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Sökning: WFRF:(Kent Peter)

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1.
  • Evangelou, Evangelos, et al. (författare)
  • Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
  • 2018
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
  • Tidskriftsartikel (refereegranskat)abstract
    • High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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2.
  • Birney, Ewan, et al. (författare)
  • Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
  • 2007
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
  • Tidskriftsartikel (refereegranskat)abstract
    • We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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3.
  • Wain, Louise V., et al. (författare)
  • Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney
  • 2017
  • Ingår i: Hypertension. - 0194-911X .- 1524-4563. ; 70:3, s. e4-e19
  • Tidskriftsartikel (refereegranskat)abstract
    • Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
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4.
  • Wuttke, Matthias, et al. (författare)
  • A catalog of genetic loci associated with kidney function from analyses of a million individuals
  • 2019
  • Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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5.
  • van de Vegte, Yordi, et al. (författare)
  • Genetic insights into resting heart rate and its role in cardiovascular disease
  • 2023
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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6.
  • Joshi, Peter K, et al. (författare)
  • Directional dominance on stature and cognition in diverse human populations
  • 2015
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
  • Tidskriftsartikel (refereegranskat)abstract
    • Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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7.
  • Surendran, Praveen, et al. (författare)
  • Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
  • 2020
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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8.
  • Abazajian, Kevork, et al. (författare)
  • CMB-S4 : Forecasting Constraints on Primordial Gravitational Waves
  • 2022
  • Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
  • Tidskriftsartikel (refereegranskat)abstract
    • CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL.
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9.
  • Frazier-Wood, Alexis C., et al. (författare)
  • Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
  • 2016
  • Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
  • Tidskriftsartikel (refereegranskat)abstract
    • Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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10.
  • Lu, Yingchang, et al. (författare)
  • New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
  • 2016
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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11.
  • Roselli, Carolina, et al. (författare)
  • Multi-ethnic genome-wide association study for atrial fibrillation
  • 2018
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
  • Tidskriftsartikel (refereegranskat)abstract
    • Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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12.
  • Roy, Sushmita, et al. (författare)
  • Identification of functional elements and regulatory circuits by Drosophila modENCODE.
  • 2010
  • Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 330:6012, s. 1787-1797
  • Tidskriftsartikel (refereegranskat)abstract
    • To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.
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13.
  • Ade, Peter, et al. (författare)
  • The Simons Observatory : science goals and forecasts
  • 2019
  • Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :2
  • Tidskriftsartikel (refereegranskat)abstract
    • The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial con figuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping approximate to 10% of the sky to a white noise level of 2 mu K-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of sigma(r) = 0.003. The large aperture telescope will map approximate to 40% of the sky at arcminute angular resolution to an expected white noise level of 6 mu K-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.
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14.
  • Asselbergs, Folkert W., et al. (författare)
  • Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci
  • 2012
  • Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 91:5, s. 823-838
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
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15.
  • Feitosa, Mary F., et al. (författare)
  • Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
  • 2018
  • Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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16.
  • Furberg, Helena, et al. (författare)
  • Genome-wide meta-analyses identify multiple loci associated with smoking behavior
  • 2010
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 134-441
  • Tidskriftsartikel (refereegranskat)abstract
    • Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], b = 1.03, standard error (s.e.) = 0.053, beta = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], b = 0.367, s. e. = 0.059, beta = 5.7 x 10(-10); and rs1028936[A], b = 0.446, s. e. = 0.074, beta = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], b = 0.333, s. e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
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17.
  • Gorski, Mathias, et al. (författare)
  • Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
  • 2021
  • Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
  • Tidskriftsartikel (refereegranskat)abstract
    • Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
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18.
  • Mahajan, Anubha, et al. (författare)
  • Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
  • 2018
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
  • Tidskriftsartikel (refereegranskat)abstract
    • We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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19.
  • Ntalla, Ioanna, et al. (författare)
  • Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
  • 2020
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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20.
  • Sung, Yun Ju, et al. (författare)
  • A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
  • 2019
  • Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 28:15, s. 2615-2633
  • Tidskriftsartikel (refereegranskat)abstract
    • Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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21.
  • Wheeler, Eleanor, et al. (författare)
  • Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations : A transethnic genome-wide meta-analysis
  • 2017
  • Ingår i: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 14:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findings: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 x 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI0.55-0.74) of African American adults with T2Dto remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.Conclusions: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
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22.
  • Williamson, Alice, et al. (författare)
  • Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake
  • 2023
  • Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:6, s. 973-983
  • Tidskriftsartikel (refereegranskat)abstract
    • Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
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23.
  • Niemi, MEK, et al. (författare)
  • 2021
  • swepub:Mat__t
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24.
  • Kanai, M, et al. (författare)
  • 2023
  • swepub:Mat__t
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25.
  • Arner, P., et al. (författare)
  • Circulating Carnosine Dipeptidase 1 associates with weight loss and poor prognosis in gastrointestinal cancer
  • 2015
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Cancer cachexia (CC) is linked to poor prognosis. Although the mechanisms promoting this condition are not known, several circulating proteins have been proposed to contribute. We analyzed the plasma proteome in cancer subjects in order to identify factors associated with cachexia. Design/Subjects: Plasma was obtained from a screening cohort of 59 patients, newly diagnosed with suspected gastrointestinal cancer, with (n = 32) or without (n = 27) cachexia. Samples were subjected to proteomic profiling using 760 antibodies (targeting 698 individual proteins) from the Human Protein Atlas project. The main findings were validated in a cohort of 93 patients with verified and advanced pancreas cancer. Results: Only six proteins displayed differential plasma levels in the screening cohort. Among these, Carnosine Dipeptidase 1 (CNDP1) was confirmed by sandwich immunoassay to be lower in CC (p = 0.008). In both cohorts, low CNDP1 levels were associated with markers of poor prognosis including weight loss, malnutrition, lipid breakdown, low circulating albumin/IGF1 levels and poor quality of life. Eleven of the subjects in the discovery cohort were finally diagnosed with non-malignant disease but omitting these subjects from the analyses did not have any major influence on the results. Conclusions: In gastrointestinal cancer, reduced plasma levels of CNDP1 associate with signs of catabolism and poor outcome. These results, together with recently published data demonstrating lower circulating CNDP1 in subjects with glioblastoma and metastatic prostate cancer, suggest that CNDP1 may constitute a marker of aggressive cancer and CC.
