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| 2. |
- Forsgren, Mikael F, 1983-, et al.
(författare)
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Biomarkers of liver fibrosis : prospective comparison of multimodal magnetic resonance, serum algorithms and transient elastography.
- 2020
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Ingår i: Scandinavian Journal of Gastroenterology. - : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 55:7, s. 848-859
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Accurate biomarkers for quantifying liver fibrosis are important for clinical practice and trial end-points. We compared the diagnostic performance of magnetic resonance imaging (MRI), including gadoxetate-enhanced MRI and 31P-MR spectroscopy, with fibrosis stage and serum fibrosis algorithms in a clinical setting. Also, in a subset of patients, MR- and transient elastography (MRE and TE) was evaluated when available.METHODS: Patients were recruited prospectively if they were scheduled to undergo liver biopsy on a clinical indication due to elevated liver enzyme levels without decompensated cirrhosis. Within a month of the clinical work-up, an MR-examination and liver needle biopsy were performed on the same day. Based on late-phase gadoxetate-enhanced MRI, a mathematical model calculated hepatobiliary function (relating to OATP1 and MRP2). The hepatocyte gadoxetate uptake rate (KHep) and the normalised liver-to-spleen contrast ratio (LSC_N10) were also calculated. Nine serum fibrosis algorithms were investigated (GUCI, King's Score, APRI, FIB-4, Lok-Index, NIKEI, NASH-CRN regression score, Forns' score, and NAFLD-fibrosis score).RESULTS: The diagnostic performance (AUROC) for identification of significant fibrosis (F2-4) was 0.78, 0.80, 0.69, and 0.78 for MRE, TE, LSC_N10, and GUCI, respectively. For the identification of advanced fibrosis (F3-4), the AUROCs were 0.93, 0.84, 0.81, and 0.82 respectively.CONCLUSION: MRE and TE were superior for non-invasive identification of significant fibrosis. Serum fibrosis algorithms developed for specific liver diseases are applicable in this cohort of diverse liver diseases aetiologies. Gadoxetate-MRI was sufficiently sensitive to detect the low function losses associated with fibrosis. None was able to efficiently distinguish between stages within the low fibrosis stages.Lay summaryExcessive accumulation of scar tissue, fibrosis, in the liver is an important aspect in chronic liver disease. To replace the invasive needle biopsy, we have explored non-invasive methods to assess liver fibrosis. In our study we found that elastographic methods, which assess the mechanical properties of the liver, are superior in assessing fibrosis in a clinical setting. Of interest from a clinical trial point-of-view, none of the tested methods was sufficiently accurate to distinguish between adjacent moderate fibrosis stages.
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| 3. |
- Biteus, Jonas, 1977-, et al.
(författare)
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Improving Airplane Safety by Incorporating Diagnosis into Existing Safety Practice
- 2004
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Safety has always been at premium in airfare. There is a long history of systematic work in the field, and current practice has established a high degree of safety that has resulted in so low failure numbers that the public finds confidence in the process of air worthiness certification. However, the design and development process of airplanes to achieve this is costly and may be even more so since modern airplanes become more and more complex. Furthermore, recent trends towards Unmanned Aerial Vehicles (UAV) are likely to require even more efforts and costs, to fulfill the increased safety requirements. Therefore it is interesting to investigate modern techniques that promises to improve safety at reduced costs. One such technique is diagnosis. Diagnosis in general is a term that includes several research and application fields. Examples of such fields, that are technology drivers, are the fields of supervision both on-line (on-board) and off-line (on ground), operator support that evolved from the Harrisburg accident, and law based emission diagnostics regulation e.g. as stipulated by California Air Resource Board (CARB).The current work is an investigation in the cross field between safety assessment and diagnosis techniques. The first step was to root the work in existing safety practice. This means that the Swedish defense procedure has been adopted as described in H SystSäk E. It is a safety framework that uses fault tree analysis and failure mode effect analysis as important tools. Thereafter some flight applications were investigated together with Saab specialists to capture and formulate some aspects that are non-trivial to cast in the existing safety framework. Examples of such aspects found are for instance related to performance requirements in different operational model. A principle case study was then formulated using laboratory equipment, with the aim to capture some of the identified aspects in the problem formulation. A complete process for safety analysis was then completed along the lines of H SystSäk E including all meetings and documents required therein. Several observations were done during this work, but the overall conclusion so far is that the effect of introducing diagnosis algorithms can be handled in the safety analysis, and, yes, that there is a promise that diagnosis algorithms can improve safety in a structured quantitative way by lowering the contribution to the total failure risk from the subsystem being diagnosed.
