http://www.dspace.cam.ac.uk:80/handle/1810/227540 Tue, 21 May 2013 22:31:53 GMT 2013-05-21T22:31:53Z http://www.dspace.cam.ac.uk:80/handle/1810/237803 Title: Comparison of multimarker logistic regression models, with application to a genomewide scan of schizophrenia. Authors: Wason, James M S; Dudbridge, Frank Abstract: Abstract Background Genome-wide association studies (GWAS) are a widely used study design for detecting genetic causes of complex diseases. Current studies provide good coverage of common causal SNPs, but not rare ones. A popular method to detect rare causal variants is haplotype testing. A disadvantage of this approach is that many parameters are estimated simultaneously, which can mean a loss of power and slower fitting to large datasets. Haplotype testing effectively tests both the allele frequencies and the linkage disequilibrium (LD) structure of the data. LD has previously been shown to be mostly attributable to LD between adjacent SNPs. We propose a generalised linear model (GLM) which models the effects of each SNP in a region as well as the statistical interactions between adjacent pairs. This is compared to two other commonly used multimarker GLMs: one with a main-effect parameter for each SNP; one with a parameter for each haplotype. Results We show the haplotype model has higher power for rare untyped causal SNPs, the main-effects model has higher power for common untyped causal SNPs, and the proposed model generally has power in between the two others. We show that the relative power of the three methods is dependent on the number of marker haplotypes the causal allele is present on, which depends on the age of the mutation. Except in the case of a common causal variant in high LD with markers, all three multimarker models are superior in power to single-SNP tests. Including the adjacent statistical interactions results in lower inflation in test statistics when a realistic level of population stratification is present in a dataset. Using the multimarker models, we analyse data from the Molecular Genetics of Schizophrenia study. The multimarker models find potential associations that are not found by single-SNP tests. However, multimarker models also require stricter control of data quality since biases can have a larger inflationary effect on multimarker test statistics than on single-SNP test statistics. Conclusions Analysing a GWAS with multimarker models can yield candidate regions which may contain rare untyped causal variants. This is useful for increasing prior odds of association in future whole-genome sequence analyses. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Wed, 08 Sep 2010 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/237803 2010-09-08T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/237620 Title: Computational modeling of the EGFR network elucidates control mechanisms regulating signal dynamics Authors: Wang, Dennis Y Q; Cardelli, Luca; Phillips, Andrew; Piterman, Nir; Fisher, Jasmin Abstract: Abstract Background The epidermal growth factor receptor (EGFR) signaling pathway plays a key role in regulation of cellular growth and development. While highly studied, it is still not fully understood how the signal is orchestrated. One of the reasons for the complexity of this pathway is the extensive network of inter-connected components involved in the signaling. In the aim of identifying critical mechanisms controlling signal transduction we have performed extensive analysis of an executable model of the EGFR pathway using the stochastic pi-calculus as a modeling language. Results Our analysis, done through simulation of various perturbations, suggests that the EGFR pathway contains regions of functional redundancy in the upstream parts; in the event of low EGF stimulus or partial system failure, this redundancy helps to maintain functional robustness. Downstream parts, like the parts controlling Ras and ERK, have fewer redundancies, and more than 50% inhibition of specific reactions in those parts greatly attenuates signal response. In addition, we suggest an abstract model that captures the main control mechanisms in the pathway. Simulation of this abstract model suggests that without redundancies in the upstream modules, signal transduction through the entire pathway could be attenuated. In terms of specific control mechanisms, we have identified positive feedback loops whose role is to prolong the active state of key components (e.g., MEK-PP, Ras-GTP), and negative feedback loops that help promote signal adaptation and stabilization. Conclusions The insights gained from simulating this executable model facilitate the formulation of specific hypotheses regarding the control mechanisms of the EGFR signaling, and further substantiate the benefit to construct abstract executable models of large complex biological networks. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Tue, 22 Dec 2009 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/237620 2009-12-22T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/237589 Title: Response to: DNA identification by pedigree likelihood ratio accommodating population substructure and mutations Authors: Egeland, Thore; Dawid, A Philip; Mortera, Julia; Mostad, Petter; Tillmar, Andreas Abstract: Abstract Mutation models are important in many areas of genetics including forensics. This letter criticizes the model of the paper 'DNA identification by pedigree likelihood ratio accommodating population substructure and mutations' by Ge et al. (2010). Furthermore, we argue that the paper in some cases misrepresents previously published papers. Please see related letter: http://www.investigativegenetics.com/content/2/1/8. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Fri, 25 Mar 2011 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/237589 2011-03-25T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/236624 Title: Comparing Grothendieck-Witt Groups of a Complex Variety to its Real Topological K-Groups Authors: Zibrowius, Marcus Abstract: On a complex variety X, two different approaches to K-theory are available: the algebraic K-theory of the variety, and the topological K-theory of the underlying topological space. In this context, the algebraic variant known as Hermitian K-theory corresponds to topological KO-theory. Our aim is to compare the two approaches. We start by constructing a comparison map from certain Hermitian K-groups of X to the KO-groups of X. It is clear what this map must be on groups in degree zero, but the definitions of relative and higher groups differ widely in the algebraic and the topological setting. This difficulty can be overcome by viewing relative and higher groups as subgroups of degree zero groups of certain auxiliary spaces. Once the definition of our comparison map is in place, we prove a number of fundamental properties, in particular compatibility with pushforwards along closed embeddings. We also show how we can use it to compare an exact sequence relating usual algebraic K-theory to Hermitian K-theory with a portion of the Bott sequence in topology. This finally allows us to deduce that the map is an isomorphism on smooth cellular varieties. We conclude with some details concerning projective spaces, for which independent computations of the algebraic and the topological groups exist. Thu, 01 Jan 2009 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/236624 2009-01-01T00:00:00Z