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26.
  • Buschur, Kristina L., et al. (författare)
  • Distinct COPD subtypes in former smokers revealed by gene network perturbation analysis
  • 2023
  • Ingår i: Respiratory Research. - : Springer Nature. - 1465-9921 .- 1465-993X. ; 24:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundChronic obstructive pulmonary disease (COPD) varies significantly in symptomatic and physiologic presentation. Identifying disease subtypes from molecular data, collected from easily accessible blood samples, can help stratify patients and guide disease management and treatment.MethodsBlood gene expression measured by RNA-sequencing in the COPDGene Study was analyzed using a network perturbation analysis method. Each COPD sample was compared against a learned reference gene network to determine the part that is deregulated. Gene deregulation values were used to cluster the disease samples.ResultsThe discovery set included 617 former smokers from COPDGene. Four distinct gene network subtypes are identified with significant differences in symptoms, exercise capacity and mortality. These clusters do not necessarily correspond with the levels of lung function impairment and are independently validated in two external cohorts: 769 former smokers from COPDGene and 431 former smokers in the Multi-Ethnic Study of Atherosclerosis (MESA). Additionally, we identify several genes that are significantly deregulated across these subtypes, including DSP and GSTM1, which have been previously associated with COPD through genome-wide association study (GWAS).ConclusionsThe identified subtypes differ in mortality and in their clinical and functional characteristics, underlining the need for multi-dimensional assessment potentially supplemented by selected markers of gene expression. The subtypes were consistent across cohorts and could be used for new patient stratification and disease prognosis.
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27.
  • Coenen, Pieter, et al. (författare)
  • The association of adolescent spinal-pain-related absenteeism with early adulthood work absenteeism : A six-year follow-up data from a population-based cohort
  • 2018
  • Ingår i: Scandinavian Journal of Work, Environment and Health. - : Nordic Association of Occupational Safety and Health. - 0355-3140 .- 1795-990X. ; 44:5, s. 521-529
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Spinal (ie, back and neck) pain often develops as early as during adolescence and can set a trajectory for later life. However, whether early-life spinal-pain-related behavioral responses of missing school/work are predictive of future work absenteeism is yet unknown. We assessed the association of adolescent spinal-pain-related work or school absenteeism with early adulthood work absenteeism in a prospective population-based cohort.Methods: Six year follow-up data from the Western Australian Pregnancy Cohort (Raine) study were used (N=476; with a 54% response rate). At age 17, participants reported spinal pain (using the Nordic questionnaire) and adolescent spinal-pain-related work/school absenteeism (with a single item question). Annual total and health-related work absenteeism was assessed with the Health and Work Performance questionnaire distributed in four quarterly text messages during the 23rd year of age. We modelled the association of adolescent spinal-pain-related absenteeism with work absenteeism during early adulthood, using negative binomial regression adjusting for sex, occupation and comorbidities.Results: Participants with adolescent low-back or neck pain with work/school absenteeism reported higher total work absenteeism in early adulthood [148.7, standard deviation (SD) 243.4 hours/year], than those without pain [43.7 (SD 95.2) hours/year); incidence rate ratio 3.4 (95% CI 1.2-9.2)]. Comparable findings were found when considering low-back and neck separately, and when considering health-related absenteeism.Conclusions: We found a more than three-fold higher risk of work absenteeism in early adulthood among those with adolescent spinal-pain-related absenteeism, compared to those without. These findings suggest that, to keep a sustainable workforce, pain prevention and management should focus on pain-related behaviors as early as in adolescence.
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28.
  • Costa, Nathalia, et al. (författare)
  • A Definition of "Flare" in Low Back Pain: A Multiphase Process Involving Perspectives of Individuals With Low Back Pain and Expert Consensus
  • 2019
  • Ingår i: Journal of Pain. - : CHURCHILL LIVINGSTONE. - 1526-5900 .- 1528-8447. ; 20:11, s. 1267-1275
  • Tidskriftsartikel (refereegranskat)abstract
    • Low back pain (LBP) varies over time. Consumers, clinicians, and researchers use various terms to describe LBP fluctuations, such as episodes, recurrences and flares. Although "flare" is use commonly, there is no consensus on how it is defined. This study aimed to obtain consensus for a LBP flare definition using a mixed-method approach. Step 1 involved the derivation of a preliminary candidate flare definition based on thematic analysis of views of 130 consumers in consultation with an expert consumer writer. In step 2, a workshop was conducted to incorporate perspectives of 19 LBP experts into the preliminary flare definition, which resulted in 2 alternative LBP flare definitions. Step 3 refined the definition using a 2-round Delphi consensus with 50 experts in musculoskeletal conditions. The definition favored by experts was further tested with 16 individuals with LBP in step 4, using the definition in three scenarios. This multiphase study produced a definition of LBP flare that distinguishes it from other LBP fluctuations, represents consumers views, involves expert consensus, and is understandable by consumers in clinical and research contexts: "A flare-up is a worsening of your condition that lasts from hours to weeks that is difficult to tolerate and generally impacts your usual activities and/or emotions." Perspective: A multiphase process, incorporating consumers views and expert consensus, produced a definition of LBP flare that distinguishes it from other LBP fluctuations. (C) 2019 by the American Pain Society
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29.
