| 1. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 2. |
- Burgelman, Nico, et al.
(författare)
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Influence of wheel-rail contact modelling on vehicle dynamic simulation
- 2015
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Ingår i: Vehicle System Dynamics. - : Informa UK Limited. - 0042-3114 .- 1744-5159. ; 53:8, s. 1190-1203
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents a comparison of four models of rolling contact used for online contact force evaluation in rail vehicle dynamics. Until now only a few wheel-rail contact models have been used for online simulation in multibody software (MBS). Many more models exist and their behaviour has been studied offline, but a comparative study of the mutual influence between the calculation of the creep forces and the simulated vehicle dynamics seems to be missing. Such a comparison would help researchers with the assessment of accuracy and calculation time. The contact methods investigated in this paper are FASTSIM, Linder, Kik-Piotrowski and Stripes. They are compared through a coupling between an MBS for the vehicle simulation and Matlab for the contact models. This way the influence of the creep force calculation on the vehicle simulation is investigated. More specifically this study focuses on the influence of the contact model on the simulation of the hunting motion and on the curving behaviour.
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| 3. |
- Casanueva, Carlos, 1981-, et al.
(författare)
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Comparison of wear prediction models for different contact conditions
- 2016
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Ingår i: Proceedings of the 24th Symposium of the International Association for Vehicle System Dynamics (IAVSD 2015), Graz, Austria, 17-21 August 2015. - : CRC Press. - 9781138028852 - 9781498777025 ; , s. 871-878
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Konferensbidrag (refereegranskat)abstract
- Simulation of wheel and rail wear allows to predict long term profile evolution and thus, study the consequences of wheel damage in the dynamic behaviour of the vehicle, or study future maintenance requirements. Several models have been developed which try to solve the wear issue by relating the energy dissipated in the wheel-rail contact to the worn out material, from which two can be highlighted (Tg/A and Archard) which have significant differences on contact level. Even though, the prediction of long term wheel profile evolution has been validated with these two models, which means that for regular applications they seem to have an equivalent behaviour. In this work similarities and differences between the long term wear prediction methodologies are analysed, discussing their actual limitations. Then, these differences are exploited in specific operational cases to compare their wear prediction performance.
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| 4. |
- Casanueva, Carlos, 1981-, et al.
(författare)
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On integrated wheel and track damage prediction using vehicle-track dynamic simulations
- 2017
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Ingår i: Proceedings of the Institution of mechanical engineers. Part F, journal of rail and rapid transit. - : Sage Publications. - 0954-4097 .- 2041-3017. ; 231:7, s. 775-785
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Tidskriftsartikel (refereegranskat)abstract
- The renewal costs for wheels and rails are a substantial part of the costs for rolling stock operators and infrastructure managers all over the world. The causes for reprofiling or grinding are, in most cases, related to the following: (1) wheel or rail profiles with unacceptable wear, (2) appearance of rolling contact fatigue cracks in the surface, and (3) wheel flats caused by locking wheels during braking. The first two causes are related to the dynamic behavior of the vehicle-track system, and can be predicted using multibody simulations. However, there are several limitations that restrain the usefulness of these prediction techniques, such as simulation time constraints, necessary simplifications, and lack of experimental data that lead to educated assumptions. In this paper, we take the end-user perspective in order to show whether the latest developments in wheel-rail damage prediction can be integrated in a simplified framework, and subsequently used by the different stakeholders for an improved management of the different assets involved in the operation of rail vehicles.
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| 5. |
- de Vrind, V. A. J., et al.
