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Endeavour
Selected AbstractsEuropean Mathematical Genetics Meeting, Heidelberg, Germany, 12th,13th April 2007ANNALS OF HUMAN GENETICS, Issue 4 2007Article first published online: 28 MAY 200 Saurabh Ghosh 11 Indian Statistical Institute, Kolkata, India High correlations between two quantitative traits may be either due to common genetic factors or common environmental factors or a combination of both. In this study, we develop statistical methods to extract the contribution of a common QTL to the total correlation between the components of a bivariate phenotype. Using data on bivariate phenotypes and marker genotypes for sib-pairs, we propose a test for linkage between a common QTL and a marker locus based on the conditional cross-sib trait correlations (trait 1 of sib 1 , trait 2 of sib 2 and conversely) given the identity-by-descent sharing at the marker locus. The null hypothesis cannot be rejected unless there exists a common QTL. We use Monte-Carlo simulations to evaluate the performance of the proposed test under different trait parameters and quantitative trait distributions. An application of the method is illustrated using data on two alcohol-related phenotypes from the Collaborative Study On The Genetics Of Alcoholism project. Rémi Kazma 1 , Catherine Bonaïti-Pellié 1 , Emmanuelle Génin 12 INSERM UMR-S535 and Université Paris Sud, Villejuif, 94817, France Keywords: Gene-environment interaction, sibling recurrence risk, exposure correlation Gene-environment interactions may play important roles in complex disease susceptibility but their detection is often difficult. Here we show how gene-environment interactions can be detected by investigating the degree of familial aggregation according to the exposure of the probands. In case of gene-environment interaction, the distribution of genotypes of affected individuals, and consequently the risk in relatives, depends on their exposure. We developed a test comparing the risks in sibs according to the proband exposure. To evaluate the properties of this new test, we derived the formulas for calculating the expected risks in sibs according to the exposure of probands for various values of exposure frequency, relative risk due to exposure alone, frequencies of latent susceptibility genotypes, genetic relative risks and interaction coefficients. We find that the ratio of risks when the proband is exposed and not exposed is a good indicator of the interaction effect. We evaluate the power of the test for various sample sizes of affected individuals. We conclude that this test is valuable for diseases with moderate familial aggregation, only when the role of the exposure has been clearly evidenced. Since a correlation for exposure among sibs might lead to a difference in risks among sibs in the different proband exposure strata, we also add an exposure correlation coefficient in the model. Interestingly, we find that when this correlation is correctly accounted for, the power of the test is not decreased and might even be significantly increased. Andrea Callegaro 1 , Hans J.C. Van Houwelingen 1 , Jeanine Houwing-Duistermaat 13 Dept. of Medical Statistics and Bioinformatics, Leiden University Medical Center, The Netherlands Keywords: Survival analysis, age at onset, score test, linkage analysis Non parametric linkage (NPL) analysis compares the identical by descent (IBD) sharing in sibling pairs to the expected IBD sharing under the hypothesis of no linkage. Often information is available on the marginal cumulative hazards (for example breast cancer incidence curves). Our aim is to extend the NPL methods by taking into account the age at onset of selected sibling pairs using these known marginal hazards. Li and Zhong (2002) proposed a (retrospective) likelihood ratio test based on an additive frailty model for genetic linkage analysis. From their model we derive a score statistic for selected samples which turns out to be a weighed NPL method. The weights depend on the marginal cumulative hazards and on the frailty parameter. A second approach is based on a simple gamma shared frailty model. Here, we simply test whether the score function of the frailty parameter depends on the excess IBD. We compare the performance of these methods using simulated data. Céline Bellenguez 1 , Carole Ober 2 , Catherine Bourgain 14 INSERM U535 and University Paris Sud, Villejuif, France 5 Department of Human Genetics, The University of Chicago, USA Keywords: Linkage analysis, linkage disequilibrium, high density SNP data Compared with microsatellite markers, high density SNP maps should be more informative for linkage analyses. However, because they are much closer, SNPs present important linkage disequilibrium (LD), which biases classical nonparametric multipoint analyses. This problem is even stronger in population isolates where LD extends over larger regions with a more stochastic pattern. We investigate the issue of linkage analysis with a 500K SNP map in a large and inbred 1840-member Hutterite pedigree, phenotyped for asthma. Using an efficient pedigree breaking strategy, we first identified linked regions with a 5cM microsatellite map, on which we focused to evaluate the SNP map. The only method that models LD in the NPL analysis is limited in both the pedigree size and the number of markers (Abecasis and Wigginton, 2005) and therefore could not be used. Instead, we studied methods that identify sets of SNPs with maximum linkage information content in our pedigree and no LD-driven bias. Both algorithms that directly remove pairs of SNPs in high LD and clustering methods were evaluated. Null simulations were performed to control that Zlr calculated with the SNP sets were not falsely inflated. Preliminary results suggest that although LD is strong in such populations, linkage information content slightly better than that of microsatellite maps can be extracted from dense SNP maps, provided that a careful marker selection is conducted. In particular, we show that the specific LD pattern requires considering LD between a wide range of marker pairs rather than only in predefined blocks. Peter Van Loo 1,2,3 , Stein Aerts 1,2 , Diether Lambrechts 4,5 , Bernard Thienpont 2 , Sunit Maity 4,5 , Bert Coessens 3 , Frederik De Smet 4,5 , Leon-Charles Tranchevent 3 , Bart De Moor 2 , Koen Devriendt 3 , Peter Marynen 1,2 , Bassem Hassan 1,2 , Peter Carmeliet 4,5 , Yves Moreau 36 Department of Molecular and Developmental Genetics, VIB, Belgium 7 Department of Human Genetics, University of Leuven, Belgium 8 Bioinformatics group, Department of Electrical Engineering, University of Leuven, Belgium 9 Department of Transgene Technology and Gene Therapy, VIB, Belgium 10 Center for Transgene Technology and Gene Therapy, University of Leuven, Belgium Keywords: Bioinformatics, gene prioritization, data fusion The identification of genes involved in health and disease remains a formidable challenge. Here, we describe a novel bioinformatics method to prioritize candidate genes underlying pathways or diseases, based on their similarity to genes known to be involved in these processes. It is freely accessible as an interactive software tool, ENDEAVOUR, at http://www.esat.kuleuven.be/endeavour. Unlike previous methods, ENDEAVOUR generates distinct prioritizations from multiple heterogeneous data sources, which are then integrated, or fused, into one global ranking using order statistics. ENDEAVOUR prioritizes candidate genes in a three-step process. First, information about a disease or pathway is gathered from a set of known "training" genes by consulting multiple data sources. Next, the candidate genes are ranked based on similarity with the training properties obtained in the first step, resulting in one prioritized list for each data source. Finally, ENDEAVOUR fuses each of these rankings into a single global ranking, providing an overall prioritization of the candidate genes. Validation of ENDEAVOUR revealed it was able to efficiently prioritize 627 genes in disease data sets and 76 genes in biological pathway sets, identify candidates of 16 mono- or polygenic diseases, and discover regulatory genes of myeloid differentiation. Furthermore, the approach