  • de Vries, Paul S., et al. (författare)
  • Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
  • 2019
  • Ingår i: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
  • Tidskriftsartikel (refereegranskat)abstract
    • A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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30.
  • Dehghan, Abbas, et al. (författare)
  • Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies : The CHARGE Consortium
  • 2016
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:3
  • 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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31.
  • Fagman, Johan Bourghardt, 1980, et al. (författare)
  • EGFR, but not COX-2, protein in resected pancreatic ductal adenocarcinoma is associated with poor survival.
  • 2019
  • Ingår i: Oncology letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 17:6, s. 5361-5368
  • Tidskriftsartikel (refereegranskat)abstract
    • The effects of EGFR and COX-2 protein overexpression on clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) patients remains unclear. Therefore, the aim of the present study was to evaluate the protein expression of epithelial growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) in tumor cells in surgically resected PDAC, in comparison with clinicopathological characteristics and clinical outcomes. Immunohistochemical staining of formalin-fixed paraffin-embedded tissue derived from surgically resected tumors was performed. Tissue slides were evaluated for membrane wild-type EGFR and cytoplasmic COX-2 staining using a histoscore system. Statistical associations between EGFR and COX-2 staining and clinicopathological characteristics were examined to predict survival. In a cohort of 32 resected PDAC patients, high EGFR protein expression in tumor cells was significantly associated with shorter median overall survival (7.9 vs. 39.2 months, P=0.0038). The corresponding hazard ratio (HR) for patients with high EGFR protein expression in tumor cells was 3.12 [95% confidence interval (CI): 1.39-7.00, P=0.006]. COX-2 protein expression was not associated with survival (22.6 vs. 24.5 months P=0.60; HR 1.22 95% CI: 0.59-2.51, P=0.60). Following multivariate Cox regression analysis, high EGFR protein expression in tumor cells (P=0.043) remained as significant independent prognostic factor for survival. In conclusion, high wild-type EGFR protein expression, but not COX-2 protein expression, in tumor cells is a prognostic factor for reduced overall survival following pancreatic tumor resection, supporting a role for EGFR in identifying resected patients that may benefit from EGFR-targeted therapy.
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32.
  • Gorski, Mathias, et al. (författare)
  • Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
  • 2022
  • Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
  • Tidskriftsartikel (refereegranskat)abstract
    • Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
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33.
  • Jung, Christian, et al. (författare)
  • A comparison of very old patients admitted to intensive care unit after acute versus elective surgery or intervention
  • 2019
  • Ingår i: Journal of critical care. - : W B SAUNDERS CO-ELSEVIER INC. - 0883-9441 .- 1557-8615. ; 52, s. 141-148
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: We aimed to evaluate differences in outcome between patients admitted to intensive care unit (ICU) after elective versus acute surgery in a multinational cohort of very old patients (80 years; VIP). Predictors of mortality, with special emphasis on frailty, were assessed.Methods: In total, 5063 VIPs were induded in this analysis, 922 were admitted after elective surgery or intervention, 4141 acutely, with 402 after acute surgery. Differences were calculated using Mann-Whitney-U test and Wilcoxon test. Univariate and multivariable logistic regression were used to assess associations with mortality.Results: Compared patients admitted after acute surgery, patients admitted after elective surgery suffered less often from frailty as defined as CFS (28% vs 46%; p < 0.001), evidenced lower SOFA scores (4 +/- 5 vs 7 +/- 7; p < 0.001). Presence of frailty (CFS >4) was associated with significantly increased mortality both in elective surgery patients (7% vs 12%; p = 0.01), in acute surgery (7% vs 12%; p = 0.02).Conclusions: VIPs admitted to ICU after elective surgery evidenced favorable outcome over patients after acute surgery even after correction for relevant confounders. Frailty might be used to guide clinicians in risk stratification in both patients admitted after elective and acute surgery. 
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34.
  • Lubitz, Steven A, et al. (författare)
  • Genetic Risk Prediction of Atrial Fibrillation
  • 2017
  • Ingår i: Circulation. - 0009-7322. ; 135:14, s. 1311-1320
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND—: Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. METHODS—: To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in five prospective studies comprising 18,919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3,028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from <1x10 to <1x10 in a prior independent genetic association study. RESULTS—: Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95%CI, 1.13-1.46; P=1.5x10) to 1.67 (25 variants; 95%CI, 1.47-1.90; P=9.3x10). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95%CI, 1.39-4.58; P=2.7x10). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 1.20-4.40; P=0.01). CONCLUSIONS—: Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors, though offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms.
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35.
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36.
