| 1. |
- Pulit, S. L., et al.
(författare)
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Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes
- 2018
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Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
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| 2. |
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| 3. |
- Marini, S., et al.
(författare)
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Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis
- 2019
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:4, s. 480-491
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. OBJECTIVE To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) epsilon 4 alleles, the most potent genetic risk factor for ICH. DESIGN, SETTING, AND PARTICIPANTS This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. MAIN OUTCOMES AND MEASURES Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. RESULTS In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE epsilon 2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE epsilon 4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE epsilon 4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE epsilon 2 and epsilon 4 did not show an association with nonlobar ICH risk in any race/ethnicity. CONCLUSIONS AND RELEVANCE APOE epsilon 4 and epsilon 2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.
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| 4. |
- Chubb, Daniel, et al.
(författare)
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Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:10, s. 366-1221
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Tidskriftsartikel (refereegranskat)abstract
- To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 x 10(-14)), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 x 10(-11)), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 x 10(-9)) and 22q13.1 (rs877529, CBX7, P = 7.63 x 10(-16)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition.
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| 5. |
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| 6. |
- Schmidt, Amand F., et al.
(författare)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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Ingår i: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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| 7. |
- Vijayakrishnan, Jayaram, et al.
(författare)
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A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1
- 2017
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 31:3, s. 573-579
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10-11) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10-9). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology.
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| 8. |
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| 9. |
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| 10. |
- Broderick, Peter, et al.
(författare)
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Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:1, s. 58-83
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Tidskriftsartikel (refereegranskat)abstract
- To identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci for multiple myeloma at 3p22.1 (rs1052501 in ULK4; odds ratio (OR) = 1.32; P = 7.47 x 10(-9)) and 7p15.3 (rs4487645, OR = 1.38; P = 3.33 x 10(-15)). In addition, we observed a promising association at 2p23.3 (rs6746082, OR = 1.29; P = 1.22 x 10(-7)). Our study identifies new genomic regions associated with multiple myeloma risk that may lead to new etiological insights.
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| 11. |
- Shivakumar, Abhishek, et al.
(författare)
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Drivers of renewable energy deployment in the EU : An analysis of past trends and projections
- 2019
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Ingår i: Energy Strategy Reviews. - : Elsevier. - 2211-467X .- 2211-4688. ; 26
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Tidskriftsartikel (refereegranskat)abstract
- Energy policy in the European Union (EU) is driven by the objective to transition to an affordable, reliable, and low carbon energy system. To achieve this objective, the EU has explicitly stated targets for greenhouse reduction, shares of renewable energy sources (RES), and energy efficiency improvements for 2020 and 2030. In this paper, we focus on the drivers, barriers and enablers to achieving the EU's RES targets (20% by 2020 and 27% by 2030). Effective energy policies play a key role in the deployment of RES technologies. In order to design effective policies, a clear understanding of past trends and projections for future deployment is required. In this paper, we first analyse the past deployment of RES technologies for electricity supply (RES-E) in selected EU Member States. This highlights the key drivers, barriers, and enablers for deployment of RES in the past. In a second step, we conduct a meta-analysis of projections for RES-E shares from multiple well-established studies. Such an analysis will help in supporting the design of more effective energy policies and successfully achieving the EU's energy targets.
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| 12. |
- Weinhold, Niels, et al.
(författare)
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The CCND1 c.870G > A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:5, s. 522-525
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Tidskriftsartikel (refereegranskat)abstract
- A number of specific chromosomal abnormalities define the subgroups of multiple myeloma. In a meta-analysis of two genome-wide association studies of multiple myeloma including a total of 1,661 affected individuals, we investigated risk for developing a specific tumor karyotype. The t(11;14)(q13;q32) translocation in which CCND1 is placed under the control of the immunoglobulin heavy chain enhancer was strongly associated with the CCND1 c.870G>A polymorphism (P = 7.96 x 10(-11)). These results provide a model in which a constitutive genetic factor is associated with risk of a specific chromosomal translocation.
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| 13. |
- Welsch, Manuel, et al.
