| 1. |
- Brunius, Carl, 1974, et al.
(författare)
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Prediction and modeling of pre-analytical sampling errors as a strategy to improve plasma NMR metabolomics data
- 2017
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1460-2059 .- 1367-4811. ; 33:22, s. 3567-3574
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Tidskriftsartikel (refereegranskat)abstract
- Biobanks are important infrastructures for life science research. Optimal sample handling regarding e.g. collection and processing of biological samples is highly complex, with many variables that could alter sample integrity and even more complex when considering multiple study centers or using legacy samples with limited documentation on sample management. Novel means to understand and take into account such variability would enable high-quality research on archived samples. This study investigated whether pre-analytical sample variability could be predicted and reduced by modeling alterations in the plasma metabolome, measured by NMR, as a function of pre-centrifugation conditions (1-36 h pre-centrifugation delay time at 4 A degrees C and 22 A degrees C) in 16 individuals. Pre-centrifugation temperature and delay times were predicted using random forest modeling and performance was validated on independent samples. Alterations in the metabolome were modeled at each temperature using a cluster-based approach, revealing reproducible effects of delay time on energy metabolism intermediates at both temperatures, but more pronounced at 22 A degrees C. Moreover, pre-centrifugation delay at 4 A degrees C resulted in large, specific variability at 3 h, predominantly of lipids. Pre-analytical sample handling error correction resulted in significant improvement of data quality, particularly at 22 A degrees C. This approach offers the possibility to predict pre-centrifugation delay temperature and time in biobanked samples before use in costly downstream applications. Moreover, the results suggest potential to decrease the impact of undesired, delay-induced variability. However, these findings need to be validated in multiple, large sample sets and with analytical techniques covering a wider range of the metabolome, such as LC-MS.
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| 2. |
- Rullgard, H., et al.
(författare)
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Simulation of transmission electron microscope images of biological specimens
- 2011
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Ingår i: Journal of Microscopy. - : Wiley. - 0022-2720 .- 1365-2818. ; 243:3, s. 234-256
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Tidskriftsartikel (refereegranskat)abstract
- We present a new approach to simulate electron cryo-microscope images of biological specimens. The framework for simulation consists of two parts; the first is a phantom generator that generates a model of a specimen suitable for simulation, the second is a transmission electron microscope simulator. The phantom generator calculates the scattering potential of an atomic structure in aqueous buffer and allows the user to define the distribution of molecules in the simulated image. The simulator includes a well defined electron-specimen interaction model based on the scalar Schrodinger equation, the contrast transfer function for optics, and a noise model that includes shot noise as well as detector noise including detector blurring. To enable optimal performance, the simulation framework also includes a calibration protocol for setting simulation parameters. To test the accuracy of the new framework for simulation, we compare simulated images to experimental images recorded of the Tobacco Mosaic Virus (TMV) in vitreous ice. The simulated and experimental images show good agreement with respect to contrast variations depending on dose and defocus. Furthermore, random fluctuations present in experimental and simulated images exhibit similar statistical properties. The simulator has been designed to provide a platform for development of new instrumentation and image processing procedures in single particle electron microscopy, two-dimensional crystallography and electron tomography with well documented protocols and an open source code into which new improvements and extensions are easily incorporated.
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| 3. |
- Brocke, Ekaterina, et al.
(författare)
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Efficient Integration of Coupled Electrical-Chemical Systems in Multiscale Neuronal Simulations
- 2016
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Ingår i: Frontiers in Computational Neuroscience. - : Frontiers Media SA. - 1662-5188. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Multiscale modeling and simulations in neuroscience is gaining scientific attention due to its growing importance and unexplored capabilities. For instance, it can help to acquire better understanding of biological phenomena that have important features at multiple scales of time and space. This includes synaptic plasticity, memory formation and modulation, homeostasis. There are several ways to organize multiscale simulations depending on the scientific problem and the system to be modeled. One of the possibilities is to simulate different components of a multiscale system simultaneously and exchange data when required. The latter may become a challenging task for several reasons. First, the components of a multiscale system usually span different spatial and temporal scales, such that rigorous analysis of possible coupling solutions is required. Then, the components can be defined by different mathematical formalisms. For certain classes of problems a number of coupling mechanisms have been proposed and successfully used. However, a strict mathematical theory is missing in many cases. Recent work in the field has not so far investigated artifacts that may arise during coupled integration of different approximation methods. Moreover, in neuroscience, the coupling of widely used numerical fixed step size solvers may lead to unexpected inefficiency. In this paper we address the question of possible numerical artifacts that can arise during the integration of a coupled system. We develop an efficient strategy to couple the components comprising a multiscale test problem in neuroscience. We introduce an efficient coupling method based on the second-order backward differentiation formula (BDF2) numerical approximation. The method uses an adaptive step size integration with an error estimation proposed by Skelboe (2000). The method shows a significant advantage over conventional fixed step size solvers used in neuroscience for similar problems. We explore different coupling strategies that define the organization of computations between system components. We study the importance of an appropriate approximation of exchanged variables during the simulation. The analysis shows a substantial impact of these aspects on the solution accuracy in the application to our multiscale neuroscientific test problem. We believe that the ideas presented in the paper may essentially contribute to the development of a robust and efficient framework for multiscale brain modeling and simulations in neuroscience.