  • Silfverskiöld, Stefan, et al. (författare)
  • Technology Forecast 2013 Military Utility of Six Technologies : a Report from Seminars at the SNDC Department of Military-Technology
  • 2013
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • Four technology forecast reports from the Fraunhofer Institute and two internet based search reports from Recorded Future have been reviewed by staff at the Department of Military- Technology at the Swedish National Defence College (Note that there probably are other technology areas, equally interesting, but not included in this study). The task given by FMV was to assess the military utility of the chosen technologies in a time frame from 2025 to 2030, from a SwAF viewpoint.We assess the military utility of a certain technology, as its contribution to the operational capabilities of the SwAF, within identified relevant scenarios.The technologies were grouped in three classes; technologies with potentially significant, uncertain or negligible military utility.The following technologies were assessed to have a potential for significant military utility;Alternative fuelsHigh altitude platformsUnmanned Aerial VehiclesCyber DefenceThe forecasting and analysis technology described in the report "Future of Cyber Threats" if the tool is combined with advanced artificial intelligence algorithmsThe following technology was assessed to have uncertain military utility;The forecasting and analysis technology described in the report "Future of Cyber Threats" in its present formThe following technology was assessed to have negligible military utility;Walking machinesThe method used was first to make a summary of each forecast report. The technology was then put into one or more scenarios that are assessed to be the best in order to show possible military utility as well as possibilities and drawbacks of the technologies. Based on a SWOT-analysis, the contribution to SwAF capabilities and the cost in terms of acquisition, C2 footprint, logistic footprint, doctrine/TTP, training, facilities and R&D were assessed. Conclusions regarding the military utility of the technology were drawn.Our evaluation of the method used shows that there is a risk that the assessment is biased by the participating experts’ presumptions and experiences from their own field of research. The scenarios that were chosen do not cover all aspects of the technology and their possible contribution to operational capabilities. It should be stressed that we have assessed the six technologies’ potential military utility within the presented scenarios, not the technology itself.The chosen definition of military utility clearly affects the result of the study. The definition (the military utility of a certain technology is its contribution to the operational capabilities of the SwAF, within identified relevant scenarios) has been slightly modified from the one used in the Technology Forecast 2012. It is believed to be good enough for this report, but could be further elaborated in the future.The greatest value of the method used is its simplicity, cost effectiveness and the tradeoff that it promotes learning within the working group. The composition of the working group and the methodology used is believed to provide for a broad and balanced coverage of the technologies under study. This report provides executive summaries of the Fraunhofer and Recorded Future reports and helps the SwAF Headquarter to evaluate the military utility of emerging technologies within identified relevant scenarios.Given the limited quantitative base (only 2 reports) for assessing the potential value of using the tool Temporal Analytics™ used by Recorded Future, our conclusion is nevertheless that the overall value of using the tool for technology forecasting is rather poor. Our assessment is that Recorded Future at present can’t be used as an alternative to the Fraunhofer Institute. Overall, the quality of the Fraunhofer reports is considered to be balanced and of a high level of critical analysis regarding technology development. These reports are in line with our task to evaluate the military utility of the emerging technologies. In the case of Recorded Future’s technology forecast, the sources that are relevant for making military predictions are considered to be ill-suited for aggregation in the form the tool in focus, Temporal Analytics™, provides. The tool requires further development to fit military purposes. Further use of Recorded Future in the technology forecast process is therefore not recommended, at least not until the tool has been combined with advanced artificial intelligence algorithms.We propose that the Department of Military Technology at SNDC could be involved in the early phase of the Technology Forecast process giving support to FMV in choosing which technology areas that should be selected to be studied by the Fraunhofer Institute within the framework of the Technology Forecast project (Teknisk Prognos).
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37.
  • Silfverskiöld, Stefan, et al. (författare)
  • Technology Forecast 2014 Military Utility of Four Technologies : A Report from Seminars at the SNDC Department of Military-Technology
  • 2014
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • Four technology forecast reports from the Fraunhofer Institute have been reviewed by staff at the Department of Military-Technology at the Swedish National Defence College. The task given by the Swedish Defence Material Administration, FMV, was to assess the military utility of the given technologies in a time frame to 2040, from a Swedish Armed Forces (SwAF) point of view.We assess the military utility of a certain technology as its contribution to the operational capabilities of the SwAF, based on identified relevant scenarios. Since a new capability catalogue is under development at the SwAF Headquarters, we will only present general assessments of the capability impact from the technologies under study.The technologies were grouped in three classes; technologies with potentially significant, uncertain or negligible military utility. The classification uncertain is given for technologies that are difficult to put in the two other classes, however it is not because the technology readiness level (TRL) is not reached by 2040.The following technologies were assessed to have a potential for significant military utility;Kinodynamic motion planning This technology is a prerequisite for reaching full autonomy of highly agile unmanned systems and is probably a logical, evolutionary way to go forward. It will affect most SwAF capabilities through enhanced mobility. This technology should be studied by the SwAF, preferably within all operational environments.Bio-inspired Adaptive Camouflage Surfaces "Bio-inspired camouflage" should be viewed in a broad multispectral perspective involving design requirements for low contrast in the visual- and IR-spectrum as well as, for most applications, low reflectivity in the radar-band. There is an ongoing duel between sensor development and camouflage systems and our assessment is that the fewer and more valuable platforms we have, we will need better camouflage performance in order to maintain low probability of detection and short detection distances for an adversary, at least if faced with a technologically mature adversary. Our overall assessment is that bio-inspired adaptive camouflage systems have significant potential for military utility.UCAV If the idea that UCAV are superior in air combat is realizable, we may be facing a paradigm shift of the same magnitude as that which airborne radar or air-to-air missiles introduced. Thus, UCAV are deemed to have potential for significant military utility in future air operations even though it is, at present, hard to predict how they will be used to maximize their military utility.The following technology was assessed to have uncertain military utility;Bulk metallic glass (BMG) If BMG innovations prove to form a new performance step in armour and weapons development, it will from a Swedish perspective be crucial to take part in that development or else take the risk of being inferior on the battlefield. Given the many uncertainties concerning production and applications, we assess BMGs to have uncertain potential for military utility in 2040. However, the SwAF should monitor the development and applications in this area.None of the studied technologies were found to have negligible military utility. .The method used in this technology forecast report was to assign each Fraunhofer report to one reviewer in the working group. First, a summary of each forecast report was made. The Fraunhofer assessment of technical readiness level (TRL) in 2030-40 was held to be correct. The technology was then put into one or more scenarios that were assessed to be suitable in order to assess the military utility as well as indicate possibilities and drawbacks of the technologies. Based on a SWOT-analysis, the contribution to SwAF capabilities and the cost in terms of acquisition, C2 footprint, logistic footprint, doctrine/TTP, training, facilities and R&D were assessed. Finally, conclusions regarding the potential military utility of the technology were drawn.The chosen definition of military utility clearly affects the result of the study. The definition (the military utility of a certain technology is its contribution to the operational capabilities of the SwAF, within identified relevant scenarios) is the same that was used in the Technology Forecast 2013. It is believed to be good enough for this report, but could be further elaborated in the future. An article that in depth presents our concept of military utility has been elaborated at the department.1Our evaluation of the method used shows that there is a risk that the assessment is biased by the participating experts’ presumptions and experiences from their own field of research. The scenarios that were chosen do not cover all aspects of the technology and their possible contribution to operational capabilities. It should be stressed that we have assessed the four technologies’ potential military utility within the specific presented scenarios, not the technology itself. When additional results have been found in the analysis this is mentioned.The greatest value of the method used is its simplicity, cost effectiveness and the tradeoff that it promotes learning within the working group. The composition of the working group and the methodology used is believed to provide for a broad and balanced coverage of the technologies under study. This report provides executive summaries of the Fraunhofer and Recorded Future reports and the intention is to help the SwAF Headquarter to evaluate the military utility of emerging technologies within identified relevant scenarios.Overall, the quality of the Fraunhofer reports is considered to be balanced and of a high level of critical analysis regarding technology development. These reports are in line with our task to evaluate the military utility of the emerging technologies.We appreciate that the Department of Military Technology at SNDC this time has been involved in the early phase of the Technology Forecast process.
