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| 2. |
- Porcu, E, et al.
(författare)
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Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3300-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.
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| 3. |
- Hop, Paul J., et al.
(författare)
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Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
- 2022
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:633
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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| 4. |
- d'Alessandro, Elisa, et al.
(författare)
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Thrombo-Inflammation in Cardiovascular Disease : An Expert Consensus Document from the Third Maastricht Consensus Conference on Thrombosis
- 2020
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 120:4, s. 538-564
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Tidskriftsartikel (refereegranskat)abstract
- Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism.
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| 5. |
- Potters, M. G., et al.
(författare)
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Optimal Experiment Design in Closed Loop with Unknown, Nonlinear and Implicit Controllers using Stealth Identification
- 2014
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Ingår i: 2014 European Control Conference, ECC 2014. - : IEEE. - 9783952426913 ; , s. 726-731
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Konferensbidrag (refereegranskat)abstract
- We present a novel optimal experiment design method that is applicable to linear time-invariant systems regulated by unknown, nonlinear and implicitly-defined controllers. Current methods require an explicit expression for the controller in order to construct the optimal excitation spectrum. Consequently, these are limited to linearly-controlled systems. The identification scheme suggested in this paper circumvents the aforementioned requirement by ensuring that the excitation signal remains unnoticed by the controller, i.e., the identification data is gathered in an open-loop fashion. Our theoretical analysis is complemented with a numerical study on a six-parameter, single-input single-output linear system controlled by an MPC. We find that our method generates least-costly excitation signals which deliver identified models that lie close to the true system whilst honoring quality constraints, validating the novel optimal experiment design framework.
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| 6. |
- Mesbah, A., et al.
(författare)
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A unified experiment design framework for detection and identification in closed-loop performance diagnosis
- 2012
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Ingår i: Decision and Control (CDC), 2012 IEEE 51st Annual Conference on. - : IEEE. ; , s. 2152-2157
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Konferensbidrag (refereegranskat)abstract
- This paper presents a least-costly experiment design framework for closed-loop performance diagnosis using prediction error identification. The performance diagnosis methodology consists in verifying whether an identified model of the true system lies in a performance-related region of interest. The experiment design framework minimizes the overall excitation cost incurred for detecting the cause of the performance drop and re-identifying the system dynamics when the degraded performance is due to control-relevant system changes. The optimal design of excitation signals is performed for a desired detection rate and a pre-specified level of accuracy required for the re-identified model.
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| 7. |
- Bombois, X., et al.
(författare)
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Effect of model structure and signal-to-noise ratio on finite-time uncertainty bounding in prediction error identification
- 2009
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Ingår i: Proceedings of the 48th IEEE Conference on Decision and Control, 2009 held jointly with the 2009 28th Chinese Control Conference. CDC/CCC 2009. - : IEEE. - 9781424438716 ; , s. 494-499
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Konferensbidrag (refereegranskat)abstract
- In prediction error identification, confidence regions are most commonly derived from the asymptotic statistical properties of the parameter estimator. Therefore, these confidence regions are only asymptotically valid and, for finite samples, their actual coverage rate can be smaller than the desired coverage rate. In this paper, we analyze the influence of the SNR and of the type of model structure on the difference between the actual and desired coverage rates. In addition, we propose alternatives to the classical approach to constructing probabilistic confidence regions for Box-Jenkins systems.
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| 8. |
- Forgione, M., et al.
(författare)
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Experiment design for parameter estimation in nonlinear systems based on multilevel excitation
- 2014
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Ingår i: 2014 European Control Conference, ECC 2014. - 9783952426913 ; , s. 25-30
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Konferensbidrag (refereegranskat)abstract
- An experiment design procedure for parameter estimation in nonlinear dynamical systems is presented in this paper. The input to the system is designed in such a way that the information content of the data, as measured by a scalar function of the information matrix, is maximized. By restricting the input to a finite number of possible levels, the experiment design problem is formulated as a convex optimization problem which can be solved efficiently. The method is applied to a Continuous Stirred Tank Reactor in a simulation study. The parameter estimation based on the input signal obtained in our procedure is shown to outperform the one based on random binary signals.
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| 9. |
- Özkan, Leyla, et al.
(författare)
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Advanced autonomous model-based operation of industrial process systems (Autoprofit) : Technological developments and future perspectives
- 2016
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Ingår i: ANNUAL REVIEWS IN CONTROL. - : Elsevier. - 1367-5788. ; 42, s. 126-142
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Forskningsöversikt (refereegranskat)abstract
- Model-based operation support technology such as Model Predictive Control (MPC) is a proven and accepted technology for multivariable and constrained large scale control problems in process industry. Despite the growing number of successful implementations, the low level of operational efficiency of MPC is an existing problem, specifically the lack of advanced maintenance technology. To this end, within the EU FP 7 program, a project (Autoprofit (1)) has been executed to advance the level of autonomy and automated maintenance of MPC technology. Taking linear model-based technology as a starting point, in the project a philosophy has been developed for autonomous performance monitoring, diagnosis, experiment design, model adaptation and controller re-tuning, that is driven by economic criteria in each step, working towards an operation support system in which effective maintenance and adaptation of MPC controllers becomes feasible. In this development, challenging research questions have been addressed in the areas of on-line performance monitoring and diagnosis, least costly experiment design, automated adaptation of models, and auto-tuning, and new fundamental techniques have been developed. Although a full fledge and industrially proven (semi-)automated system is not yet realised, parts of the on-line system have been implemented and validated on real life cases provided by the industrial partners, showing that the formulated objectives are within reach.
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