(författare)
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Europe's energy transition : Insights for policy making
- 2017
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Europe's Energy Transition: Insights for Policy Making looks at the availability and cost of accessing energy and how it significantly affects economic growth and competitiveness in global markets. The results in this book, from a European Commission (EC) financed project by INSIGHT_E, provide an overview of the most recent analyses, focusing on energy markets and their implications for society. Designed to inform European policymaking, elements of this book will be integrated into upcoming EC policies, giving readers invaluable insights into the cost and availability of energy, the effect of price increases affecting vulnerable consumer groups, and current topics of interest to the EC and ongoing energy debate. INSIGHT_E provides decision-makers with unbiased policy advice and insights on the latest developments, including an assessment of their potential impact. Presents answers to strategic questions posed by the European Commission. Coherently assesses the energy transition, from policies to energy supply, markets, system requirements, and consumer needs. Informed the EC "Clean Energy for All Europeans" package from end of 2016, e.g., regarding aspects of energy poverty. Endorsed by thought leaders from within and outside of Europe, including utilities, energy agencies, research institutes, journal editors, think tanks, and the European Commission.
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| 14. |
- Dobbins, James T, et al.
(författare)
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Multi-Institutional Evaluation of Digital Tomosynthesis, Dual-Energy Radiography, and Conventional Chest Radiography for the Detection and Management of Pulmonary Nodules.
- 2017
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Ingår i: Radiology. - : Radiological Society of North America (RSNA). - 1527-1315 .- 0033-8419. ; 282:1
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To conduct a multi-institutional, multireader study to compare the performance of digital tomosynthesis, dual-energy (DE) imaging, and conventional chest radiography for pulmonary nodule detection and management. Materials and Methods In this binational, institutional review board-approved, HIPAA-compliant prospective study, 158 subjects (43 subjects with normal findings) were enrolled at four institutions. Informed consent was obtained prior to enrollment. Subjects underwent chest computed tomography (CT) and imaging with conventional chest radiography (posteroanterior and lateral), DE imaging, and tomosynthesis with a flat-panel imaging device. Three experienced thoracic radiologists identified true locations of nodules (n = 516, 3-20-mm diameters) with CT and recommended case management by using Fleischner Society guidelines. Five other radiologists marked nodules and indicated case management by using images from conventional chest radiography, conventional chest radiography plus DE imaging, tomosynthesis, and tomosynthesis plus DE imaging. Sensitivity, specificity, and overall accuracy were measured by using the free-response receiver operating characteristic method and the receiver operating characteristic method for nodule detection and case management, respectively. Results were further analyzed according to nodule diameter categories (3-4 mm, >4 mm to 6 mm, >6 mm to 8 mm, and >8 mm to 20 mm). Results Maximum lesion localization fraction was higher for tomosynthesis than for conventional chest radiography in all nodule size categories (3.55-fold for all nodules, P < .001; 95% confidence interval [CI]: 2.96, 4.15). Case-level sensitivity was higher with tomosynthesis than with conventional chest radiography for all nodules (1.49-fold, P < .001; 95% CI: 1.25, 1.73). Case management decisions showed better overall accuracy with tomosynthesis than with conventional chest radiography, as given by the area under the receiver operating characteristic curve (1.23-fold, P < .001; 95% CI: 1.15, 1.32). There were no differences in any specificity measures. DE imaging did not significantly affect nodule detection when paired with either conventional chest radiography or tomosynthesis. Conclusion Tomosynthesis outperformed conventional chest radiography for lung nodule detection and determination of case management; DE imaging did not show significant differences over conventional chest radiography or tomosynthesis alone. These findings indicate performance likely achievable with a range of reader expertise. (©) RSNA, 2016 Online supplemental material is available for this article.
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| 15. |
- Dobbins, Trevor David, 1965, et al.