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38.
  • Silfverskiöld, Stefan, 1964-, et al. (författare)
  • Technology Forecast 2017 - Military Utility of Future Technologies : A Report from Seminars at the Swedish Defence University’s (SEDU) Military-Technology Division
  • 2017
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • Two technology forecast reports from the Fraunhofer Institute, three reports from the Swedish Defence Research Institute (FOI) and two publications from the Massachusetts Institute of Technology (MIT) have been reviewed by staff at the Military-Technology Division at the Swedish Defence University (SEDU). The task given by the Defence Material Administration (FMV) was to assess the military utility of the given technologies in a time frame to up 2040, from a Swedish Armed Forces (SwAF) perspective.In the review we assessed the military utility of certain technologies as possible contributions to the operational capabilities of the SwAF, based on identified and relevant scenarios. Because a new capability catalogue is under development at the SwAF Headquarters, this report only presents general assessments of the capability impact of the technologies studied.The technologies were grouped into four classes: potentially significant, moderate, negligible, or uncertain military utility.The classification uncertain military utility was given to technologies that are difficult to put in the other three classes, it was not because the technology readiness level (TRL) will not bereached by 2040.The following technologies were assessed to have the potential for significant military utility:- Nanocarbons for photonic applicationsThe following technologies were assessed to have a potential for moderate military utility;- Internet of things (IoT)- Materials and technologies for protection against chemical agentsThe following technologies were assessed to have uncertain military utility;- Post-quantum cryptography- New applications for hyperspectral image analysis for chemical and biological agentsNo technology was found to have negligible military utility.The method used in this technology forecast report was to assign each report to one reviewer in the working group. Firstly, each forecast report was summarized. The Fraunhofer assessment of technical readiness level (TRL) in the time period was held to be correct. Each technology was then put into one or more scenarios that were assessed to be suitable for assessing the military utility as well as indicating any possibilities and drawbacks. Based on a SWOTanalysis, the assessed contributions to the fundamental capabilities, and to the factors DOTMPLFI (Doctrine, Organization, Training, Materiel, Leadership, Personnel, Facilities and Interoperability), were listed. Furthermore, the expected SwAF R&D requirements, to facilitate the introduction of the technology are given. The Military utility was assessed using a model developed by the Military-Technology Division. Finally, conclusions and an overall rating of the potential military utility of each technology were presented.The chosen definition of military utility clearly affects the result of the study. The definition used here (“the military utility of a certain technology is its contribution to the operational capabilities of the SwAF, within identified relevant scenarios”) has been used in our Technology Forecasts since 2013.Our evaluation of the method used shows that there is a risk that assessments can be biased by the participating experts’ presumptions and experience from their own field of research. It should also be stressed that the seven technologies’ potential military utility was assessed within the specific presented scenarios and their possible contribution to operational capabilities within those specific scenarios, not in general. When additional results have been found in the analysis, this is mentioned.The greatest value of the method used is its simplicity, cost effectiveness and that it promotes learning within the working group. The composition of the working group and the methodology used are believed to provide a broad and balanced coverage of the technologies being studied. This report should be seen as an executive summary of the research reports and the intention is to help the SwAF Headquarters to evaluate the military utility of emerging technologies within identified relevant scenarios.Overall, the research reports are considered to be balanced and of high quality in terms of their level of critical analysis regarding technology development. These reports are in line with our task to evaluate the military utility of the emerging technologies.
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39.
  • Simpson, Phoebe, et al. (författare)
  • Training of Physical Therapists to Deliver Individualized Biopsychosocial Interventions to Treat Musculoskeletal Pain Conditions : A Scoping Review
  • 2021
  • Ingår i: Physical Therapy. - : Oxford University Press. - 0031-9023 .- 1538-6724. ; 101:10
  • Forskningsöversikt (refereegranskat)abstract
    • OBJECTIVE: Current guidelines recommend management of musculoskeletal pain conditions from a biopsychosocial approach, however biopsychosocial interventions delivered by physical therapists vary considerably in effectiveness. It is unknown whether the differences are explained by the intervention itself, the training and/or competency of physical therapists delivering the intervention, or fidelity of the intervention. The aim was to investigate and map the training, competency assessments and fidelity checking of individualized biopsychosocial interventions delivered by physical therapists to treat musculoskeletal pain conditions.METHODS: A scoping review methodology was employed, using Arksey and O'Malley's framework. Seven electronic databases were searched between January to March 2019, with a bridge search completed in January 2020. Full text peer-reviewed papers, with an individualized biopsychosocial intervention were considered, and thirty-two studies were included.RESULTS: Reporting overall was sparse and highly variable. There was a broad spectrum of the training. More sophisticated training involved workshops combining didactic and experiential learning, over longer durations with supervision and feedback. Less sophisticated training was brief, involving lectures or seminars, with no supervision or feedback. Competency assessments and fidelity testing were underperformed.CONCLUSION: Training in some interventions may not have facilitated the implementation of skills or techniques to enable the paradigm shift and behavior change required for physical therapists to effectively deliver a biopsychosocial intervention. Lack of competency assessments and fidelity checking may have impacted on the methodological quality of biopsychosocial interventions.IMPACT: This study highlighted problematic reporting, training, assessment of competency and fidelity checking of physical therapist delivered individualized biopsychosocial interventions. Findings here highlight why previous interventions may have shown small effect sizes and areas for improvement in future interventions. These findings can help inform future research and facilitate more widespread implementation of physical therapist delivered biopsychosocial interventions for people with musculoskeletal pain and thereby improve their quality of life.