identified YPEL1 as a novel gene involved in craniofacial development from a 2-Mb chromosomal region, deleted in some patients with DiGeorge-like birth defects. Finally, we are currently evaluating a pipeline combining array-CGH, ENDEAVOUR and in vivo validation in zebrafish to identify novel genes involved in congenital heart defects. Mark Broom 1 , Graeme Ruxton 2 , Rebecca Kilner 311 Mathematics Dept., University of Sussex, UK 12 Division of Environmental and Evolutionary Biology, University of Glasgow, UK 13 Department of Zoology, University of Cambridge, UK Keywords: Evolutionarily stable strategy, parasitism, asymmetric game Brood parasites chicks vary in the harm that they do to their companions in the nest. In this presentation we use game-theoretic methods to model this variation. Our model considers hosts which potentially abandon single nestlings and instead choose to re-allocate their reproductive effort to future breeding, irrespective of whether the abandoned chick is the host's young or a brood parasite's. The parasite chick must decide whether or not to kill host young by balancing the benefits from reduced competition in the nest against the risk of desertion by host parents. The model predicts that three different types of evolutionarily stable strategies can exist. (1) Hosts routinely rear depleted broods, the brood parasite always kills host young and the host never then abandons the nest. (2) When adult survival after deserting single offspring is very high, hosts always abandon broods of a single nestling and the parasite never kills host offspring, effectively holding them as hostages to prevent nest desertion. (3) Intermediate strategies, in which parasites sometimes kill their nest-mates and host parents sometimes desert nests that contain only a single chick, can also be evolutionarily stable. We provide quantitative descriptions of how the values given to ecological and behavioral parameters of the host-parasite system influence the likelihood of each strategy and compare our results with real host-brood parasite associations in nature. Martin Harrison 114 Mathematics Dept, University of Sussex, UK Keywords: Brood parasitism, games, host, parasite The interaction between hosts and parasites in bird populations has been studied extensively. Game theoretical methods have been used to model this interaction previously, but this has not been studied extensively taking into account the sequential nature of this game. We consider a model allowing the host and parasite to make a number of decisions, which depend on a number of natural factors. The host lays an egg, a parasite bird will arrive at the nest with a certain probability and then chooses to destroy a number of the host eggs and lay one of it's own. With some destruction occurring, either natural or through the actions of the parasite, the host chooses to continue, eject an egg (hoping to eject the parasite) or abandon the nest. Once the eggs have hatched the game then falls to the parasite chick versus the host. The chick chooses to destroy or eject a number of eggs. The final decision is made by the host, choosing whether to raise or abandon the chicks that are in the nest. We consider various natural parameters and probabilities which influence these decisions. We then use this model to look at real-world situations of the interactions of the Reed Warbler and two different parasites, the Common Cuckoo and the Brown-Headed Cowbird. These two parasites have different methods in the way that they parasitize the nests of their hosts. The hosts in turn have a different reaction to these parasites. Arne Jochens 1 , Amke Caliebe 2 , Uwe Roesler 1 , Michael Krawczak 215 Mathematical Seminar, University of Kiel, Germany 16 Institute of Medical Informatics and Statistics, University of Kiel, Germany Keywords: Stepwise mutation model, microsatellite, recursion equation, temporal behaviour We consider the stepwise mutation model which occurs, e.g., in microsatellite loci. Let X(t,i) denote the allelic state of individual i at time t. We compute expectation, variance and covariance of X(t,i), i=1,,,N, and provide a recursion equation for P(X(t,i)=z). Because the variance of X(t,i) goes to infinity as t grows, for the description of the temporal behaviour, we regard the scaled process X(t,i)-X(t,1). The results furnish a better understanding of the behaviour of the stepwise mutation model and may in future be used to derive tests for neutrality under this model. Paul O'Reilly 1 , Ewan Birney 2 , David Balding 117 Statistical Genetics, Department of Epidemiology and Public Health, Imperial, College London, UK 18 European Bioinformatics Institute, EMBL, Cambridge, UK Keywords: Positive selection, Recombination rate, LD, Genome-wide, Natural Selection In recent years efforts to develop population genetics methods that estimate rates of recombination and levels of natural selection in the human genome have intensified. However, since the two processes have an intimately related impact on genetic variation their inference is vulnerable to confounding. Genomic regions subject to recent selection are likely to have a relatively recent common ancestor and consequently less opportunity for historical recombinations that are detectable in contemporary populations. Here we show that selection can reduce the population-based recombination rate estimate substantially. In genome-wide studies for detecting selection we observe a tendency to highlight loci that are subject to low levels of recombination. We find that the outlier approach commonly adopted in such studies may have low power unless variable recombination is accounted for. We introduce a new genome-wide method for detecting selection that exploits the sensitivity to recent selection of methods for estimating recombination rates, while accounting for variable recombination using pedigree data. Through simulations we demonstrate the high power of the Ped/Pop approach to discriminate between neutral and adaptive evolution, particularly in the context of choosing outliers from a genome-wide distribution. Although methods have been developed showing good power to detect selection ,in action', the corresponding window of opportunity is small. In contrast, the power of the Ped/Pop method is maintained for many generations after the fixation of an advantageous variant Sarah Griffiths 1 , Frank Dudbridge 120 MRC Biostatistics Unit, Cambridge, UK Keywords: Genetic association, multimarker tag, haplotype, likelihood analysis In association studies it is generally too expensive to genotype all variants in all subjects. We can exploit linkage disequilibrium between SNPs to select a subset that captures the variation in a training data set obtained either through direct resequencing or a public resource such as the HapMap. These ,tag SNPs' are then genotyped in the whole sample. Multimarker tagging is a more aggressive adaptation of pairwise tagging that allows for combinations of two or more tag SNPs to predict an untyped SNP. Here we describe a new method for directly testing the association of an untyped SNP using a multimarker tag. Previously, other investigators have suggested testing a specific tag haplotype, or performing a weighted analysis using weights derived from the training data. However these approaches do not properly account for the imperfect correlation between the tag haplotype and the untyped SNP. Here we describe a straightforward approach to testing untyped SNPs using a missing-data likelihood analysis, including the tag markers as nuisance parameters. The training data is stacked on top of the main body of genotype data so there is information on how the tag markers predict the genotype of the untyped SNP. The uncertainty in this prediction is automatically taken into account in the likelihood analysis. This approach yields more power and also a more accurate prediction of the odds ratio of the untyped SNP. Anke Schulz 1 , Christine Fischer 2 , Jenny Chang-Claude 1 , Lars Beckmann 121 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany 22 Institute of Human Genetics, University of Heidelberg, Germany Keywords: Haplotype, haplotype sharing, entropy, Mantel statistics, marker selection