(författare)
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Human-centred, scalable, combat system design for littoral operations
- 2015
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Ingår i: International Conference on Warship 2015: Future Surface Vessels; Bath; United Kingdom; 10 June 2015 through 11 June 2015. - 9781909024410 ; , s. 103-113
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Konferensbidrag (refereegranskat)abstract
- Combat operations in the littoral and amphibious environments present unique challenges to both the warfighters, and the system designers. High-tempo navigation, in shallow / congested waters, and in degraded visual environments, increases the stresses on the individuals and teams before combat related tasks are considered. All combat tasks require the crew, and the crafts systems, to have the appropriate level of situation awareness and decision making capability. This Joint Cognitive System (JCS) supports the interoperability needed to achieve successful operational outcomes, particularly in joint operations. Resilience, is essential in the high-tempo coastal environment. Littoral / amphibious craft, being typically small and fast, and by necessity lean manned must be efficient and optimised. Understanding the crew's roles, tasks and competences provides the definitions required for the information architectures and flow, both intra and inter vessel, that supports the JCS and defines the vessel's Combat System. The JCS, and therefore the Combat System, can be scaled with the vessels size, as a number of the crews / systems functions remain the same. Designing the combat JCS from a human-centred perspective, provides an essential foundation for designing the vessel and delivering the required littoral / amphibious capability.
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| 16. |
- Dobbins, Trevor David, 1965, et al.
(författare)
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Search & rescue and maritime security in the arctic - System design challenges and solutions
- 2015
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Ingår i: International Conference on Ice Class Vessels; London; United Kingdom. - 9781909024397 ; , s. 17-22
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Konferensbidrag (refereegranskat)abstract
- The increasing prevalence of voyages within the Arctic region is highlighting the growing need to understand the implications of delivering Search And Rescue (SAR) and Maritime Security (MARSEC) within the Arctic. Operating within this hostile environment requires specific system capabilities and resilience. This capability is not delivered by a single type or class of vessel, but rather a system-of-systems, including multinational cooperation. The issue of the large distances between safe havens is recognized, particularly the problem of it taking a long time for help to reach a vessel in distress assuming communication is possible. Therefore vessels need to be designed and outfitted with systems and equipment to support the crew and passengers for many days in harsh conditions, as well as the capability to help other vessels in distress, e.g. greater capability for deployable rescue craft assets. Therefore Arctic SAR and MARSEC operations require resilient System-of-Systems solutions, with embedded Human Systems Integration (HSI), to support safe and effective Arctic voyages.
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| 17. |
- Dobbins, T, et al.
(författare)
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Information architecture for fast response craft - Command & control & human systems integration
- 2013
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Ingår i: RINA, Royal Institution of Naval Architects - International Conference on SURV 2013, Surveillance Search and Rescue Craft. - 9781909024137 ; , s. 117-120
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Konferensbidrag (refereegranskat)abstract
- Command & Control (C2) is required for safe and effective maritime operations. To facilitate effective decision-making and C2, it is essential that the crew can access the required information. It is therefore essential that the appropriate information architecture is used. Navigation, being an essential aspect of C2, has seen a radical change from paper charts and individual instruments to computer systems capable of sophisticated data fusion to provide enhanced situational awareness. The development of the required information architecture is not a software/engineering issue, but rather lies within the human factors domain as it requires an understanding of how humans perceive information, how they use mental models and subsequently make safe and effective decisions. © 2013: The Royal Institution of Naval Architects.
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| 18. |
- Shete, Sanjay, et al.
(författare)
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Genome-wide association study identifies five susceptibility loci for glioma.
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41:8, s. 899-904
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Tidskriftsartikel (refereegranskat)abstract
- To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 x 10(-17)), 8q24.21 (rs4295627, CCDC26; P = 2.34 x 10(-18)), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 x 10(-15)), 20q13.33 (rs6010620, RTEL1; P = 2.52 x 10(-12)) and 11q23.3 (rs498872, PHLDB1; P = 1.07 x 10(-8)). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.
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| 19. |
- Timofeeva, Maria N, et al.
(författare)
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Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer.
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10(-7)), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10(-7)); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10(-7) and OR = 1.09, P = 7.4 × 10(-8)); rs1129406 (12q13) in ATF1 (OR = 1.11, P = 8.3 × 10(-9)), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P < 2.90 × 10(-6)). We found an excess of rare, damaging variants in base-excision (P = 2.4 × 10(-4)) and DNA mismatch repair genes (P = 6.1 × 10(-4)) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC.
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