, design insight, modality comparison, experiences with interactive voice response systems, assistive technology and accessibility, user speech production, using speech technology for development, peoples' experiences with intelligent personal assistants and how user memory affects speech interface interaction. From these insights we identify gaps and challenges in speech research, notably taking into account technological advancements, the need to develop theories of speech interface interaction, grow critical mass in this domain, increase design work and expand research from single to multiple user interaction contexts so as to reflect current use contexts. We also highlight the need to improve measure reliability, validity and consistency, in the wild deployment and reduce barriers to building fully functional speech interfaces for research.
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| 6. |
- Daneshjou, Roxana, et al.
(författare)
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Working toward precision medicine : Predicting phenotypes from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges
- 2017
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 38:9, s. 1182-1192
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Tidskriftsartikel (refereegranskat)abstract
- Precision medicine aims to predict a patient's disease risk and best therapeutic options by using that individual's genetic sequencing data. The Critical Assessment of Genome Interpretation (CAGI) is a community experiment consisting of genotype-phenotype prediction challenges; participants build models, undergo assessment, and share key findings. For CAGI 4, three challenges involved using exome-sequencing data: Crohn's disease, bipolar disorder, and warfarin dosing. Previous CAGI challenges included prior versions of the Crohn's disease challenge. Here, we discuss the range of techniques used for phenotype prediction as well as the methods used for assessing predictive models. Additionally, we outline some of the difficulties associated with making predictions and evaluating them. The lessons learned from the exome challenges can be applied to both research and clinical efforts to improve phenotype prediction from genotype. In addition, these challenges serve as a vehicle for sharing clinical and research exome data in a secure manner with scientists who have a broad range of expertise, contributing to a collaborative effort to advance our understanding of genotype-phenotype relationships.
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| 7. |
- Diment, Bethany, et al.
(författare)
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Exercise Intensity and Duration Effects on In Vivo Immunity
- 2015
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Ingår i: Medicine & Science in Sports & Exercise. - 0195-9131 .- 1530-0315. ; 47:7, s. 1390-1398
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To examine the effects of intensity and duration of exercise stress on induction of in vivo immunity in humans using experimental contact hypersensitivity (CHS) with the novel antigen diphenylcyclopropenone (DPCP).Methods: Sixty-four healthy males completed either 30 min running at 60% V˙O2peak (30MI), 30 min running at 80% V˙O2peak (30HI), 120 min running at 60% V˙O2peak (120MI), or seated rest (CON). Twenty min later, the subjects received a sensitizing dose of DPCP; and 4 wk later, the strength of immune reactivity was quantified by measuring the cutaneous responses to a low dose-series challenge with DPCP on the upper inner arm. Circulating epinephrine, norepinephrine and cortisol were measured before, after, and 1 h after exercise or CON. Next, to understand better whether the decrease in CHS response on 120MI was due to local inflammatory or T-cell-mediated processes, in a crossover design, 11 healthy males performed 120MI and CON, and cutaneous responses to a dose series of the irritant, croton oil (CO), were assessed on the upper inner arm.Results: Immune induction by DPCP was impaired by 120MI (skinfold thickness -67% vs CON; P < 0.05). However, immune induction was unaffected by 30MI and 30HI despite elevated circulating catecholamines (30HI vs pre: P < 0.01) and greater circulating cortisol post 30HI (vs CON; P < 0.01). There was no effect of 120MI on skin irritant responses to CO.Conclusions: Prolonged moderate-intensity exercise, but not short-lasting high- or short-lasting moderate-intensity exercise, decreases the induction of in vivo immunity. No effect of prolonged moderate-intensity exercise on the skin's response to irritant challenge points toward a suppression of cell-mediated immunity in the observed decrease in CHS. Diphenylcyclopropenone provides an attractive tool to assess the effect of exercise on in vivo immunity.
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| 8. |
- Hanstock, Helen, 1989-, et al.
(författare)
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Tear Fluid SIgA as a Noninvasive Biomarker of Mucosal Immunity and Common Cold Risk
- 2016
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Ingår i: Medicine & Science in Sports & Exercise. - 0195-9131 .- 1530-0315. ; 48:3, s. 569-577
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Research has not convincingly demonstrated the utility of saliva secretory Immunoglobulin-A (SIgA) as a biomarker of upper-respiratory-tract-infection (URTI) risk and disagreement exists about the influence of heavy exercise ('open-window-theory') and dehydration on saliva SIgA. Prompted by the search for viable alternatives, we compared the utility of tear and saliva SIgA to predict URTI prospectively (study-one) and assessed the influence of exercise (study-two) and dehydration (study-three) using a repeated-measures-crossover design.Methods: In study-one, forty subjects were recruited during the common-cold season. Subjects provided tear and saliva samples weekly and recorded upper-respiratory-symptoms (URS) daily for 3-weeks. RT-PCR confirmed common-cold pathogens in 9 of 11 subjects reporting URS (82%). Predictive utility of tear and saliva SIgA was explored by comparing healthy samples with those collected the week pre-URS. In study-two, thirteen subjects performed a 2-hour run at 65% VO2peak. In study-three, thirteen subjects performed exercise-heat-stress to 3% body-mass-loss followed by overnight fluid restriction.Results: Tear SIgA concentration and secretion rate were 48% and 51% lower respectively during URTI and 34% and 46% lower the week pre-URS (P<0.05) but saliva SIgA remained unchanged. URS risk the following week increased 9-fold (95% CI: 1.7 to 48) when tear SIgA secretion rate <5.5 μg[BULLET OPERATOR]min and 6-fold (95% CI: 1.2 to 29) when tear SIgA secretion rate decreased >30%. Tear SIgA secretion rate >5.5 μg[BULLET OPERATOR]min or no decrease >30% predicted subjects free of URS in >80% of cases. Tear SIgA concentration decreased post-exercise (-57%: P<0.05) in line with the 'open-window-theory' but was unaffected by dehydration. Saliva flow rate decreased and saliva SIgA concentration increased post-exercise and during dehydration (P<0.05).Conclusion: Tear SIgA has utility as a non-invasive biomarker of mucosal immunity and common-cold risk.
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| 9. |
- Ihantola, Petri, et al.
(författare)
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Educational Data Mining and Learning Analytics in Programming : Literature Review and Case Studies
- 2016
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Ingår i: Proceedings of the 2015 ITiCSE on Working Group Reports. - New York, NY, USA : ACM Digital Library. - 9781450341462 ; , s. 41-63
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Konferensbidrag (refereegranskat)abstract
- Educational data mining and learning analytics promise better understanding of student behavior and knowledge, as well as new information on the tacit factors that contribute to student actions. This knowledge can be used to inform decisions related to course and tool design and pedagogy, and to further engage students and guide those at risk of failure. This working group report provides an overview of the body of knowledge regarding the use of educational data mining and learning analytics focused on the teaching and learning of programming. In a literature survey on mining students' programming processes for 2005-2015, we observe a significant increase in work related to the field. However, the majority of the studies focus on simplistic metric analysis and are conducted within a single institution and a single course. This indicates the existence of further avenues of research and a critical need for validation and replication to better understand the various contributing factors and the reasons why certain results occur. We introduce a novel taxonomy to analyse replicating studies and discuss the importance of replicating and reproducing previous work. We describe what is the state of the art in collecting and sharing programming data. To better understand the challenges involved in replicating or reproducing existing studies, we report our experiences from three case studies using programming data. Finally, we present a discussion of future directions for the education and research community.
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| 10. |
- Johansson, Mattias, et al.
(författare)
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The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study
- 2019
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
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