We previously introduced a new method to map genes involved in complex diseases, using haplotype sharing-based Mantel statistics to correlate genetic and phenotypic similarity. Although the Mantel statistic is powerful in narrowing down candidate regions, the precise localization of a gene is hampered in genomic regions where linkage disequilibrium is so high that neighboring markers are found to be significant at similar magnitude and we are not able to discriminate between them. Here, we present a new approach to localize susceptibility genes by combining haplotype sharing-based Mantel statistics with an iterative entropy-based marker selection algorithm. For each marker at which the Mantel statistic is evaluated, the algorithm selects a subset of surrounding markers. The subset is chosen to maximize multilocus linkage disequilibrium, which is measured by the normalized entropy difference introduced by Nothnagel et al. (2002). We evaluated the algorithm with respect to type I error and power. Its ability to localize the disease variant was compared to the localization (i) without marker selection and (ii) considering haplotype block structure. Case-control samples were simulated from a set of 18 haplotypes, consisting of 15 SNPs in two haplotype blocks. The new algorithm gave correct type I error and yielded similar power to detect the disease locus compared to the alternative approaches. The neighboring markers were clearly less often significant than the causal locus, and also less often significant compared to the alternative approaches. Thus the new algorithm improved the precision of the localization of susceptibility genes. Mark M. Iles 123 Section of Epidemiology and Biostatistics, LIMM, University of Leeds, UK Keywords: tSNP, tagging, association, HapMap Tagging SNPs (tSNPs) are commonly used to capture genetic diversity cost-effectively. However, it is important that the efficacy of tSNPs is correctly estimated, otherwise coverage may be insufficient. If the pilot sample from which tSNPs are chosen is too small or the initial marker map too sparse, tSNP efficacy may be overestimated. An existing estimation method based on bootstrapping goes some way to correct for insufficient sample size and overfitting, but does not completely solve the problem. We describe a novel method, based on exclusion of haplotypes, that improves on the bootstrap approach. Using simulated data, the extent of the sample size problem is investigated and the performance of the bootstrap and the novel method are compared. We incorporate an existing method adjusting for marker density by ,SNP-dropping'. We find that insufficient sample size can cause large overestimates in tSNP efficacy, even with as many as 100 individuals, and the problem worsens as the region studied increases in size. Both the bootstrap and novel method correct much of this overestimate, with our novel method consistently outperforming the bootstrap method. We conclude that a combination of insufficient sample size and overfitting may lead to overestimation of tSNP efficacy and underpowering of studies based on tSNPs. Our novel approach corrects for much of this bias and is superior to the previous method. Sample sizes larger than previously suggested may still be required for accurate estimation of tSNP efficacy. This has obvious ramifications for the selection of tSNPs from HapMap data. Claudio Verzilli 1 , Juliet Chapman 1 , Aroon Hingorani 2 , Juan Pablo-Casas 1 , Tina Shah 2 , Liam Smeeth 1 , John Whittaker 124 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, UK 25 Division of Medicine, University College London, UK Keywords: Meta-analysis, Genetic association studies We present a Bayesian hierarchical model for the meta-analysis of candidate gene studies with a continuous outcome. Such studies often report results from association tests for different, possibly study-specific and non-overlapping markers (typically SNPs) in the same genetic region. Meta analyses of the results at each marker in isolation are seldom appropriate as they ignore the correlation that may exist between markers due to linkage disequlibrium (LD) and cannot assess the relative importance of variants at each marker. Also such marker-wise meta analyses are restricted to only those studies that have typed the marker in question, with a potential loss of power. A better strategy is one which incorporates information about the LD between markers so that any combined estimate of the effect of each variant is corrected for the effect of other variants, as in multiple regression. Here we develop a Bayesian hierarchical linear regression that models the observed genotype group means and uses pairwise LD measurements between markers as prior information to make posterior inference on adjusted effects. The approach is applied to the meta analysis of 24 studies assessing the effect of 7 variants in the C-reactive protein (CRP) gene region on plasma CRP levels, an inflammatory biomarker shown in observational studies to be positively associated with cardiovascular disease. Cathryn M. Lewis 1 , Christopher G. Mathew 1 , Theresa M. Marteau 226 Dept. of Medical and Molecular Genetics, King's College London, UK 27 Department of Psychology, King's College London, UK Keywords: Risk, genetics, CARD15, smoking, model Recently progress has been made in identifying mutations that confer susceptibility to complex diseases, with the potential to use these mutations in determining disease risk. We developed methods to estimate disease risk based on genotype relative risks (for a gene G), exposure to an environmental factor (E), and family history (with recurrence risk ,R for a relative of type R). ,R must be partitioned into the risk due to G (which is modelled independently) and the residual risk. The risk model was then applied to Crohn's disease (CD), a severe gastrointestinal disease for which smoking increases disease risk approximately 2-fold, and mutations in CARD15 confer increased risks of 2.25 (for carriers of a single mutation) and 9.3 (for carriers of two mutations). CARD15 accounts for only a small proportion of the genetic component of CD, with a gene-specific ,S, CARD15 of 1.16, from a total sibling relative risk of ,S= 27. CD risks were estimated for high-risk individuals who are siblings of a CD case, and who also smoke. The CD risk to such individuals who carry two CARD15 mutations is approximately 0.34, and for those carrying a single CARD15 mutation the risk is 0.08, compared to a population prevalence of approximately 0.001. These results imply that complex disease genes may be valuable in estimating with greater precision than has hitherto been possible disease risks in specific, easily identified subgroups of the population with a view to prevention. Yurii Aulchenko 128 Department of Epidemiology & Biostatistics, Erasmus Medical Centre Rotterdam, The Netherlands Keywords: Compression, information, bzip2, genome-wide SNP data, statistical genetics With advances in molecular technology, studies accessing millions of genetic polymorphisms in thousands of study subjects will soon become common. Such studies generate large amounts of data, whose effective storage and management is a challenge to the modern statistical genetics. Standard file compression utilities, such as Zip, Gzip and Bzip2, may be helpful to minimise the storage requirements. Less obvious is the fact that the data compression techniques may be also used in the analysis of genetic data. It is known that the efficiency of a particular compression algorithm depends on the probability structure of the data. In this work, we compared different standard and customised tools using the data from human HapMap project. Secondly, we investigate the potential uses of data compression techniques for the analysis of linkage, association and linkage disequilibrium Suzanne Leal 1 , Bingshan Li 129 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA Keywords: Consanguineous pedigrees, missing genotype data Missing genotype data can increase false-positive evidence for linkage when either parametric or nonparametric analysis is carried out ignoring intermarker linkage disequilibrium (LD). Previously it was demonstrated by Huang et