| 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. |
- 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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| 3. |
- 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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| 4. |
- Armengaud, E., et al.
(författare)
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Model-based toolchain for the efficient development of safety-relevant automotive embedded systems
- 2011
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Ingår i: SAE technical paper series. - 400 Commonwealth Drive, Warrendale, PA, United States : SAE International. - 0148-7191.
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Tidskriftsartikel (refereegranskat)abstract
- Advanced functionalities unthinkable a few decades ago are now being introduced into automotive vehicles through embedded systems for reasons like emission control, vehicle connectivity, safety and cooperative behaviors. As the development often involves stakeholders from different engineering disciplines and organizations, the complexity due to shared requirements, interdependencies of data, functions, and resources, as well as tight constraints in regards to timing, safety, and resource efficiency makes the system integration, quality control and assurance, reuse and change management increasingly more difficult. This calls for a more rigorous approach to the development of automotive embedded systems and components. This paper describes the CESAR reference technology platform (RTP) that supports the formalization of various engineering concerns in the development of safety-relevant embedded systems and thereby a model-based integration of various tools and methods to form seamless environments or toolchains for the development of such systems.
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| 5. |
- Chen, De Jiu, et al.
(författare)
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A Virtual Environment for the Management and Development of Cyber-Physical Manufacturing Systems
- 2015
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Ingår i: IFAC DCDS15. - : IFAC Papers Online. ; , s. 29-36
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Konferensbidrag (refereegranskat)abstract
- Modern machineries are often cyber-physical system-of-systems controlled by intelligent controllersfor collaborative operations on the productions of complex products. To assure theefficiency and effectiveness, a consolidation of concerns across managerial levels, product lifecyclestages, and product lines or families becomes necessary. This calls for a common informationinfrastructure in terms of ontology, models, methods and tools. For industrial manufacturerssubjected to increased cost pressure and market volatility, the availability of such an informationinfrastructure would promote their abilities of making optimized and proactive decisions andthereby their competitiveness and survivability. This paper presents a virtual environment thatconstitutes an information infrastructure for the management and development of evolvableproduction systems (EPS) in manufacturing. It adopts mature modeling frameworks throughEAST-ADL for an effective model-based approach. The contribution is centered on a meta-modelthat offers a common data specification and semantic basis for information management acrossproduct lifecycle, models and tools, both for resource planning and for anomaly treatment. Aprototype tool implementation of this virtual environment for validation is also presented.
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| 6. |
- Chen, De Jiu, et al.
(författare)
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Design of a knowledge-base strategy for capability-aware treatment of uncertainties of automated driving systems
- 2018
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Ingår i: Lect. Notes Comput. Sci.. - Cham : Springer International Publishing. - 9783319992280 - 9783319992297 ; , s. 446-457
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Konferensbidrag (refereegranskat)abstract
- Automated Driving Systems (ADS) represent a key technological advancement in the area of Cyber-physical systems (CPS) and Embedded Control Systems (ECS) with the aim of promoting traffic safety and environmental sustainability. The operation of ADS however exhibits several uncertainties that if improperly treated in development and operation would lead to safety and performance related problems. This paper presents the design of a knowledge-base (KB) strategy for a systematic treatment of such uncertainties and their system-wide implications on design-space and state-space. In the context of this approach, we use the term Knowledge-Base (KB) to refer to the model that stipulates the fundamental facts of a CPS in regard to the overall system operational states, action sequences, as well as the related costs or constraint factors. The model constitutes a formal basis for describing, communicating and inferring particular operational truths as well as the belief and knowledge representing the awareness or comprehension of such truths. For the reasoning of ADS behaviors and safety risks, each system operational state is explicitly formulated as a conjunction of environmental state and some collective states showing the ADS capabilities for perception, control and actuations. Uncertainty Models (UM) are associated as attributes to such state definitions for describing and quantifying the corresponding belief or knowledge status due to the presences of evidences about system performance and deficiencies, etc. On a broader perspective, the approach is part of our research on bridging the gaps among intelligent functions, system capability and dependability for mission-&safety-critical CPS, through a combination of development- and run-time measures. © Springer Nature Switzerland AG 2018.
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| 7. |
- Johansson, R., et al.
(författare)
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A strategy for assessing safe use of sensors in autonomous road vehicles
- 2017
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Ingår i: 36th International Conference on Computer Safety, Reliability, and Security, SAFECOMP 2017. - Cham : Springer. - 9783319662657 ; , s. 149-161
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Konferensbidrag (refereegranskat)abstract
- When arguing safety for an autonomous road vehicle it is considered very hard to show that the sensing capability is sufficient for all possible scenarios that might occur. Already for today’s manually driven road vehicles equipped with advanced driver assistance systems (ADAS), it is far from trivial how to argue that the sensor systems are sufficiently capable of enabling a safe behavior. In this paper, we argue that the transition from ADAS to automated driving systems (ADS) enables new solution patterns for the safety argumentation dependent on the sensor systems. A key factor is that the ADS itself can compensate for a lower sensor capability, by for example lowering the speed or increasing the distances. The proposed design strategy allocates safety requirements on the sensors to determine their own capability. This capability is then to be balanced by the tactical decisions of the ADS equipped road vehicle.
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| 8. |
- Bucaioni, Alessio, 1987-
(författare)
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Raising Abstraction of Timing Analysis through Model-Driven Engineering
- 2015
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The complexity of software running on vehicular embedded systems is constantlyincreasing and this negatively affects its development costs and time tomarket. One way to deal with these issues is to boost abstraction in the formof models to (i) ease the reasoning about the system architecture, (ii) automatecertain stages of the development, (iii) early detect flaws in the system architecturethrough fundamental analysis and (iv) take appropriate countermeasuresbefore the system is implemented.Considering the importance of timing requirements in the design of softwarefor vehicular embedded systems, in this licentiate thesis we leverageModel-Driven Engineering for realizing a semi-automatic approach which allowsthe developer to perform end-to-end delay timing analysis on design models,without having to manually model timing elements and set their values.The proposed approach, starting from a design model of an automotivesoftware functionality, automatically generates a set of models enriched withtiming elements whose values are set at generation time. End-to-end delay timinganalysis is run on the generated models and, based on the analysis results,the approach automatically selects the generated models which better meet aspecific set of timing requirements.
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| 9. |
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| 10. |
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Integrating safety analysis into the model-based development toolchain of automotive embedded systems
- 2010
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Proceedings (redaktörskap) (refereegranskat)abstract
- The automotive industry has a growing demand for the seamless integration of safety analysis tools into the model-based development tool chain for embedded systems. This requires translating concepts of the automotive domain to the safety domain. We automate such a translation between the automotive architecture description language EAST-ADL2 and the safety analysis tool HiPHOPS by using model transformations and by leveraging the advantages of different model transformation techniques. By means of this integration, the safety analysis can be conducted early in the development process, when the system can be redesigned to fulfill safety goals with relatively low effort and cost.
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