| 1. |
- Young, William J., et al.
(författare)
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Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
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| 2. |
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| 3. |
- Bravo, L, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 4. |
- Tabiri, S, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 5. |
- Barrera Rolla, Leandro, et al.
(författare)
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Implementation of the forward-advancing wave expansion method (FWEM) for numerical solution of three dimensional large-scale sound propagation problems
- 2007
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Ingår i: 36th International Congress and Exposition on Noise Control Engineering, INTER-NOISE. - 9781605603858 ; , s. 4796-4805
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- In this paper a “one-way” wave based field discretization method for solving the Helmholtz equation in large-scale problems is proposed and is referred to as the Forward Wave Expansion Method (FWEM). The FWEM is derived from a highly efficient discretization procedure based on the interpolation of wave functions known as the Wave Expansion Method (WEM) and computes the propagated sound field by means of an exclusively forward advancing solution. This technique does not require the inversion of large system matrices and thus enables the solution of large scale acoustic problems where backscatter is not of interest. A computationally light model is thus formulated which retains many advantages of WEM. Accurate results were obtained for a free field sound propagation benchmarking problem. The method was also implemented to successfully model some diffraction effects. The FWEM offers a simple, flexible and efficient discretization method to solve the Helmholtz equation for extensive domains with mesh densities as low as 3 nodes per wavelength. This makes the FWEM a promising method for long range sound propagation problems.
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| 6. |
- Bharath, G., et al.
(författare)
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Iterative solutions of the three-dimensional Helmholtz equation using the wave expansion method for high frequency acoustic scattering problems
- 2007
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Ingår i: 36th International Congress and Exposition on Noise Control Engineering, INTER-NOISE. - 9781605603858 ; , s. 4788-4795
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Modelling sound propagation over large domains presents severe challenges with respect to computational requirements. In general, direct solutions of system equations resulting from the full field discretization of many three-dimensional problems of practical interest cannot be attempted. The present study investigates iterative solutions for solving a Three-Dimensional Helmholtz equation. The discretization of the Helmholtz equation is done by a Wave Based Finite Difference scheme known as the Wave Expansion Method (WEM). The WEM requires only 2-3 nodes per wavelength to obtain accurate solutions which offers a potential for major improvement in efficiency compares to conventional techniques such as the Finite Element/Finite Difference approaches which require around 8-10 nodes per wavelength. The solver employed here is the standard Bi-Conjugate Gradient Stabilized (Bi-CGSTAB) algorithm. Results are presented for high frequency acoustic scattering problems occurring in aircrafts. Investigations are also carried out to check the effectiveness of the standard preconditioning strategies such as the Incomplete LU decomposition with drop tolerance method. The influence of the scatterer is also studied in this paper.
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| 7. |
- Cameron, Christopher John, 1980-
(författare)
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Design of Multifunctional Body Panels for Conflicting Structural and Acoustic Requirements in Automotive Applications
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Over the past century, the automobile has become an integral part of society, with vastincreases in safety, refinement, and complexity, but most unfortunately in mass. Thetrend of increasing mass cannot be maintained in the face of increasingly stringentregulations on fuel consumption and emissions.The body of work within this thesis exists to help the vehicle industry to take a stepforward in producing vehicles for the future in a sustainable manner in terms of botheconomic and ecological costs. In particular, the fundamentally conflicting requirementsof low weight and high stiffness in a structure which should have good acousticperformance is addressed.An iterative five step design method based on the concepts of multifunctionality andmultidisciplinary engineering is proposed to address the problem, and explained witha case study.In the first step of the process, the necessary functional requirements of the systemare evaluated. Focus is placed on the overall system behavior and diverted from subproblems.For the case study presented, the functional requirements included: structuralstiffness for various loading scenarios, mass efficiency, acoustic absorption, vibrationaldamping, protecting from the elements, durability of the external surfaces,and elements of styling.In the second step of the process, the performance requirements of the system wereestablished. This involved a thorough literature survey to establish the state of theart, a rigorous testing program, and an assessment of numerical models and tools toevaluate the performance metrics.In the third step of the process, a concept to fulfil requirements is proposed. Here, amulti-layered, multi-functional panel using composite materials, and polymer foamswith varying structural and acoustic properties was proposed.In the fourth step of the process, a method of refinement of the concept is proposed.Numerical tools and parameterized models were used to optimize the three dimensionaltopology of the panel,material properties, and dimensions of the layers in a stepwisemanner to simultaneously address the structural and acoustic performance.In the fifth and final step of the process, the final result and effectiveness of the methodused to achieve it is examined. Both the tools used and the final result in itself shouldbe examined. In the case study the process is repeated several times with increasingdegrees of complexity and success in achieving the overall design objectives.In addition to the design method, the concept of a multifunctional body panel is definedand developed and a considerable body of knowledge and understanding is presented.Variations in core topology, materials used, stacking sequence of layers, effects ofperforations, and air gaps within the structure are examined and their effects on performanceare explored and discussed. The concept shows promise in reducing vehicleweight while maintaining the structural and acoustic performance necessary in the contextof sustainable vehicle development.
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| 8. |
- Dehghan, Abbas, et al.
(författare)
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Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies : The CHARGE Consortium
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5x10(-6) in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5x10(-6); 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8x10(-3)) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2x10(-9)). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2x10(-3)). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
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| 9. |
- Eicher, John D., et al.
(författare)
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Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:1, s. 40-55
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Tidskriftsartikel (refereegranskat)abstract
- Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common(ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV(PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
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| 10. |
- Ellinor, Patrick T., et al.
(författare)
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Meta-analysis identifies six new susceptibility loci for atrial fibrillation
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:6, s. 88-670
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Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death(1). We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 x 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
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