al (2005) that no bias occurs in this situation for affected sib-pairs with unrelated parents when either both parents are genotyped or genotype data is available for two additional unaffected siblings when parental genotypes are missing. However, this is not the case for consanguineous pedigrees, where missing genotype data for any pedigree member within a consanguinity loop can increase false-positive evidence of linkage. The false-positive evidence for linkage is further increased when cryptic consanguinity is present. The amount of false-positive evidence for linkage is highly dependent on which family members are genotyped. When parental genotype data is available, the false-positive evidence for linkage is usually not as strong as when parental genotype data is unavailable. Which family members will aid in the reduction of false-positive evidence of linkage is highly dependent on which other family members are genotyped. For a pedigree with an affected proband whose first-cousin parents have been genotyped, further reduction in the false-positive evidence of linkage can be obtained by including genotype data from additional affected siblings of the proband or genotype data from the proband's sibling-grandparents. When parental genotypes are not available, false-positive evidence for linkage can be reduced by including in the analysis genotype data from either unaffected siblings of the proband or the proband's married-in-grandparents. Najaf Amin 1 , Yurii Aulchenko 130 Department of Epidemiology & Biostatistics, Erasmus Medical Centre Rotterdam, The Netherlands Keywords: Genomic Control, pedigree structure, quantitative traits The Genomic Control (GC) method was originally developed to control for population stratification and cryptic relatedness in association studies. This method assumes that the effect of population substructure on the test statistics is essentially constant across the genome, and therefore unassociated markers can be used to estimate the effect of confounding onto the test statistic. The properties of GC method were extensively investigated for different stratification scenarios, and compared to alternative methods, such as the transmission-disequilibrium test. The potential of this method to correct not for occasional cryptic relations, but for regular pedigree structure, however, was not investigated before. In this work we investigate the potential of the GC method for pedigree-based association analysis of quantitative traits. The power and type one error of the method was compared to standard methods, such as the measured genotype (MG) approach and quantitative trait transmission-disequilibrium test. In human pedigrees, with trait heritability varying from 30 to 80%, the power of MG and GC approach was always higher than that of TDT. GC had correct type 1 error and its power was close to that of MG under moderate heritability (30%), but decreased with higher heritability. William Astle 1 , Chris Holmes 2 , David Balding 131 Department of Epidemiology and Public Health, Imperial College London, UK 32 Department of Statistics, University of Oxford, UK Keywords: Population structure, association studies, genetic epidemiology, statistical genetics In the analysis of population association studies, Genomic Control (Devlin & Roeder, 1999) (GC) adjusts the Armitage test statistic to correct the type I error for the effects of population substructure, but its power is often sub-optimal. Turbo Genomic Control (TGC) generalises GC to incorporate co-variation of relatedness and phenotype, retaining control over type I error while improving power. TGC is similar to the method of Yu et al. (2006), but we extend it to binary (case-control) in addition to quantitative phenotypes, we implement improved estimation of relatedness coefficients, and we derive an explicit statistic that generalizes the Armitage test statistic and is fast to compute. TGC also has similarities to EIGENSTRAT (Price et al., 2006) which is a new method based on principle components analysis. The problems of population structure(Clayton et al., 2005) and cryptic relatedness (Voight & Pritchard, 2005) are essentially the same: if patterns of shared ancestry differ between cases and controls, whether distant (coancestry) or recent (cryptic relatedness), false positives can arise and power can be diminished. With large numbers of widely-spaced genetic markers, coancestry can now be measured accurately for each pair of individuals via patterns of allele-sharing. Instead of modelling subpopulations, we work instead with a coancestry coefficient for each pair of individuals in the study. We explain the relationships between TGC, GC and EIGENSTRAT. We present simulation studies and real data analyses to illustrate the power advantage of TGC in a range of scenarios incorporating both substructure and cryptic relatedness. References Clayton, D. G.et al. (2005) Population structure, differential bias and genomic control in a large-scale case-control association study. Nature Genetics37(11) November 2005. Devlin, B. & Roeder, K. (1999) Genomic control for association studies. Biometics55(4) December 1999. Price, A. L.et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics38(8) (August 2006). Voight, B. J. & Pritchard, J. K. (2005) Confounding from cryptic relatedness in case-control association studies. Public Library of Science Genetics1(3) September 2005. Yu, J.et al. (2006) A unified mixed-model method for association mapping that accounts for multiple levels of relatedness. Nature Genetics38(2) February 2006. Hervé Perdry 1 , Marie-Claude Babron 1 , Françoise Clerget-Darpoux 133 INSERM U535 and Univ. Paris Sud, UMR-S 535, Villejuif, France Keywords: Modifier genes, case-parents trios, ordered transmission disequilibrium test A modifying locus is a polymorphic locus, distinct from the disease locus, which leads to differences in the disease phenotype, either by modifying the penetrance of the disease allele, or by modifying the expression of the disease. The effect of such a locus is a clinical heterogeneity that can be reflected by the values of an appropriate covariate, such as the age of onset, or the severity of the disease. We designed the Ordered Transmission Disequilibrium Test (OTDT) to test for a relation between the clinical heterogeneity, expressed by the covariate, and marker genotypes of a candidate gene. The method applies to trio families with one affected child and his parents. Each family member is genotyped at a bi-allelic marker M of a candidate gene. To each of the families is associated a covariate value; the families are ordered on the values of this covariate. As the TDT (Spielman et al. 1993), the OTDT is based on the observation of the transmission rate T of a given allele at M. The OTDT aims to find a critical value of the covariate which separates the sample of families in two subsamples in which the transmission rates are significantly different. We investigate the power of the method by simulations under various genetic models and covariate distributions. Acknowledgments H Perdry is funded by ARSEP. Pascal Croiseau 1 , Heather Cordell 2 , Emmanuelle Génin 134 INSERM U535 and University Paris Sud, UMR-S535, Villejuif, France 35 Institute of Human Genetics, Newcastle University, UK Keywords: Association, missing data, conditionnal logistic regression Missing data is an important problem in association studies. Several methods used to test for association need that individuals be genotyped at the full set of markers. Individuals with missing data need to be excluded from the analysis. This could involve an important decrease in sample size and a loss of information. If the disease susceptibility locus (DSL) is poorly typed, it is also possible that a marker in linkage disequilibrium gives a stronger association signal than the DSL. One may then falsely conclude that the marker is more likely to be the DSL. We recently developed a Multiple Imputation method to infer missing data on case-parent trios Starting from the observed data, a few number of complete data sets are generated by Markov-Chain Monte Carlo approach. These complete datasets are analysed using standard statistical package and the results are