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- Thompson, B.A., et al.
(författare)
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Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:2, s. 107-115
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Tidskriftsartikel (refereegranskat)abstract
- The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases. © 2014 Nature America, Inc.
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| 3. |
- Hudson, Thomas J., et al.
(författare)
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International network of cancer genome projects
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Tidskriftsartikel (refereegranskat)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 4. |
- Fall, Tove, et al.
(författare)
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The Role of Adiposity in Cardiometabolic Traits : A Mendelian Randomization Analysis
- 2013
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 10:6, s. e1001474-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
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| 7. |
- Sarin, H., et al.
(författare)
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Comparing time histories for validation of simulation models : Error measures and metrics
- 2010
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Ingår i: Journal of Dynamic Systems Measurement, and Control. - : ASME International. - 0022-0434 .- 1528-9028. ; 132:6
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Tidskriftsartikel (refereegranskat)abstract
- Computer modeling and simulation are the cornerstones of product design and development in the automotive industry. Computer-aided engineering tools have improved to the extent that virtual testing may lead to significant reduction in prototype building and testing of vehicle designs. In order to make this a reality, we need to assess our confidence in the predictive capabilities of simulation models. As a first step in this direction, this paper deals with developing measures and a metric to compare time histories obtained from simulation model outputs and experimental tests. The focus of the work is on vehicle safety applications. We restrict attention to quantifying discrepancy between time histories as the latter constitute the predominant form of responses of interest in vehicle safety considerations. First, we evaluate popular measures used to quantify discrepancy between time histories in fields such as statistics, computational mechanics, signal processing, and data mining. Three independent error measures are proposed for vehicle safety applications, associated with three physically meaningful characteristics (phase, magnitude, and slope), which utilize norms, cross-correlation measures, and algorithms such as dynamic time warping to quantify discrepancies. A combined use of these three measures can serve as a metric that encapsulates the important aspects of time history comparison. It is also shown how these measures can be used in conjunction with ratings from subject matter experts to build regression-based validation metrics.
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| 8. |
- Surakka, Ida, et al.
(författare)
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A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol
- 2011
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:10, s. e1002333-
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Tidskriftsartikel (refereegranskat)abstract
- Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain similar to 25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79 x 10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
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| 9. |
- Yafi, Amr, et al.
(författare)
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Postoperative Quantitative Assessment of Reconstructive Tissue Status in a Cutaneous Flap Model Using Spatial Frequency Domain Imaging
- 2011
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Ingår i: Plastic and reconstructive surgery (1963). - : Ovid Technologies (Wolters Kluwer Health). - 0032-1052 .- 1529-4242. ; 127:1, s. 117-130
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Tidskriftsartikel (refereegranskat)abstract
- Background:The purpose of this study was to investigate the capabilities of a novel optical wide-field imaging technology known as spatial frequency domain imaging to quantitatively assess reconstructive tissue status.Methods:Twenty-two cutaneous pedicle flaps were created on 11 rats based on the inferior epigastric vessels. After baseline measurement, all flaps underwent vascular ischemia, induced by clamping the supporting vessels for 2 hours (either arteriovenous or selective venous occlusions); normal saline was injected into the control flap and hypertonic-hyperoncotic saline solution was injected into the experimental flap. Flaps were monitored for 2 hours after reperfusion. The spatial frequency domain imaging system was used for quantitative assessment of flap status over the duration of the experiment.Results:All flaps demonstrated a significant decline in oxyhemoglobin and tissue oxygen saturation in response to occlusion. Total hemoglobin and deoxyhemoglobin were increased markedly in the selective venous occlusion group. After reperfusion and the administration of solutions, oxyhemoglobin and tissue oxygen saturation in those flaps that survived gradually returned to baseline levels. However, flaps for which oxyhemoglobin and tissue oxygen saturation did not show any signs of recovery appeared to be compromised and eventually became necrotic within 24 to 48 hours in both occlusion groups.Conclusions:Spatial frequency domain imaging technology provides a quantitative, objective method of assessing tissue status. This study demonstrates the potential of this optical technology to assess tissue perfusion in a very precise and quantitative way, enabling wide-field visualization of physiologic parameters. The results of this study suggest that spatial frequency domain imaging may provide a means for prospectively identifying dysfunctional flaps well in advance of failure.
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