(författare)
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Effects of GABA and Leptin Receptor-Expressing Neurons in the Lateral Hypothalamus on Feeding, Locomotion, and Thermogenesis
- 2019
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Ingår i: Obesity. - : Wiley. - 1930-7381 .- 1930-739X. ; 27:7, s. 1123-1132
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The lateral hypothalamus (LH) is known for its role in feeding, and it also regulates other aspects of energy homeostasis. How genetically defined LH neuronal subpopulations mediate LH effects on energy homeostasis remains poorly understood. The behavioral effects of chemogenetically activating LH gamma-aminobutyric acid (GABA) and the more selective population of LH GABA neurons that coexpress the leptin receptor (LepR) were compared. Methods: LepR-cre and VGAT-cre mice were injected with AAV5-hSyn-DIO-hM3DGq-mCherry in the LH. The behavioral effects of LH GABA or LH LepR neuronal activation on feeding, locomotion, thermogenesis, and body weight were assessed. Results: The activation of LH GABA neurons increased body temperature (P ≤ 0.008) and decreased body weight (P ≤ 0.01) despite decreased locomotor activity (P = 0.03) and transiently increased chow intake (P ≤ 0.009). Also, similar to other studies, this study found that activation of LH GABA neurons induced gnawing on both food and nonfood (P = 0.001) items. Activation of LH LepR neurons decreased body weight (P ≤ 0.01) and chow intake when presented on the cage floor (P ≤ 0.04) but not when presented in the cage top and increased locomotor activity (P = 0.002) and body temperature (P = 0.03). Conclusions: LH LepR neurons are a subset of LH GABA neurons, and LH LepR activation more specifically regulates energy homeostasis to promote a negative energy balance. © 2019 The Authors. Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS)
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| 6. |
- Dirks, Babette, et al.
(författare)
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Prediction of wheel profile wear and crack growth : Comparisons with measurements
- 2015
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Ingår i: CM 2015 - 10th International Conference on Contact Mechanics of Wheel / Rail Systems.
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Konferensbidrag (refereegranskat)abstract
- A model which can predict the surface crack length and crack depth in rails was developed in a previous study by the authors1. In the present study, this crack prediction model in combination with a wear prediction model is verified against wheel measurements. For a period of 15 months, the wheels of three units of a Stockholm commuter train were measured with respect to wear and crack development. Vehicle-track dynamics simulations were used to calculate the forces and contact positions for the wear and crack prediction models. It can be concluded that the wear prediction model gives reasonable results, especially considering the large scatter in the wheel profile measurements. Although the crack prediction model had to be adjusted for the current wheel application, the results appear promising.
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| 7. |
- Dirks, Babette, et al.
(författare)
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Prediction of wheel profile wear and crack growth - comparisons with measurements
- 2016
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Ingår i: Wear. - : Elsevier. - 0043-1648 .- 1873-2577. ; 366, s. 84-94
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Tidskriftsartikel (refereegranskat)abstract
- A model which can predict the length of the surface crack and crack depth in rails was developed in a previous study by the authors B. Dirks, R. Enblom, A. Ekberg, M. Berg (2015) []. In the present study, verification of this crack prediction model in combination with a wear prediction model was done against wheel measurements. For a period of 15 months, the wheels of three units of a Stockholm commuter train were measured with respect to wear and crack development for verification of the wheel life prediction tool. Vehicle-track dynamics simulations were used to calculate the forces and contact positions for the wear and crack prediction models. It can be concluded that the wear prediction model gives reasonable results, especially considering the large scatter in the wheel profile measurements. Although the wheel life prediction tool could not be verified, since the crack prediction model had to be recalibrated for the current wheel application, the results appear promising.