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| 5. |
- Cedersund, Gunnar, 1978
(författare)
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Core-box Modelling - Theoretical Contributions and Applications to Glucose Homeostasis Related Systems
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The study of biological systems through a combination of in vitro characterisations, quantitative in vivo experiments, and mathematical modelling, is receiving an increasingly growing interest through the field system biology. Systems biology uses methods from many different research fields, but the existing methods need to be extended and adapted to fit the new situations. This dissertation presents new methods for various modelling situations, and the developments have been driven by examples related to glucose homeostasis. The modelling methods are contained in a new modelling framework denoted core-box modelling. Core-box modelling attempts to combine the strengths of mechanistic grey-box models (e.g., to describe detailed processes) with the strengths of minimal models (e.g., identifiability and hypothesis testing). The main new steps in the modelling process are: identifiability analysis, model reduction, system identification and a translation between different versions of the same model. In all these sub-disciplines, a review is given and new methods are developed; these contributions are of course valid in any framework. Methods are given for detection and handling of both structural and practical unidentifiability in individual rate expressions. This also yields in vivo expressions for the reactions. Special methods are derived for systems with oscillations. First, two methods for identification of the interactions generating the oscillations in a model are given. Then, two methods are! presented for parameter estimation of a system close to a Hopf bifurcation. The first method reduces the dimension of the parameters appearing in the differential equations, and the second method eliminates the parameters describing the initial state at time zero. Finally, it is shown how the results can be back-translated to a core-box model; a model with all the details of the original grey-box model, but with quality tags from the core model to its possible predictions.The new methodologies are applied to the development of three models. The first is a core-box model for insulin signalling in fat cells. The core model is obtained using hypothesis testing, which shows that the internalisation is necessary to generate the observed dynamics, and that the internalisation is of the same time-scale as an observed overshoot in the data. These predictions are validated experimentally, and the advantages of the core-box model with respect to the both the core and grey-box model are illustrated. The second model describes oscillations in yeast glycolysis. Many of the developed methods are applied, and their performances are demonstrated. This leads, e.g., to a refined prediction of the biochemical mechanisms generating the oscillations. The third model describes muscle metabolism under anaerobic exercise. The developed model is used to resolve a 25 year old contradiction between data and current biochemical understandings regarding the control of g! lycolysis following anaerobic contraction. Finally, an existing model of neutrophil metabolism is analysed. The main conclusion is that the model's apparent lack of robustness lies on the structural level and not on the parametric level. All these contributions show, in various ways, how the combined usage of models, biochemical characterisations, and quantitative in vivo data can work together in a fruitful way; a way which surpasses the abilities of either of these research fields working in isolation.
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| 6. |
- Cedersund, Gunnar, 1978-, et al.
(författare)
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Improved parameter estimation for systems with an experimentally located Hopf bifurcation
- 2005
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Ingår i: IEE Proceedings - Systems Biology. - : IEEE. - 1741-2471 .- 1741-248X. ; 152:3, s. 161-168
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Tidskriftsartikel (refereegranskat)abstract
- When performing system identification, we have two sources of information: experimental data and prior knowledge. Many cell-biological systems are oscillating, and sometimes we know an input where the system reaches a Hopf bifurcation. This is the case, for example, for glycolysis in yeast cells and for the Belousov-Zhabotinsky reaction, and for both of these systems there exist significant numbers of quenching data, ideal for system identification. We present a method that includes prior knowledge of the location of a Hopf bifurcation in estimation based on time-series. The main contribution is a reformulation of the prior knowledge into the standard formulation of a constrained optimisation problem. This formulation allows for any of the standard methods to be applied, including all the theories regarding the methods properties. The reformulation is carried out through an over-parametrisation of the original problem. The over-parametrisation allows for extra constraints to be formed, and the net effect is a reduction of the search space. A method that can solve the new formulation of the problem is presented, and the advantage of adding the prior knowledge is demonstrated on the Brusselator.
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| 7. |
- Cedersund, Gunnar, 1978-, et al.
(författare)
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Optimization in biology parameter estimation and the associated optimization problem
- 2016
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Ingår i: Uncertainty in biology. - Cham : Springer. - 9783319212951 - 9783319212968 ; , s. 177-197
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Bokkapitel (refereegranskat)abstract
- Parameter estimation – the assignment of values to the parameters in a model – is an important and time-consuming task in computational biology. Recent computational and algorithmic developments have provided novel tools to improve this estimation step. One of these improvements concerns the optimization step, where the parameter space is explored to find interesting regions. In this chapter we review the parameter estimation problem, with a special emphasis on the associated optimization methods. In relation to this, we also provide concepts and tools to help you select the appropriate methodology for a specific scenario.