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| 4. |
- Rekić, Dinko, 1984, et al.
(författare)
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In silico prediction of efavirenz and rifampicin drug-drug interaction considering weight and CYP2B6 phenotype
- 2011
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 71:4, s. 536-43
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To test whether a pharmacokinetic simulation model could extrapolate non-clinical drug data to predict human efavirenz exposure after single and continuous dosing as well as the effects of concomitant rifampicin and further to evaluate the weight based dosage recommendations used to counteract the rifampicin-efavirenz interaction. Methods: Efavirenz pharmacokinetics were simulated using a physiologically-based pharmacokinetic model implemented in the Simcyp population-based simulator. Physicochemical and metabolism data obtained from the literature were used as input for prediction of pharmacokinetic parameters. The model was used to simulate the effects of rifampicin on efavirenz pharmacokinetics in 400 virtual patients, taking into account bodyweight and CYP2B6 phenotype. Results: Apart from the absorption phase, the simulation model predicted efavirenz concentration-time profiles reasonably well with close agreement with clinical data. The simulated effects of rifampicin co-administration on efavirenz treatment showed only a minor decrease of 16% (95%CI 13; 19) in efavirenz area under the concentration-time curve (AUC), in magnitude with what has been clinically observed (22%). Efavirenz exposure depended on CYP2B6 phenotype and bodyweight. Increasing the efavirenz dose during concomitant rifampicin was predicted to be most successful in patients over 50 kg regardless of CYP2B6 status. Conclusion: Our findings, although based on a simulation approach using limited in vitro data, support the current recommendations for using a 50 kg bodyweight cut-off for efavirenz dose increment when co-treating with rifampicin.
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| 5. |
- Öktem, Ozan, 1969-, et al.
(författare)
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A component-wise iterated relative entropy regularization method with updated prior and regularization parameter
- 2007
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Ingår i: Inverse Problems. - : Institute of Physics (IOP). - 0266-5611 .- 1361-6420. ; 23:5, s. 2121-2139
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Tidskriftsartikel (refereegranskat)abstract
- We present a componentwise iterated relative entropy regularization method (COMET) where the prior and regularization parameter could be updated in the iterates. Such a reconstruction method could be useful for multicomponent inverse problems, such as the one occurring in electron tomography. The paper also contains a brief introduction to regularization theory with emphasis on variational based regularization methods, and we rigorously prove that the tolerance-based entropy reconstruction method that occurs in the COMET iterates is a regularization method. We conclude by showing examples of COMET applied to electron tomography data.
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| 6. |
- Danielsson, Frida, et al.
(författare)
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Assessing the consistency of public human tissue RNA-seq data sets
- 2015
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Ingår i: Briefings in Bioinformatics. - : Oxford University Press. - 1467-5463 .- 1477-4054. ; 16:6, s. 941-949
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Tidskriftsartikel (refereegranskat)abstract
- Sequencing-based gene expression methods like RNA-sequencing (RNA-seq) have become increasingly common, but it is often claimed that results obtained in different studies are not comparable owing to the influence of laboratory batch effects, differences in RNA extraction and sequencing library preparation methods and bioinformatics processing pipelines. It would be unfortunate if different experiments were in fact incomparable, as there is great promise in data fusion and meta-analysis applied to sequencing data sets. We therefore compared reported gene expression measurements for ostensibly similar samples (specifically, human brain, heart and kidney samples) in several different RNA-seq studies to assess their overall consistency and to examine the factors contributing most to systematic differences. The same comparisons were also performed after preprocessing all data in a consistent way, eliminating potential bias from bioinformatics pipelines. We conclude that published human tissue RNA-seq expression measurements appear relatively consistent in the sense that samples cluster by tissue rather than laboratory of origin given simple preprocessing transformations. The article is supplemented by a detailed walkthrough with embedded R code and figures.