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| 8. |
- Dirks, Babette, 1976-
(författare)
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Simulation and Measurement of Wheel on Rail Fatigue and Wear
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The life of railway wheels and rails has been decreasing in recent years. This is mainly caused by more traffic and running at higher vehicle speed. A higher speed usually generates higher forces, unless compensated by improved track and vehicle designs, in the wheel-rail contact, resulting in more wear and rolling contact fatigue (RCF) damage to the wheels and rails. As recently as 15 years ago, RCF was not recognised as a serious problem. Nowadays it is a serious problem in many countries and ''artificial wear'' is being used to control the growth of cracks by preventive re-profiling and grinding of, respectively, the wheels and rails. This can be used because a competition exists between wear and surface initiated RCF: At a high wear rate, RCF does not have the opportunity to develop further. Initiated cracks are in this case worn off and will not be able to propagate deep beneath the surface of the rail or wheel.When wheel-rail damage in terms of wear and RCF can be predicted, measures can be taken to decrease it. For example, the combination of wheel and rail profiles, or the combination of vehicle and track, can be optimised to control the damage. Not only can this lead to lower maintenance costs, but also to a safer system since high potential risks can be detected in advance.This thesis describes the development of a wheel-rail life prediction tool with regard to both wear and surface-initiated RCF. The main goal of this PhD work was to develop such a tool where vehicle-track dynamics simulations are implemented. This way, many different wheel-rail contact conditions which a wheel or a rail will encounter in reality can be taken into account.The wear prediction part of the tool had already been successfully developed by others to be used in combination with multibody simulations. The crack prediction part, however, was more difficult to be used in combination with multibody simulations since crack propagation models are time-consuming. Therefore, more concessions had to be made in the crack propagation part of the tool, since time-consuming detailed modelling of the crack, for example in Finite Elements models, was not an option. The use of simple and fast, but less accurate, crack propagation models is the first step in the development of a wheel-rail life prediction model.Another goal of this work was to verify the wheel-rail prediction tool against measurements of profile and crack development. For this purpose, the wheel profiles of trains running on the Stockholm commuter network have been measured together with the crack development on these wheels. Three train units were selected and their wheels have been measured over a period of more than a year. The maximum running distance for these wheels was 230,000 km.A chosen fatigue model was calibrated against crack and wear measurements of rails to determine two unknown parameters. The verification of the prediction tool against the wheel measurements, however, showed that one of the calibrated parameters was not valid to predict RCF on wheels. It could be concluded that wheels experience relatively less RCF damage than rails. Once the two parameters were calibrated against the wheel measurements, the prediction tool showed promising results for predicting both wear and RCF and their trade-off. The predicted position of the damage on the tread of the wheel also agreed well with the position found in the measurements.
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| 9. |
- Dirks, Babette, et al.
(författare)
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The development of a crack propagation model for railway wheels and rails
- 2015
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Ingår i: Fatigue and Fracture of Engineering Materials and Structures. - : Wiley. - 8756-758X .- 1460-2695. ; 38:12, s. 1478-1491
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Tidskriftsartikel (refereegranskat)abstract
- Rolling contact fatigue (RCF) and wear of railway wheels and rails are the main phenom-ena that affect their m aintenance costs. When crack propagation and wear rates can bepredicted, maintenance planning can be optimised, and cost-effective measures can bedeveloped. Several RCF models exist, but none which can be used in combination withvehicle dynamics simulations and can predict the actual crack depth. This study showsthe development of a crack propagation model that can be applied for both railwaywheels and rails. Two unknow n material parameters in the model were calibrated againstcrack measurements in a curve on the Dutch railways over a period of 5 years. Two dif-ferent RCF models were used to calculate the stress magnitudes for the propagationmodel. The propagation model can be used in combination with vehicle-track dynamicssimulations and shows promise in predicting the actual crack depth and/or surface length.Further research is needed to determine the model’s validity for other operationalconditions.
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| 10. |
- Engert, Andreas, et al.
(författare)
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The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
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Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
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Tidskriftsartikel (refereegranskat)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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| 11. |
- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 12. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 13. |
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| 14. |
- Machiela, Mitchell J., et al.
(författare)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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| 15. |
- Machiela, Mitchell J, et al.
(författare)
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Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
- 2016
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
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| 16. |
- Nicolas, Aude, et al.
(författare)
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Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
- 2018
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Ingår i: Neuron. - : Cell Press. - 0896-6273 .- 1097-4199. ; 97:6, s. 1268-1283.e6
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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| 17. |
- Rådegran, Göran, et al.
(författare)
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Characteristics and survival of adult Swedish PAH and CTEPH patients 2000-2014
- 2016
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Ingår i: Scandinavian Cardiovascular Journal. - : Taylor & Francis. - 1401-7431 .- 1651-2006. ; 50:4, s. 243-250
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The Swedish Pulmonary Arterial Hypertension Register (SPAHR) is an open continuous register, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients from 2000 and onwards. We hereby launch the first data from SPAHR, defining baseline characteristics and survival of Swedish PAH and CTEPH patients.DESIGN: Incident PAH and CTEPH patients 2008-2014 from all seven Swedish PAH-centres were specifically reviewed.RESULTS: There were 457 PAH (median age: 67 years, 64% female) and 183 CTEPH (median age: 70 years, 50% female) patients, whereof 77 and 81%, respectively, were in functional class III-IV at diagnosis. Systemic hypertension, diabetes, ischaemic heart disease and atrial fibrillation were common comorbidities, particularly in those >65 years. One-, 3- and 5-year survival was 85%, 71% and 59% for PAH patients. Corresponding numbers for CTEPH patients with versus without pulmonary endarterectomy were 96%, 89% and 86% versus 91%, 75% and 69%, respectively. In 2014, the incidence of IPAH/HPAH, associated PAH and CTEPH was 5, 3 and 2 per million inhabitants and year, and the prevalence was 25, 24 and 19 per million inhabitants.CONCLUSION: The majority of the PAH and CTEPH patients were diagnosed at age >65 years, in functional class III-IV, and exhibiting several comorbidities. PAH survival in SPAHR was similar to other registers.
