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| 2. |
- Jayawardena, Mahen, et al.
(författare)
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Using parallel computing and grid systems for genetic mapping of multifactorial traits
- 2005
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- We present a flexible parallel implementation of the exhaustive grid search algorithm for multidimensional QTL mapping problems. A generic, parallel algorithm is presented and a two-level scheme is introduced for partitioning the work corresponding to the independent computational tasks in the algorithm. At the outer level, a static block-cyclic partitioning is used, and at the inner level a dynamic pool-of-tasks model is used. The implementation of the parallelism at the outer level is performed using scripts, while MPI is used at the inner level. By comparing to results from the SweGrid system to those obtained using a shared memory server, we show that this type of application is highly suitable for execution in a grid framework.
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| 3. |
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| 4. |
- Ljungberg, Kajsa B, et al.
(författare)
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Computational Modelling of Inhibitor Binding to Human Thrombin
- 2001
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Ingår i: Eur. J. Pharm. Sci.. ; 12:4, s. 441-446
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Tidskriftsartikel (refereegranskat)abstract
- Thrombin is an essential protein involved in blood clot formation and an important clinical target, since disturbances of the coagulation process cause serious cardiovascular diseases such as thrombosis. Here we evaluate the performance of a molecular dynamics based method for predicting the binding affinities of different types ofhuman thrombin inhibitors. Far a series of eight ligands the method ranks their relative affinities reasonably well. The binding free energy difference between high and low affinity representatives in the test set is quantitatively reproduced, as well as the stereospecificity for a chiral inhibitor. The original parametrisation of this linear interaction energy method requires the addition of a constant energy term in the case of thrombin. This yields a mean unsigned error of 0.68 kcal/mol for the absolute binding free energies. This type of approach is also useful for elucidating three-dimensional structure-activity relationships in terms ofmicroscopic interactions of the ligands with the solvated enzyme.
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| 5. |
- Ljungberg, Kajsa, et al.
(författare)
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Efficient Algorithms for Multi-Dimensional Global Optimization in Genetic Mapping of Complex Traits
- 2010
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Ingår i: Advances and Applications in Bioinformatics and Chemistry. - 1178-6949. ; 3:1, s. 75-88
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Tidskriftsartikel (refereegranskat)abstract
- We present a two-phase strategy for optimizing a multidimensional, nonconvex function arising during genetic mapping of quantitative traits. Such traits are believed to be affected by multiple so called quantitative trait loci (QTL), and searching for d QTL results in a d-dimensional optimization problem with a large number of local optima. We combine the global algorithm DIRECT with a number of local optimization methods that accelerate the final convergence, and adapt the algorithms to problem-specific features. We also improve the evaluation of the QTL mapping objective function to enable exploitation of the smoothness properties of the optimization landscape. Our best two-phase method is demonstrated to be accurate in at least six dimensions and up to ten times faster than currently used QTL mapping algorithms.
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| 6. |
- Ljungberg, Kajsa, et al.
(författare)
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Efficient algorithms for multi-dimensional global optimization in genetic mapping of complex traits
- 2005
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- We present a two-phase strategy for optimizing a multi-dimensional, non-convex function arising during genetic mapping of quantitative traits. Such traits are believed to be affected by multiple so called QTL, and searching for d QTL results in a d-dimensional optimization problem with a large number of local optima. We combine the global algorithm DIRECT of Jones et al. with a number of local optimization methods that accelerate the final convergence, and adapt the algorithms to problem-specific features. We also improve the evaluation of the QTL mapping objective function to enable exploitation of the smoothness properties of the optimization landscape. Our best two-phase method is demonstrated to be accurate in at least six dimensions and up to ten times faster than currently used QTL mapping algorithms.
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| 7. |
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| 8. |
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| 9. |
- Ljungberg, Kajsa
(författare)
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Efficient evaluation of the residual sum of squares for quantitative trait locus models in the case of complete marker genotype information
- 2005
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Motivation: A core computation of many popular quantitative trait locus, QTL, mapping methods is determining the residual sum of squares, RSS, for a regression of trait values on (pseudo-)marker genotypes. A single evaluation is easily performed using the standard method QR factorization, but together the RSS computations take considerable time and often constitute the major part of the computational effort.Results: We present an algorithm for RSS evaluation that is mathematically equivalent to evaluation via QR factorization but 10-100 times faster depending on the model and data dimensions. It can be used for all standard QTL models. Our method opens the possibility for more detailed data analysis and more extensive model comparisons.Availability: C code, detailed derivations and general implementation strategies are available from the author on request.
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| 10. |
- Ljungberg, Kajsa, et al.
(författare)
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Efficient kernel algorithms for QTL mapping problems
- 2002
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The advent of sophisticated and powerful methods for molecular genetics pushes the need for efficient methods for data analysis. Advanced algorithms are necessary for extracting all possible information from laboriously obtained data sets. We present a general linear algebra framework for QTL mapping, applicable to many commonly used methods, using both linear regression and maximum likelihood estimation. The formulation simplifies future comparisons between and analyses of the methods. We show how the common structure of QTL analysis models can be used to improve the kernel algorithms, drastically reducing the computational effort while retaining the original analysis results. We have evaluated our new algorithms on data sets originating from two large F2 populations of domestic animals. Using an updating approach, we show that 1-3 orders of magnitude reduction in computational demand can be achieved for matrix factorizations. For interval mapping/composite interval mapping settings using a maximum likelihood model, we also show how to use the original EM algorithm instead of the ECM approximation, significantly improving the convergence and introducing an additional reduction in the computational time. The algorithmic improvements makes it feasible to perform analyses previously deemed impractical or even impossible. For example, using the new algorithms it is reasonable to perform permutation testing using exhaustive search on populations of 200 individuals for fully epistatic two-QTL models with a large number of parameters.