combined as described in Little & Rubin (2002). Here we report the results of simulations performed to examine, for different patterns of missing data, how often the true DSL gives the highest association score among different loci in LD. We found that multiple imputation usually correctly detect the DSL site even if the percentage of missing data is high. This is not the case for the naïve approach that consists in discarding trios with missing data. In conclusion, Multiple imputation presents the advantage of being easy to use and flexible and is therefore a promising tool in the search for DSL involved in complex diseases. Salma Kotti 1 , Heike Bickeböller 2 , Françoise Clerget-Darpoux 136 University Paris Sud, UMR-S535, Villejuif, France 37 Department of Genetic Epidemiology, Medical School, University of Göttingen, Germany Keywords: Genotype relative risk, internal controls, Family based analyses Family based analyses using internal controls are very popular both for detecting the effect of a genetic factor and for estimating the relative disease risk on the corresponding genotypes. Two different procedures are often applied to reconstitute internal controls. The first one considers one pseudocontrol genotype formed by the parental non-transmitted alleles called also 1:1 matching of alleles, while the second corresponds to three pseudocontrols corresponding to all genotypes formed by the parental alleles except the one of the case (1:3 matching). Many studies have compared between the two procedures in terms of the power and have concluded that the difference depends on the underlying genetic model and the allele frequencies. However, the estimation of the Genotype Relative Risk (GRR) under the two procedures has not been studied. Based on the fact that on the 1:1 matching, the control group is composed of the alleles untransmitted to the affected child and on the 1:3 matching, the control group is composed amongst alleles already transmitted to the affected child, we expect a difference on the GRR estimation. In fact, we suspect that the second procedure leads to biased estimation of the GRRs. We will analytically derive the GRR estimators for the 1:1 and 1:3 matching and will present the results at the meeting. Family based analyses using internal controls are very popular both for detecting the effect of a genetic factor and for estimating the relative disease risk on the corresponding genotypes. Two different procedures are often applied to reconstitute internal controls. The first one considers one pseudocontrol genotype formed by the parental non-transmitted alleles called also 1:1 matching of alleles, while the second corresponds to three pseudocontrols corresponding to all genotypes formed by the parental alleles except the one of the case (1:3 matching). Many studies have compared between the two procedures in terms of the power and have concluded that the difference depends on the underlying genetic model and the allele frequencies. However, the estimation of the Genotype Relative Risk (GRR) under the two procedures has not been studied. Based on the fact that on the 1:1 matching, the control group is composed of the alleles untransmitted to the affected child and on the 1:3 matching, the control group is composed amongst alleles already transmitted to the affected child, we expect a difference on the GRR estimation. In fact, we suspect that the second procedure leads to biased estimation of the GRR. We will analytically derive the GRR estimator for the 1:1 and 1:3 matching and will present the results at the meeting. Luigi Palla 1 , David Siegmund 239 Department of Mathematics,Free University Amsterdam, The Netherlands 40 Department of Statistics, Stanford University, California, USA Keywords: TDT, assortative mating, inbreeding, statistical power A substantial amount of Assortative Mating (AM) is often recorded on physical and psychological, dichotomous as well as quantitative traits that are supposed to have a multifactorial genetic component. In particular AM has the effect of increasing the genetic variance, even more than inbreeding because it acts across loci beside within loci, when the trait has a multifactorial origin. Under the assumption of a polygenic model for AM dating back to Wright (1921) and refined by Crow and Felsenstein (1968,1982), the effect of assortative mating on the power to detect genetic association in the Transmission Disequilibrium Test (TDT) is explored as parameters, such as the effective number of genes and the allelic frequency vary. The power is reflected by the non centrality parameter of the TDT and is expressed as a function of the number of trios, the relative risk of the heterozygous genotype and the allele frequency (Siegmund and Yakir, 2007). The noncentrality parameter of the relevant score statistic is updated considering the effect of AM which is expressed in terms of an ,effective' inbreeding coefficient. In particular, for dichotomous traits it is apparent that the higher the number of genes involved in the trait, the lower the loss in power due to AM. Finally an attempt is made to extend this relation to the Q-TDT (Rabinowitz, 1997), which involves considering the effect of AM also on the phenotypic variance of the trait of interest, under the assumption that AM affects only its additive genetic component. References Crow, & Felsenstein, (1968). The effect of assortative mating on the genetic composition of a population. Eugen.Quart.15, 87,97. Rabinowitz,, 1997. A Transmission Disequilibrium Test for Quantitative Trait Loci. Human Heredity47, 342,350. Siegmund, & Yakir, (2007) Statistics of gene mapping, Springer. Wright, (1921). System of mating.III. Assortative mating based on somatic resemblance. Genetics6, 144,161. Jérémie Nsengimana 1 , Ben D Brown 2 , Alistair S Hall 2 , Jenny H Barrett 141 Leeds Institute of Molecular Medicine, University of Leeds, UK 42 Leeds Institute for Genetics, Health and Therapeutics, University of Leeds, UK Keywords: Inflammatory genes, haplotype, coronary artery disease Genetic Risk of Acute Coronary Events (GRACE) is an initiative to collect cases of coronary artery disease (CAD) and their unaffected siblings in the UK and to use them to map genetic variants increasing disease risk. The aim of the present study was to test the association between CAD and 51 single nucleotide polymorphisms (SNPs) and their haplotypes from 35 inflammatory genes. Genotype data were available for 1154 persons affected before age 66 (including 48% before age 50) and their 1545 unaffected siblings (891 discordant families). Each SNP was tested for association to CAD, and haplotypes within genes or gene clusters were tested using FBAT (Rabinowitz & Laird, 2000). For the most significant results, genetic effect size was estimated using conditional logistic regression (CLR) within STATA adjusting for other risk factors. Haplotypes were assigned using HAPLORE (Zhang et al., 2005), which considers all parental mating types consistent with offspring genotypes and assigns them a probability of occurence. This probability was used in CLR to weight the haplotypes. In the single SNP analysis, several SNPs showed some evidence for association, including one SNP in the interleukin-1A gene. Analysing haplotypes in the interleukin-1 gene cluster, a common 3-SNP haplotype was found to increase the risk of CAD (P = 0.009). In an additive genetic model adjusting for covariates the odds ratio (OR) for this haplotype is 1.56 (95% CI: 1.16-2.10, p = 0.004) for early-onset CAD (before age 50). This study illustrates the utility of haplotype analysis in family-based association studies to investigate candidate genes. References Rabinowitz, D. & Laird, N. M. (2000) Hum Hered50, 211,223. Zhang, K., Sun, F. & Zhao, H. (2005) Bioinformatics21, 90,103. Andrea Foulkes 1 , Recai Yucel 1 , Xiaohong Li 143 Division of Biostatistics, University of Massachusetts, USA Keywords: Haploytpe, high-dimensional, mixed modeling The explosion of molecular level information coupled with large epidemiological studies presents an exciting opportunity to uncover the genetic underpinnings of complex diseases; however, several analytical challenges remain to be addressed. Characterizing