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| 18. |
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| 19. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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| 20. |
- Shahzamanian Sichani, Matin, et al.
(författare)
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An alternative to FASTSIM for tangential solution of the wheel-rail contact
- 2016
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Ingår i: The Dynamics of Vehicles on Roads and Tracks - Proceedings of the 24th Symposium of the International Association for Vehicle System. - : CRC Press. - 9781498777025 - 9781138028852 ; , s. 1377-1385
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Konferensbidrag (refereegranskat)abstract
- In most rail vehicle dynamics simulation packages, creep forces are estimated by means of Kalker's FASTSIM algorithm. While 5%-25% error is expected for force estimation the errors of shear stress distribution, needed for wheel/rail damage analysis, may rise above 30%. This is mainly due to the use of parabolic traction bound in FASTSIM. Thus, a novel algorithm called FaStrip is proposed as an alternative to FASTSIM. It is based on the strip theory in which elliptic traction bound is used. The comparison between the two algorithms, evaluated by CONTACT, shows that using FaStrip improves the accuracy of the estimated shear stress distribution while the creep force estimation in all studied cases is significantly improved as well. In one case, for instance, the error in force estimation reduces from 18% to less than 2%. Since FaStrip is as fast as FASTSIM, it can be an alternative for tangential solution of the wheel-rail contact in simulation packages.
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| 21. |
- Shahzamanian Sichani, Matin, et al.
(författare)
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An alternative to FASTSIM for tangential solution of the wheel–rail contact
- 2016
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Ingår i: Vehicle System Dynamics. - : Taylor & Francis. - 0042-3114 .- 1744-5159. ; 54:6, s. 748-764
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Tidskriftsartikel (refereegranskat)abstract
- In most rail vehicle dynamics simulation packages, tangential solution of the wheel–rail contact is gained by means of Kalker's FASTSIM algorithm. While 5–25% error is expected for creep force estimation, the errors of shear stress distribution, needed for wheel–rail damage analysis, may rise above 30% due to the parabolic traction bound. Therefore, a novel algorithm named FaStrip is proposed as an alternative to FASTSIM. It is based on the strip theory which extends the two-dimensional rolling contact solution to three-dimensional contacts. To form FaStrip, the original strip theory is amended to obtain accurate estimations for any contact ellipse size and it is combined by a numerical algorithm to handle spin. The comparison between the two algorithms shows that using FaStrip improves the accuracy of the estimated shear stress distribution and the creep force estimation in all studied cases. In combined lateral creepage and spin cases, for instance, the error in force estimation reduces from 18% to less than 2%. The estimation of the slip velocities in the slip zone, needed for wear analysis, is also studied. Since FaStrip is as fast as FASTSIM, it can be an alternative for tangential solution of the wheel–rail contact in simulation packages.