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| 7. |
- Sjölander, Arvid, et al.
(författare)
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Between-within models for survival analysis.
- 2013
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Ingår i: Statistics in Medicine. - Hoboken, USA : Wiley-Blackwell. - 0277-6715 .- 1097-0258. ; 32:18, s. 3067-3076
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Tidskriftsartikel (refereegranskat)abstract
- A popular way to control for confounding in observational studies is to identify clusters of individuals (e.g., twin pairs), such that a large set of potential confounders are constant (shared) within each cluster. By studying the exposure-outcome association within clusters, we are in effect controlling for the whole set of shared confounders. An increasingly popular analysis tool is the between-within (BW) model, which decomposes the exposure-outcome association into a 'within-cluster effect' and a 'between-cluster effect'. BW models are relatively common for nonsurvival outcomes and have been studied in the theoretical literature. Although it is straightforward to use BW models for survival outcomes, this has rarely been carried out in practice, and such models have not been studied in the theoretical literature. In this paper, we propose a gamma BW model for survival outcomes. We compare the properties of this model with the more standard stratified Cox regression model and use the proposed model to analyze data from a twin study of obesity and mortality. We find the following: (i) the gamma BW model often produces a more powerful test of the 'within-cluster effect' than stratified Cox regression; and (ii) the gamma BW model is robust against model misspecification, although there are situations where it could give biased estimates.
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| 8. |
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| 9. |
- Morén, Björn, 1987-, et al.
(författare)
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An extended dose-volume model in high dose-rate brachytherapy : Using mean-tail-dose to reduce tumor underdosage
- 2019
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Ingår i: Medical physics (Lancaster). - : Wiley-Blackwell Publishing Inc.. - 0094-2405 .- 2473-4209. ; 46:6, s. 2556-2566
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Tidskriftsartikel (refereegranskat)abstract
- Purpose High dose-rate brachytherapy is a method of radiotherapy for cancer treatment in which the radiation source is placed within the body. In addition to give a high enough dose to a tumor, it is also important to spare nearby healthy organs [organs at risk (OAR)]. Dose plans are commonly evaluated using the so-called dosimetric indices; for the tumor, the portion of the structure that receives a sufficiently high dose is calculated, while for OAR it is instead the portion of the structure that receives a sufficiently low dose that is of interest. Models that include dosimetric indices are referred to as dose-volume models (DVMs) and have received much interest recently. Such models do not take the dose to the coldest (least irradiated) volume of the tumor into account, which is a distinct weakness since research indicates that the treatment effect can be largely impaired by tumor underdosage even to small volumes. Therefore, our aim is to extend a DVM to also consider the dose to the coldest volume. Methods An improved DVM for dose planning is proposed. In addition to optimizing with respect to dosimetric indices, this model also takes mean dose to the coldest volume of the tumor into account. Results Our extended model has been evaluated against a standard DVM in ten prostate geometries. Our results show that the dose to the coldest volume could be increased, while also computing times for the dose planning were improved. Conclusion While the proposed model yields dose plans similar to other models in most aspects, it fulfils its purpose of increasing the dose to cold tumor volumes. An additional benefit is shorter solution times, and especially for clinically relevant times (of minutes) we show major improvements in tumour dosimetric indices.
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| 10. |
- Henriksson, J., et al.
(författare)
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A Model of Sympatric Speciation Through Reinforcement
- 2010
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Ingår i: Kinetic and Related Models. - : American Institute of Mathematical Sciences (AIMS). - 1937-5093 .- 1937-5077. ; 3:1, s. 143-163
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Tidskriftsartikel (refereegranskat)abstract
- Sympatric speciation, i.e. the evolutionary split of one species into two in the same environment, has been a highly troublesome concept. It has been a questioned if it is actually possible. Even though there have been a number of reported results both in the wild and from controlled experiments in laboratories, those findings are both hard to get and hard to analyze, or even repeat. In the current study we propose a mathematical model which addresses the question of sympatric speciation and the evolution of reinforcement. Our aim has been to capture some of the essential features such as: phenotype, resources, competition, heritage, mutation, and reinforcement, in as simple a way as possible. Still, the resulting model is not too easy to grasp with purely analytical tools, so we have also complemented those studies with stochastic simulations. We present a few results that both illustrates the usefulness of such a model, but also rises new biological questions about sympatric speciation and reinforcement in particular.
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