the components to complex diseases inevitably requires consideration of synergies across multiple genetic loci and environmental and demographic factors. In addition, it is critical to capture information on allelic phase, that is whether alleles within a gene are in cis (on the same chromosome) or in trans (on different chromosomes.) In associations studies of unrelated individuals, this alignment of alleles within a chromosomal copy is generally not observed. We address the potential ambiguity in allelic phase in this high dimensional data setting using mixed effects models. Both a semi-parametric and fully likelihood-based approach to estimation are considered to account for missingness in cluster identifiers. In the first case, we apply a multiple imputation procedure coupled with a first stage expectation maximization algorithm for parameter estimation. A bootstrap approach is employed to assess sensitivity to variability induced by parameter estimation. Secondly, a fully likelihood-based approach using an expectation conditional maximization algorithm is described. Notably, these models allow for characterizing high-order gene-gene interactions while providing a flexible statistical framework to account for the confounding or mediating role of person specific covariates. The proposed method is applied to data arising from a cohort of human immunodeficiency virus type-1 (HIV-1) infected individuals at risk for therapy associated dyslipidemia. Simulation studies demonstrate reasonable power and control of family-wise type 1 error rates. Vivien Marquard 1 , Lars Beckmann 1 , Jenny Chang-Claude 144 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany Keywords: Genotyping errors, type I error, haplotype-based association methods It has been shown in several simulation studies that genotyping errors may have a great impact on the type I error of statistical methods used in genetic association analysis of complex diseases. Our aim was to investigate type I error rates in a case-control study, when differential and non-differential genotyping errors were introduced in realistic scenarios. We simulated case-control data sets, where individual genotypes were drawn from a haplotype distribution of 18 haplotypes with 15 markers in the APM1 gene. Genotyping errors were introduced following the unrestricted and symmetric with 0 edges error models described by Heid et al. (2006). In six scenarios, errors resulted from changes of one allele to another with predefined probabilities of 1%, 2.5% or 10%, respectively. A multiple number of errors per haplotype was possible and could vary between 0 and 15, the number of markers investigated. We examined three association methods: Mantel statistics using haplotype-sharing; a haplotype-specific score test; and Armitage trend test for single markers. The type I error rates were not influenced for any of all the three methods for a genotyping error rate of less than 1%. For higher error rates and differential errors, the type I error of the Mantel statistic was only slightly and of the Armitage trend test moderately increased. The type I error rates of the score test were highly increased. The type I error rates were correct for all three methods for non-differential errors. Further investigations will be carried out with different frequencies of differential error rates and focus on power. Arne Neumann 1 , Dörthe Malzahn 1 , Martina Müller 2 , Heike Bickeböller 145 Department of Genetic Epidemiology, Medical School, University of Göttingen, Germany 46 GSF-National Research Center for Environment and Health, Neuherberg & IBE-Institute of Epidemiology, Ludwig-Maximilians University München, Germany Keywords: Interaction, longitudinal, nonparametric Longitudinal data show the time dependent course of phenotypic traits. In this contribution, we consider longitudinal cohort studies and investigate the association between two candidate genes and a dependent quantitative longitudinal phenotype. The set-up defines a factorial design which allows us to test simultaneously for the overall gene effect of the loci as well as for possible gene-gene and gene time interaction. The latter would induce genetically based time-profile differences in the longitudinal phenotype. We adopt a non-parametric statistical test to genetic epidemiological cohort studies and investigate its performance by simulation studies. The statistical test was originally developed for longitudinal clinical studies (Brunner, Munzel, Puri, 1999 J Multivariate Anal 70:286-317). It is non-parametric in the sense that no assumptions are made about the underlying distribution of the quantitative phenotype. Longitudinal observations belonging to the same individual can be arbitrarily dependent on one another for the different time points whereas trait observations of different individuals are independent. The two loci are assumed to be statistically independent. Our simulations show that the nonparametric test is comparable with ANOVA in terms of power of detecting gene-gene and gene-time interaction in an ANOVA favourable setting. Rebecca Hein 1 , Lars Beckmann 1 , Jenny Chang-Claude 147 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany Keywords: Indirect association studies, interaction effects, linkage disequilibrium, marker allele frequency Association studies accounting for gene-environment interactions (GxE) may be useful for detecting genetic effects and identifying important environmental effect modifiers. Current technology facilitates very dense marker spacing in genetic association studies; however, the true disease variant(s) may not be genotyped. In this situation, an association between a gene and a phenotype may still be detectable, using genetic markers associated with the true disease variant(s) (indirect association). Zondervan and Cardon [2004] showed that the odds ratios (OR) of markers which are associated with the disease variant depend highly on the linkage disequilibrium (LD) between the variant and the markers, and whether the allele frequencies match and thereby influence the sample size needed to detect genetic association. We examined the influence of LD and allele frequencies on the sample size needed to detect GxE in indirect association studies, and provide tables for sample size estimation. For discordant allele frequencies and incomplete LD, sample sizes can be unfeasibly large. The influence of both factors is stronger for disease loci with small rather than moderate to high disease allele frequencies. A decline in D' of e.g. 5% has less impact on sample size than increasing the difference in allele frequencies by the same percentage. Assuming 80% power, large interaction effects can be detected using smaller sample sizes than those needed for the detection of main effects. The detection of interaction effects involving rare alleles may not be possible. Focussing only on marker density can be a limited strategy in indirect association studies for GxE. Cyril Dalmasso 1 , Emmanuelle Génin 2 , Catherine Bourgain 2 , Philippe Broët 148 JE 2492 , Univ. Paris-Sud, France 49 INSERM UMR-S 535 and University Paris Sud, Villejuif, France Keywords: Linkage analysis, Multiple testing, False Discovery Rate, Mixture model In the context of genome-wide linkage analyses, where a large number of statistical tests are simultaneously performed, the False Discovery Rate (FDR) that is defined as the expected proportion of false discoveries among all discoveries is nowadays widely used for taking into account the multiple testing problem. Other related criteria have been considered such as the local False Discovery Rate (lFDR) that is a variant of the FDR giving to each test its own measure of significance. The lFDR is defined as the posterior probability that a null hypothesis is true. Most of the proposed methods for estimating the lFDR or the FDR rely on distributional assumption under the null hypothesis. However, in observational studies, the empirical null distribution may be very different from the theoretical one. In this work, we propose a mixture model based approach that provides estimates of the lFDR and the FDR in the context of large-scale variance component linkage analyses. In particular, this