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| 11. |
- Ljungberg, Kajsa, 1974-
(författare)
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Numerical Algorithms for Mapping of Multiple Quantitative Trait Loci in Experimental Populations
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Most traits of medical or economic importance are quantitative, i.e. they can be measured on a continuous scale. Strong biological evidence indicates that quantitative traits are governed by a complex interplay between the environment and multiple quantitative trait loci, QTL, in the genome. Nonlinear interactions make it necessary to search for several QTL simultaneously. This thesis concerns numerical methods for QTL search in experimental populations. The core computational problem of a statistical analysis of such a population is a multidimensional global optimization problem with many local optima. Simultaneous search for d QTL involves solving a d-dimensional problem, where each evaluation of the objective function involves solving one or several least squares problems with special structure. Using standard software, already a two-dimensional search is costly, and searches in higher dimensions are prohibitively slow.Three efficient algorithms for evaluation of the most common forms of the objective function are presented. The computing time for the linear regression method is reduced by up to one order of magnitude for real data examples by using a new scheme based on updated QR factorizations. Secondly, the objective function for the interval mapping method is evaluated using an updating technique and an efficient iterative method, which results in a 50 percent reduction in computing time. Finally, a third algorithm, applicable to the imputation and weighted linear mixture model methods, is presented. It reduces the computing time by between one and two orders of magnitude.The global search problem is also investigated. Standard software techniques for finding the global optimum of the objective function are compared with a new approach based on the DIRECT algorithm. The new method is more accurate than the previously fastest scheme and locates the optimum in 1-2 orders of magnitude less time. The method is further developed by coupling DIRECT to a local optimization algorithm for accelerated convergence, leading to additional time savings of up to eight times. A parallel grid computing implementation of exhaustive search is also presented, and is suitable e.g for verifying global optima when developing efficient optimization algorithms tailored for the QTL mapping problem.Using the algorithms presented in this thesis, simultaneous search for at least six QTL can be performed routinely. The decrease in overall computing time is several orders of magnitude. The results imply that computations which were earlier considered impossible are no longer difficult, and that genetic researchers thus are free to focus on model selection and other central genetical issues.
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| 12. |
- Ljungberg, Kajsa
(författare)
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Numerical methods for mapping of multiple QTL
- 2003
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis concerns numerical methods for mapping of multiple quantitative trait loci, QTL. Interactions between multiple genetic loci influencing important traits, such as growth rate in farm animals and predisposition to cancer in humans, make it necessary to search for several QTL simultaneously. Simultaneous search for n QTL involves solving an n-dimensional global optimization problem, where each evaluation of the objective function consists of solving a generalized least squares problem. In Paper A we present efficient algorithms, mainly based on updated QR factorizations, for evaluating the objective functions of different parametric QTL mapping methods. One of these algorithms reduces the computational work required for an important function class by one order of magnitude compared with the best of the methods used by other authors. In Paper B previously utilized techniques for finding the global optimum of the objective function are compared with a new approach based on the DIRECT algorithm of Jones et al. The new method gives accurate results in one order of magnitude less time than the best of the formerly employed algorithms. Using the algorithms presented in Papers A and B, simultaneous search for at least three QTL, including computation of the relevant empirical significance thresholds, can be performed routinely.
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| 13. |
- Ljungberg, Kajsa, et al.
(författare)
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Simultaneous search for multiple QTL using the global optimization algorithm DIRECT
- 2003
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Motivation: Epistatic interactions are important for quantitative traits. To maximize the power to detect epistatic quantitative trait loci (QTLs), a simultaneous search is necessary. The computational complexity demands that the traditional exhaustive search be replaced by a more efficient global optimization algorithm.Results: We have adapted DIRECT, an algorithm presented in [Jones93], to the problem of simultaneous mapping of two and three QTL. We have compared DIRECT, in terms of accuracy and speed analyzing real data sets, with standard exhaustive search and a genetic algorithm previously used for QTL mapping in two dimensions. In all two- and three-QTL test cases, DIRECT accurately finds the global optimum two to four orders of magnitude faster than when using an exhaustive search, and one order of magnitude faster than when using the genetic algorithm. A search using a model with three fully interacting QTL is finished in six CPU minutes when using DIRECT, while an exhaustive search takes 142 CPU days. Thus three-QTL randomization testing for determining empirical significance thresholds is made feasible by the use of DIRECT. This opens the possibility to thoroughly investigate the power of simultaneous search to detect at least three interacting QTL.Availability: The source code of the prototype implementation is available at http://www.tdb.uu.se/~kl/qtl_software.html.
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| 14. |
- Marelius, J., et al.
(författare)
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Sensitivity of an Empirical Affinity Scoring Function to Changes in Receptor-Ligand Complex Conformations
- 2001
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Ingår i: European Journal of Pharmaceutical Sciences. - 0928-0987 .- 1879-0720. ; 14:1, s. 87-95
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Tidskriftsartikel (refereegranskat)abstract
- A combination of empirical scoring and conformational sampling for ligand bindingaffinity prediction is examined. The behaviour of a scoring function with respect to thesensitivity to conformational changes is investigated using ensembles of structures generated by molecular dynamics simulation. The correlation between the calculated score and the coordinate deviation from the experimental structure is clear for the complex of arabinose with arabinose-binding protein, which is dominated by hydrogen bond interactions, while the score calculated for the hydrophobic complex between retinol and retinol binding protein is rather insensitive to ligand conformational changes. For typical ensembles of stuctures generated by molecular dynamics at 300 K. the variation of the calculated score is considerably smaller than that of the underlying molecular mechanics interaction energies.
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