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| 8. |
- Cedersund, Gunnar, 1978-
(författare)
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Prediction uncertainty estimation despite unidentifiability : an overview of recent developments
- 2016
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Ingår i: Uncertainty in biology. - Cham : Springer. - 9783319212951 - 9783319212968 ; , s. 449-466
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Bokkapitel (refereegranskat)abstract
- One of the most important properties of a mathematical model is the abilityto make predictions: to predict that which has not yet been measured. Suchpredictions can sometimes be obtained from a simple simulation, but that requiresthat the parameters in the model are known from before. In biology, theparameters are usually both not known from before and not identifiable, i.e.the parameter values cannot be determined uniquely from available data. Insuch cases of unidentifiability, the space of acceptable parameters is large, ofteninfinite in certain directions. For such large spaces, sampling-based approachesthat try to characterize the entire space have difficulties. Recently, a new type ofalternative approaches that circumvent this characterization problem has beenproposed: where one only searches those directions in the space of acceptable parametersthat are relevant for the uncertainty of a particular prediction. In thisreview chapter, these recently proposed methods are compared and contrasted,both regarding theoretical properties, and regarding user experience. The focusis on methods from the field of systems biology, but also methods from biostatistics,pharmacodynamics, and biochemometrics are discussed. The hope is thatthis review will increase the usefulness and understanding of already proposedmethods, and thereby help foster a tradition where predictions only are deemedinteresting if their uncertainties have been determined.
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| 9. |
- Cedersund, Gunnar, 1978-
(författare)
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System identification of nonlinear thermochemical systems with dynamical instabilities
- 2004
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Thermochemical systems appear in applications as widespread as in combustion engines, in industrial chemical plants and inside biological cells. Science in all these areas is going towards a more model based thinking, and it is therefore important to develop good methods for system identification, especially fit for these kind of systems. The presented systems are described as nonlinear differential equations, and the common feature of the models is the presence of a boundary between an oscillating and a non-oscillating region, i.e. the presence of a bifurcation.If it is known that a certain input signal brings the system to a bifurcation manifold, and this is the case for many thermochemical systems, this knowledge can be included as an extra constraint in the parameter estimation. Except for special cases, however, this constraint can not be obtained analytically. For the general case a reformulation, adding variables and equally many constraints, have been done. This formulation allows for efficient use of standard techniques from constrained optimization theory. For systems with large state spaces the parameter vector describing the initial state becomes big (sometimes > 1000), and special treatment is required. New theory for such treatment have been shown, and the results are valid for systems operating close to a Hopf bifurcation. Through a combined center manifold and normal form reduction, the initial state is described in minimal degrees of freedom. Experiment designs are presented that force the minimal degrees of freedom two be 2 or 3, independently of the dimension of the state space. The initial state is determined by solving a sub-problem for each step in the ordinary estimation process. For systems starting in stationary oscillations the normal form reduction reveals the special structure of this sub-problem. Therefore it can be solved in a straight-forward manner, that does not have the problem of local minima, and that does not require any integration of the differential equations. It is also shown how the knowledge, coming from the presence of a bifurcation , can be used for model validation. The validation is formulated as a test quantity, and it has the benefit that it can work also with uncalibrated sensors, i.e. with sensors whose exact relation to the state variables is not known.Two new models are presented. The first is a multi-zonal model for cylinder pressure, temperature and ionization currents. It is a physically based model with the main objectives of understanding the correlation between the ionization curve and the pressure peak location. It is shown that heat transfer has a significant effect on this relation. It is further shown that the combination of a geometrically based heat transfer mode! and a dynamical NO-model predicts the correct relationship between the pressure and ionization peak location within one crank angel degree. The second developed model is for the mitogenic response to insulin in fat cells. It is the first developed model for this specific pathway and the model has been compared and estimated to experiment al data. Finally, a 16-dimensional model for activated neutrophils has been used to generate virtual data, on which the presented methods have been applied, and on which the performance of the methods were demonstrated.
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| 10. |
- Danø, Sune, et al.
(författare)
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Reduction of a biochemical model with preservation of its basic dynamic properties.
- 2006
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 273:21, s. 4862-4877
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Tidskriftsartikel (refereegranskat)abstract
- The complexity of full-scale metabolic models is a major obstacle for their effective use in computational systems biology. The aim of model reduction is to circumvent this problem by eliminating parts of a model that are unimportant for the properties of interest. The choice of reduction method is influenced both by the type of model complexity and by the objective of the reduction; therefore, no single method is superior in all cases. In this study we present a comparative study of two different methods applied to a 20D model of yeast glycolytic oscillations. Our objective is to obtain biochemically meaningful reduced models, which reproduce the dynamic properties of the 20D model. The first method uses lumping and subsequent constrained parameter optimization. The second method is a novel approach that eliminates variables not essential for the dynamics. The applications of the two methods result in models of eight (lumping), six (elimination) and three (lumping followed by elimination) dimensions. All models have similar dynamic properties and pin-point the same interactions as being crucial for generation of the oscillations. The advantage of the novel method is that it is algorithmic, and does not require input in the form of biochemical knowledge. The lumping approach, however, is better at preserving biochemical properties, as we show through extensive analyses of the models.
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