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40.
  • Turcot, Valerie, et al. (författare)
  • Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
  • 2018
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
  • 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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41.
  • Weng, Lu Chen, et al. (författare)
  • Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation : The AFGen Consortium
  • 2017
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.
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42.
  • Wessel, Jennifer, et al. (författare)
  • Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
  • 2015
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
  • Tidskriftsartikel (refereegranskat)abstract
    • Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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43.
  • Young, William J., et al. (författare)
  • Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
  • 2022
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
  • 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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44.
  • Albert, Christian, et al. (författare)
  • Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy : A Systematic Review and Meta-analysis
  • 2020
  • Ingår i: American Journal of Kidney Diseases. - : Elsevier BV. - 0272-6386 .- 1523-6838. ; 76:6, s. 826-
  • Forskningsöversikt (refereegranskat)abstract
    • Rationale & Objective: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction.Study Design: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines.Setting & Study Populations: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms.Selection Criteria for Studies: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI.Data Extraction: Individual-study-data meta analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis.Analytical Approach: Individual-study-data meta analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses.Results: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.790.81) and 0.86 (95% CI, 0.84-0.8 6). Cutoff concentrations at 95% specificity for urinary NGAL were >580 ng/mL with 27% sensitivity for severe AKI and >589 ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were >364 ng/mL with 44% sensitivity and >546 ng/mL with 26% sensitivity, respectively.Limitations: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies. Conclusions: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation.
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45.
  • Ambatipudi, Radhika, 1982- (författare)
  • High Frequency (MHz) Planar Transformers for Next Generation Switch Mode Power Supplies
  • 2013
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Increasing the power density of power electronic converters while reducing or maintaining the same cost, offers a higher potential to meet the current trend inrelation to various power electronic applications. High power density converters can be achieved by increasing the switching frequency, due to which the bulkiest parts, such as transformer, inductors and the capacitor's size in the convertercircuit can be drastically reduced. In this regard, highly integrated planar magnetics are considered as an effective approach compared to the conventional wire wound transformers in modern switch mode power supplies (SMPS). However, as the operating frequency of the transformers increase from several hundred kHz to MHz, numerous problems arise such as skin and proximity effects due to the induced eddy currents in the windings, leakage inductance and unbalanced magnetic flux distribution. In addition to this, the core losses whichare functional dependent on frequency gets elevated as the operating frequency increases. Therefore, this thesis provides an insight towards the problems related to the high frequency magnetics and proposes a solution with regards to different aspects in relation to designing high power density, energy efficient transformers.The first part of the thesis concentrates on the investigation of high power density and highly energy efficient coreless printed circuit board (PCB) step-down transformers useful for stringent height DC-DC converter applications, where the core losses are being completely eliminated. These transformers also maintain the advantages offered by existing core based transformers such as, high coupling coefficient, sufficient input impedance, high energy efficiency and wide frequencyband width with the assistance of a resonant technique. In this regard, several coreless PCB step down transformers of different turn’s ratio for power transfer applications have been designed and evaluated. The designed multilayered coreless PCB transformers for telecom and PoE applications of 8,15 and 30W show that the volume reduction of approximately 40 - 90% is possible when compared to its existing core based counterparts while maintaining the energy efficiency of the transformers in the range of 90 - 97%. The estimation of EMI emissions from the designed transformers for the given power transfer application proves that the amount of radiated EMI from a multilayered transformer is lessthan that of the two layered transformer because of the decreased radius for thesame amount of inductance.The design guidelines for the multilayered coreless PCB step-down transformer for the given power transfer application has been proposed. The designed transformer of 10mm radius has been characterized up to the power level of 50Wand possesses a record power density of 107W/cm3 with a peak energy efficiency of 96%. In addition to this, the design guidelines of the signal transformer fordriving the high side MOSFET in double ended converter topologies have been proposed. The measured power consumption of the high side gate drive circuitvitogether with the designed signal transformer is 0.37W. Both these signal andpower transformers have been successfully implemented in a resonant converter topology in the switching frequency range of 2.4 – 2.75MHz for the maximum load power of 34.5W resulting in the peak energy efficiency of converter as 86.5%.This thesis also investigates the indirect effect of the dielectric laminate on the magnetic field intensity and current density distribution in the planar power transformers with the assistance of finite element analysis (FEA). The significanceof the high frequency dielectric laminate compared to FR-4 laminate in terms of energy efficiency of planar power transformers in MHz frequency region is also explored.The investigations were also conducted on different winding strategies such as conventional solid winding and the parallel winding strategies, which play an important role in the design and development of a high frequency transformer and suggested a better choice in the case of transformers operating in the MHz frequency region.In the second part of the thesis, a novel planar power transformer with hybrid core structure has been designed and evaluated in the MHz frequency region. The design guidelines of the energy efficient high frequency planar power transformerfor the given power transfer application have been proposed. The designed corebased planar transformer has been characterized up to the power level of 50W and possess a power density of 47W/cm3 with maximum energy efficiency of 97%. This transformer has been evaluated successfully in the resonant converter topology within the switching frequency range of 3 – 4.5MHz. The peak energy efficiency ofthe converter is reported to be 92% and the converter has been tested for the maximum power level of 45W, which is suitable for consumer applications such as laptop adapters. In addition to this, a record power density transformer has been designed with a custom made pot core and has been characterized in thefrequency range of 1 - 10MHz. The power density of this custom core transformer operating at 6.78MHz frequency is 67W/cm3 and with the peak energy efficiency of 98%.In conclusion, the research in this dissertation proposed a solution for obtaining high power density converters by designing the highly integrated, high frequency(1 - 10MHz) coreless and core based planar magnetics with energy efficiencies inthe range of 92 - 97%. This solution together with the latest semiconductor GaN/SiC switching devices provides an excellent choice to meet the requirements of the next generation ultra flat low profile switch mode power supplies (SMPS).