approach allows estimating the empirical null distribution, this latter being a key quantity for any simultaneous inference procedure. The proposed method is applied on a real dataset. Arief Gusnanto 1 , Frank Dudbridge 150 MRC Biostatistics Unit, Cambridge UK Keywords: Significance, genome-wide, association, permutation, multiplicity Genome-wide association scans have introduced statistical challenges, mainly in the multiplicity of thousands of tests. The question of what constitutes a significant finding remains somewhat unresolved. Permutation testing is very time-consuming, whereas Bayesian arguments struggle to distinguish direct from indirect association. It seems attractive to summarise the multiplicity in a simple form that allows users to avoid time-consuming permutations. A standard significance level would facilitate reporting of results and reduce the need for permutation tests. This is potentially important because current scans do not have full coverage of the whole genome, and yet, the implicit multiplicity is genome-wide. We discuss some proposed summaries, with reference to the empirical null distribution of the multiple tests, approximated through a large number of random permutations. Using genome-wide data from the Wellcome Trust Case-Control Consortium, we use a sub-sampling approach with increasing density to estimate the nominal p-value to obtain family-wise significance of 5%. The results indicate that the significance level is converging to about 1e-7 as the marker spacing becomes infinitely dense. We considered the concept of an effective number of independent tests, and showed that when used in a Bonferroni correction, the number varies with the overall significance level, but is roughly constant in the region of interest. We compared several estimators of the effective number of tests, and showed that in the region of significance of interest, Patterson's eigenvalue based estimator gives approximately the right family-wise error rate. Michael Nothnagel 1 , Amke Caliebe 1 , Michael Krawczak 151 Institute of Medical Informatics and Statistics, University Clinic Schleswig-Holstein, University of Kiel, Germany Keywords: Association scans, Bayesian framework, posterior odds, genetic risk, multiplicative model Whole-genome association scans have been suggested to be a cost-efficient way to survey genetic variation and to map genetic disease factors. We used a Bayesian framework to investigate the posterior odds of a genuine association under multiplicative disease models. We demonstrate that the p value alone is not a sufficient means to evaluate the findings in association studies. We suggest that likelihood ratios should accompany p values in association reports. We argue, that, given the reported results of whole-genome scans, more associations should have been successfully replicated if the consistently made assumptions about considerable genetic risks were correct. We conclude that it is very likely that the vast majority of relative genetic risks are only of the order of 1.2 or lower. Clive Hoggart 1 , Maria De Iorio 1 , John Whittakker 2 , David Balding 152 Department of Epidemiology and Public Health, Imperial College London, UK 53 Department of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, UK Keywords: Genome-wide association analyses, shrinkage priors, Lasso Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants of small effect, which is a plausible scenario for many complex diseases. Moreover, many simulation studies assume a single causal variant and so more complex realities are ignored. Analysing large numbers of variants simultaneously is now becoming feasible, thanks to developments in Bayesian stochastic search methods. We pose the problem of SNP selection as variable selection in a regression model. In contrast to single SNP tests this approach simultaneously models the effect of all SNPs. SNPs are selected by a Bayesian interpretation of the lasso (Tibshirani, 1996); the maximum a posterior (MAP) estimate of the regression coefficients, which have been given independent, double exponential prior distributions. The double exponential distribution is an example of a shrinkage prior, MAP estimates with shrinkage priors can be zero, thus all SNPs with non zero regression coefficients are selected. In addition to the commonly-used double exponential (Laplace) prior, we also implement the normal exponential gamma prior distribution. We show that use of the Laplace prior improves SNP selection in comparison with single -SNP tests, and that the normal exponential gamma prior leads to a further improvement. Our method is fast and can handle very large numbers of SNPs: we demonstrate its performance using both simulated and real genome-wide data sets with 500 K SNPs, which can be analysed in 2 hours on a desktop workstation. Mickael Guedj 1,2 , Jerome Wojcik 2 , Gregory Nuel 154 Laboratoire Statistique et Génome, Université d'Evry, Evry France 55 Serono Pharmaceutical Research Institute, Plan-les-Ouates, Switzerland Keywords: Local Replication, Local Score, Association In gene-mapping, replication of initial findings has been put forwards as the approach of choice for filtering false-positives from true signals for underlying loci. In practice, such replications are however too poorly observed. Besides the statistical and technical-related factors (lack of power, multiple-testing, stratification, quality control,) inconsistent conclusions obtained from independent populations might result from real biological differences. In particular, the high degree of variation in the strength of LD among populations of different origins is a major challenge to the discovery of genes. Seeking for Local Replications (defined as the presence of a signal of association in a same genomic region among populations) instead of strict replications (same locus, same risk allele) may lead to more reliable results. Recently, a multi-markers approach based on the Local Score statistic has been proposed as a simple and efficient way to select candidate genomic regions at the first stage of genome-wide association studies. Here we propose an extension of this approach adapted to replicated association studies. Based on simulations, this method appears promising. In particular it outperforms classical simple-marker strategies to detect modest-effect genes. Additionally it constitutes, to our knowledge, a first framework dedicated to the detection of such Local Replications. Juliet Chapman 1 , Claudio Verzilli 1 , John Whittaker 156 Department of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, UK Keywords: FDR, Association studies, Bayesian model selection As genomewide association studies become commonplace there is debate as to how such studies might be analysed and what we might hope to gain from the data. It is clear that standard single locus approaches are limited in that they do not adjust for the effects of other loci and problematic since it is not obvious how to adjust for multiple comparisons. False discovery rates have been suggested, but it is unclear how well these will cope with highly correlated genetic data. We consider the validity of standard false discovery rates in large scale association studies. We also show that a Bayesian procedure has advantages in detecting causal loci amongst a large number of dependant SNPs and investigate properties of a Bayesian FDR. Peter Kraft 157 Harvard School of Public Health, Boston USA Keywords: Gene-environment interaction, genome-wide association scans Appropriately analyzed two-stage designs,where a subset of available subjects are genotyped on a genome-wide panel of markers at the first stage and then a much smaller subset of the most promising markers are genotyped on the remaining subjects,can have nearly as much power as a single-stage study where all subjects are genotyped on the genome-wide panel yet can be much less expensive. Typically, the "most promising" markers are selected based on evidence for a marginal association between genotypes and disease. Subsequently, the few markers found to be associated with disease at the end of the second stage are interrogated for evidence of gene-environment interaction, mainly to understand