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| 22. |
- Shahzamanian Sichani, Matin, 1986-
(författare)
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On Efficient Modelling of Wheel-Rail Contact in Vehicle Dynamics Simulation
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The wheel-rail contact is at the core of all research related to vehicletrackinteraction. This tiny interface governs the dynamic performanceof rail vehicles through the forces it transmits and, like any high stressconcentration zone, it is subjected to serious damage phenomena. Thus,a clear understanding of the rolling contact between wheel and rail is keyto realistic vehicle dynamics simulation and damage analysis.In a multi-body dynamics simulation, the demanding contact problemshould be evaluated at about every millisecond for several wheel-rail pairs.Hence, a rigorous treatment of the contact is highly time-consuming.Simplifying assumptions are therefore made to accelerate the simulationprocess. This gives rise to a trade-o between the accuracy and computationaleciency of the contact model in use.Conventionally, Hertz+FASTSIM is used for calculation of the contactforces thanks to its low computational cost. However, the elliptic patchand pressure distribution obtained by Hertz' theory is often not realisticin wheel-rail contact. Moreover, the use of parabolic traction bound inFASTSIM causes considerable error in the tangential stress estimation.This combination leads to inaccurate damage predictions.Fast non-elliptic contact models are proposed by others to tacklethis issue while avoiding the tedious numerical procedures. The studiesconducted in the present work show that the accuracy of these models iscase-dependent.To improve the accuracy of non-elliptic patch and pressure estimation,a new method is proposed. The method is implemented in an algorithmnamed ANALYN. Comparisons show improvements in patch and, particularly,pressure estimations using ANALYN.In addition, an alternative to the widely-used FASTSIM is developed, named FaStrip. Unlike FASTSIM, it employs an elliptic traction boundand is able to estimate the non-linear characteristic of tangential stressdistribution. Comparisons show more accurate estimation of tangentialstress and slip velocity distribution as well as creep forces with FaStrip.Ultimately, an ecient non-elliptic wheel-rail contact model consistingof ANALYN and FaStrip is proposed. The reasonable computationalcost of the model enables it to be used on-line in dynamics simulationand its accuracy can improve the damage predictions.
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| 23. |
- Shu, Xiang, et al.
(författare)
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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
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Tidskriftsartikel (refereegranskat)abstract
- Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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| 24. |
- Sichani, Matin Sh., et al.
(författare)
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A fast wheel-rail contact model for application to damage analysis in vehicle dynamics simulation
- 2016
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Ingår i: Wear. - : Elsevier. - 0043-1648 .- 1873-2577. ; 366, s. 123-130
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Tidskriftsartikel (refereegranskat)abstract
- A novel wheel-rail contact model is proposed to be implemented for multi-body dynamics simulation, in order to facilitate accurate online calculation of damage phenomena such as wear and rolling contact fatigue. The normal contact, i.e. contact patch and pressure distribution, is calculated using a fast non elliptic algorithm called ANALYN. The tangential contact, i.e. tangential stress distribution, stick-slip division and creep force calculation, is treated using an alternative to the FASTSIM algorithm that is based on a strip theory which extends the two-dimensional solution of rolling contact to three-dimensional contacts. The proposed contact model is compared to the Hertz+FASTSIM model and evaluated using the CONTACT code in terms of contact patch and stress distribution as well as creep force curves. The results show that the proposed model can significantly improve the estimation of the contact solution both in terms of creep force estimation and contact details, such as stress distribution, needed for damage predictions.
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| 25. |
- Sichani, Matin Shahzamanian, et al.
(författare)
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Wheel-rail contact modeling for damage predictions in dynamics simulation software
- 2015
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Ingår i: CM 2015 - 10th International Conference on Contact Mechanics of Wheel / Rail Systems. - : International Conference on Contact Mechanics of Wheel.
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Konferensbidrag (refereegranskat)abstract
- A novel wheel-rail contact model is proposed to be implemented for multi-body dynamics simulation, in order to facilitate accurate online calculation of damage phenomena such as wear and rolling contact fatigue. The normal contact, i.e. contact patch and pressure distribution, is calculated using a fast non-elliptic algorithm called ANALYN. The tangential contact, i.e. tangential stress distribution, stick-slip division and creep force calculation, is treated using an alternative to the FASTSIM algorithm that is based on a strip theory which extends the exact two-dimensional solution of rolling contact to three-dimensional contacts. The proposed contact model is compared to the Kik-Piotrowski model and evaluated using the CONTACT code in terms of contact patch and stress distribution as well as creep force curves. The results show that the proposed model can significantly improve the estimation of the contact solution both in terms of creep force estimation and contact details, such as stress distribution, needed for damage predictions.
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| 26. |
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| 27. |
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| 28. |
- van Rheenen, Wouter, et al.
(författare)
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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
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Tidskriftsartikel (refereegranskat)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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| 29. |
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| 30. |
- Zeng, Chenjie, et al.
(författare)
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
- 2016
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
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