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46.
  • Amouzgar, Kaveh (författare)
  • Metamodel based multi-objective optimization
  • 2015
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • As a result of the increase in accessibility of computational resources and the increase in the power of the computers during the last two decades, designers are able to create computer models to simulate the behavior of a complex products. To address global competitiveness, companies are forced to optimize their designs and products. Optimizing the design needs several runs of computationally expensive simulation models. Therefore, using metamodels as an efficient and sufficiently accurate approximate of the simulation model is necessary. Radial basis functions (RBF) is one of the several metamodeling methods that can be found in the literature.The established approach is to add a bias to RBF in order to obtain a robust performance. The a posteriori bias is considered to be unknown at the beginning and it is defined by imposing extra orthogonality constraints. In this thesis, a new approach in constructing RBF with the bias to be set a priori by using the normal equation is proposed. The performance of the suggested approach is compared to the classic RBF with a posteriori bias. Another comprehensive comparison study by including several modeling criteria, such as problem dimension, sampling technique and size of samples is conducted. The studies demonstrate that the suggested approach with a priori bias is in general as good as the performance of RBF with a posteriori bias. Using the a priori RBF, it is clear that the global response is modeled with the bias and that the details are captured with radial basis functions.Multi-objective optimization and the approaches used in solving such problems are briefly described in this thesis. One of the methods that proved to be efficient in solving multi-objective optimization problems (MOOP) is the strength Pareto evolutionary algorithm (SPEA2). Multi-objective optimization of a disc brake system of a heavy truck by using SPEA2 and RBF with a priori bias is performed. As a result, the possibility to reduce the weight of the system without extensive compromise in other objectives is found.Multi-objective optimization of material model parameters of an adhesive layer with the aim of improving the results of a previous study is implemented. The result of the original study is improved and a clear insight into the nature of the problem is revealed.
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47.
  • Andersen, Lars Vabbersgaard, et al. (författare)
  • Influence of foundation type and soil stratification on ground vibration - A parameter study
  • 2016
  • Ingår i: Proceedings of the INTER-NOISE 2016 - 45th International Congress and Exposition on Noise Control Engineering: Towards a Quieter Future. ; , s. 7613-7622
  • Konferensbidrag (refereegranskat)abstract
    • Vibration of machinery and construction work are major sources of noise and vibration pollution in the urban environment. The frequencies dominating the vibration, and the distances over which it spreads via the ground, depend on the source. However, soil stratification and foundation type have a significant influence. Thus, in order to achieve fair accuracy in the prediction of ground vibration caused by sources vibrating on a foundation, accurate models of the ground and foundation may be required. However, for assessment of vibration in the design phase, simple models may be preferred. The paper provides a parameter study regarding the influence of soil stratification and foundation type on the ground vibration at different distances away from the source. Especially, vibration levels caused by sources placed on surface footings and piles are compared, employing a three-dimensional numerical model. Piles of different length are included in order to analyze the differences that can be expected regarding shaft-bearing and end-bearing piles. The paper provides insight into the significance of modelling the correct foundation structure and soil stratification and discusses the differences related to vibration near a source and at longer distances away from the source. Based on this, guidelines for model simplifications are given.
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48.
  • Andersson, Kent, et al. (författare)
  • Military utility : A proposed concept to support decision-making
  • 2015
  • Ingår i: Technology in society. - : Elsevier. - 0160-791X .- 1879-3274. ; 43, s. 23-32
  • Tidskriftsartikel (refereegranskat)abstract
    • A concept called Military Utility is proposed for the study of the use of technology in military operations. The proposed concept includes a three-level structure representing key features and their detailed components. On basic level the Military Utility of a technical system, to a military actor, in a specific context, is a compound measure of the military effectiveness, of the assessed technical system's suitability to the military capability system and of the affordability. The concept is derived through conceptual analysis and is based on related concepts used in social sciences, the military domain and Systems Engineering. It is argued that the concept has qualitative explanatory powers and can support military decision-making regarding technology in forecasts, defense planning, development, utilization and the lessons learned process. The suggested concept is expected to contribute to the development of the science of Military-Technology and to be found useful to actors related to defense.
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49.
  • Andersson, Kent, et al. (författare)
  • Technology Forecast 2012: Military utility of ten technologies : a report from seminars at the SNDC Department of Military Technology
  • 2012
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • Ten technology forecast reports from the Fraunhofer Institute have been reviewed by staff at the Department of Military-Technology at the Swedish National Defence College (Note that there probably are other technology areas, equally interesting, but not included in this study). The task given by FMV was to assess the military utility of the chosen technologies in a time frame from 2025 to 2030, from a SwAF viewpoint.The method used was first to make a summary of each forecast report. The technology was then put into one or more scenarios that are assessed to be the best in order to show possible utility as well as possibilities and drawbacks of the technology. Based on a SWOT-analysis, the contribution to SwAF capabilities and the cost in terms of acquisition, C2 footprint, logistic footprint, doctrine/TTP, training, facilities and R&D were assessed. Conclusions regarding the military utility of the technology were drawn.We introduce our definition of military utility as being activities that efficiently and with the lowest cost in terms of lives and materiel lead to fulfilment of the mission objectives.The technologies were grouped in three classes; technologies with a significant potential, with uncertain potential and with negligible potential.The following technologies were assessed to have a significant potential for military utility;Augmented RealityNano air vehiclesSolid State Laser weaponsIn the scenarios studied, Augmented Reality (AR) is assessed to have a positive impact on several SwAF capabilities, especially for C2 and intelligence. AR is a relatively mature technology, applicable in many different branches. There are examples where AR is already applied with great success, e.g. Head-Up-Displays, HUD. The technology has proven its value. However, there are well known drawbacks to the technology such as weaknesses regarding models, increased weight for dismounted soldiers, power consumption etc. There is also a risk that personnel will have problems solving their tasks when AR systems fail, not being used to fighting without supporting systems.Nano air vehicles (NAV’s) have been assessed to contribute to a large range of capabilities, primarily intelligence. Their lifecycle cost has been assessed to be low, since development in this area is commercially driven, bringing down acquisition costs. Also, FAA has decided to allow NAV’s in controlled air space from 2015, which is expected to lead to an increase in civilian use of NAV’s. The technology is relatively mature even though there are obstacles concerning suitable materials, energy efficient propulsion systems as well as miniaturized microprocessors and software to control them.In the scenario studied, High Energy Solid State Lasers are assessed to have a positive impact on SwAF capabilities to engage targets on surface and in the air. The technology can be used to protect vessels on the surface and thereby increase survivability. The development of SSL in the given timeframe is expected to lower cost per shot and avoid the environmental problems with use of chemical lasers. Neighbouring military powers are expected to use laser weapons in the future, therefore SwAF should monitor the development of the laser weapons technology and develop and purchase adequate countermeasures.The following technologies were assessed to have uncertain potential for military utility;Metamaterial cloakingElectromagnetic gunSmall satellitesUltra-violet communicationMetamaterial cloaking, if realisable in the future, is assessed to be firstly implemented in the acoustic spectrum, since manufacturing of small structured cloaks for the shorter wavelengths in the optic and radar spectra is believed to be more difficult. Cloaking of submarines is primarily assessed to increase the survivability against torpedoes having active sonar. The use of cloaked mines could pose a deterring threat, even to advanced amphibious operations against Sweden. The technological development in this area should be closely monitored and compared to existing, maturing techniques for countermeasures and for the development of broad spectrum active torpedoes. The greatest concern is that cloaking will have negative impact on submarine manoeuvrability.The electro-thermal chemical (ETC) gun seems to be a first step towards a fully electrical gun such as the rail-gun or the coil-gun. The fully electrical guns have been a work in progress for some decades and there are still remaining challenges both concerning electrical power supply and design materials. When or if, they will be operational is difficult to say.The military utility of small satellites is disputed, despite an assessed contribution to several of the SwAF capabilities. The main reason for this is that there seems to be other alternatives which provide the desired capabilities, at a lower cost. Furthermore, the realisability and performance of small productionline manufactured nanosatellites is uncertain. However the scenario has shown that there are benefits to the military utility not met by other resources, e.g. the capability to perform surveillance and reconnaissance in operational areas globally without risking violation of the territorial integrity of other states or the lives of military personnel. Since there is a great interest in the technology area and several programmes are ongoing internationally the knowledgebase is assessed to be significantly better in a five year period. Also, the Swedish in depth study of space exploitation is soon to report.Ultra-violet communication has uncertain potential for military utility within the period, but the technology is assessed to have a positive impact on SwAF capability to maintain communications. The theoretical understanding of the area is low It is therefore uncertain if systems can be realized in the time frame. However, if commercial applications are developed, the prospect of military applications might change. In that case UV-communication could be a complement to RF- communication but is not foreseen to replace it. The following technologies were assessed to have negligible potential for military utility;Biomimetic unmanned underwater vehicles (UUV)Automated behaviour AnalysisEvolutionary RoboticsBiomimetic UUV’s could be used for covert surveillance and inconspicuous naval reconnaissance missions at sea or in amphibious missions. Even though the report focuses on fishlike propulsion, the military utility of UUV’s is assessed to be mostly dependent on the development of advanced automation and learning systems. As of now, we assess other existing technologies as being preferable due to lower cost and less complexity. The performance of UUV’s needed for SwAF capabilities are assessed to be far off into the future. Simpler UUV systems could however be used by potential adversaries for monitoring our own base areas and hence the development should be monitored from a protection point of view.Automated behaviour analysis may be of some relevance for increased security screening and surveillance. The primary military utility of the technology will however probably be for international activities and to a lesser extent for increased base security in Sweden. Generally the main applications for this kind of technology are assessed to be for civilian use in public spaces and close to high value areas like airports, important official buildings and other similar objects.Evolutionary Robotics, here restricted to the sub domain Advanced Robotics, has uncertain potential for military utility within the period. In the scenarios studied the technology is assessed to have a positive impact on a broad range of SwAF capabilities. The area is large and inconsistent comprising sub areas that are assessed to have significant potential, but also those that are believed to have negligible potential or where technological obstacles might retard the development.Our evaluation of the used method shows that there is a risk that the assessment is biased by the participating experts’ presumptions and experiences from their own field of research. The scenarios that were chosen do not cover all possible aspects of the technology and their possible contribution to operational capabilities. It should be stressed that we have assessed the ten technologies’ military utility in the presented scenarios, not the technology itself. The chosen definition of military utility clearly affects the result of the study. The definition is believed to be good enough for this report, but could be further elaborated in the future.The greatest value of the method used is its simplicity, cost effectiveness and the trade off that it promotes learning within the working group. The composition of the working group and the methodology used is believed to provide for a broad and balanced coverage of the technologies under study. 
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