their impact on disease etiology and public health impact. However, this approach may miss variants which have a sizeable effect restricted to one exposure stratum and therefore only a modest marginal effect. We have proposed to use information on the joint effects of genes and a discrete list of environmental exposures at the initial screening stage to select promising markers for the second stage [Kraft et al Hum Hered 2007]. This approach optimizes power to detect variants that have a sizeable marginal effect and variants that have a small marginal effect but a sizeable effect in a stratum defined by an environmental exposure. As an example, I discuss a proposed genome-wide association scan for Type II diabetes susceptibility variants based in several large nested case-control studies. Beate Glaser 1 , Peter Holmans 158 Biostatistics and Bioinformatics Unit, Cardiff University, School of Medicine, Heath Park, Cardiff, UK Keywords: Combined case-control and trios analysis, Power, False-positive rate, Simulation, Association studies The statistical power of genetic association studies can be enhanced by combining the analysis of case-control with parent-offspring trio samples. Various combined analysis techniques have been recently developed; as yet, there have been no comparisons of their power. This work was performed with the aim of identifying the most powerful method among available combined techniques including test statistics developed by Kazeem and Farrall (2005), Nagelkerke and colleagues (2004) and Dudbridge (2006), as well as a simple combination of ,2-statistics from single samples. Simulation studies were performed to investigate their power under different additive, multiplicative, dominant and recessive disease models. False-positive rates were determined by studying the type I error rates under null models including models with unequal allele frequencies between the single case-control and trios samples. We identified three techniques with equivalent power and false-positive rates, which included modifications of the three main approaches: 1) the unmodified combined Odds ratio estimate by Kazeem & Farrall (2005), 2) a modified approach of the combined risk ratio estimate by Nagelkerke & colleagues (2004) and 3) a modified technique for a combined risk ratio estimate by Dudbridge (2006). Our work highlights the importance of studies investigating test performance criteria of novel methods, as they will help users to select the optimal approach within a range of available analysis techniques. David Almorza 1 , M.V. Kandus 2 , Juan Carlos Salerno 2 , Rafael Boggio 359 Facultad de Ciencias del Trabajo, University of Cádiz, Spain 60 Instituto de Genética IGEAF, Buenos Aires, Argentina 61 Universidad Nacional de La Plata, Buenos Aires, Argentina Keywords: Principal component analysis, maize, ear weight, inbred lines The objective of this work was to evaluate the relationship among different traits of the ear of maize inbred lines and to group genotypes according to its performance. Ten inbred lines developed at IGEAF (INTA Castelar) and five public inbred lines as checks were used. A field trial was carried out in Castelar, Buenos Aires (34° 36' S , 58° 39' W) using a complete randomize design with three replications. At harvest, individual weight (P.E.), diameter (D.E.), row number (N.H.) and length (L.E.) of the ear were assessed. A principal component analysis, PCA, (Infostat 2005) was used, and the variability of the data was depicted with a biplot. Principal components 1 and 2 (CP1 and CP2) explained 90% of the data variability. CP1 was correlated with P.E., L.E. and D.E., meanwhile CP2 was correlated with N.H. We found that individual weight (P.E.) was more correlated with diameter of the ear (D.E.) than with length (L.E). Five groups of inbred lines were distinguished: with high P.E. and mean N.H. (04-70, 04-73, 04-101 and MO17), with high P.E. but less N.H. (04-61 and B14), with mean P.E. and N.H. (B73, 04-123 and 04-96), with high N.H. but less P.E. (LP109, 04-8, 04-91 and 04-76) and with low P.E. and low N.H. (LP521 and 04-104). The use of PCA showed which variables had more incidence in ear weight and how is the correlation among them. Moreover, the different groups found with this analysis allow the evaluation of inbred lines by several traits simultaneously. Sven Knüppel 1 , Anja Bauerfeind 1 , Klaus Rohde 162 Department of Bioinformatics, MDC Berlin, Germany Keywords: Haplotypes, association studies, case-control, nuclear families The area of gene chip technology provides a plethora of phase-unknown SNP genotypes in order to find significant association to some genetic trait. To circumvent possibly low information content of a single SNP one groups successive SNPs and estimates haplotypes. Haplotype estimation, however, may reveal ambiguous haplotype pairs and bias the application of statistical methods. Zaykin et al. (Hum Hered, 53:79-91, 2002) proposed the construction of a design matrix to take this ambiguity into account. Here we present a set of functions written for the Statistical package R, which carries out haplotype estimation on the basis of the EM-algorithm for individuals (case-control) or nuclear families. The construction of a design matrix on basis of estimated haplotypes or haplotype pairs allows application of standard methods for association studies (linear, logistic regression), as well as statistical methods as haplotype sharing statistics and TDT-Test. Applications of these methods to genome-wide association screens will be demonstrated. Manuela Zucknick 1 , Chris Holmes 2 , Sylvia Richardson 163 Department of Epidemiology and Public Health, Imperial College London, UK 64 Department of Statistics, Oxford Center for Gene Function, University of Oxford, UK Keywords: Bayesian, variable selection, MCMC, large p, small n, structured dependence In large-scale genomic applications vast numbers of markers or genes are scanned to find a few candidates which are linked to a particular phenotype. Statistically, this is a variable selection problem in the "large p, small n" situation where many more variables than samples are available. An additional feature is the complex dependence structure which is often observed among the markers/genes due to linkage disequilibrium or their joint involvement in biological processes. Bayesian variable selection methods using indicator variables are well suited to the problem. Binary phenotypes like disease status are common and both Bayesian probit and logistic regression can be applied in this context. We argue that logistic regression models are both easier to tune and to interpret than probit models and implement the approach by Holmes & Held (2006). Because the model space is vast, MCMC methods are used as stochastic search algorithms with the aim to quickly find regions of high posterior probability. In a trade-off between fast-updating but slow-moving single-gene Metropolis-Hastings samplers and computationally expensive full Gibbs sampling, we propose to employ the dependence structure among the genes/markers to help decide which variables to update together. Also, parallel tempering methods are used to aid bold moves and help avoid getting trapped in local optima. Mixing and convergence of the resulting Markov chains are evaluated and compared to standard samplers in both a simulation study and in an application to a gene expression data set. Reference Holmes, C. C. & Held, L. (2006) Bayesian auxiliary variable models for binary and multinomial regression. Bayesian Analysis1, 145,168. Dawn Teare 165 MMGE, University of Sheffield, UK Keywords: CNP, family-based analysis, MCMC Evidence is accumulating that segmental copy number polymorphisms (CNPs) may represent a significant portion of human genetic variation. These highly polymorphic systems require handling as phenotypes rather than co-dominant markers, placing new demands on family-based analyses. We present an integrated approach to meet these challenges in the form of a graphical model, where the underlying discrete CNP phenotype is inferred from the (single or replicate) quantitative measure within the analysis, whilst assuming an allele based system segregating through the pedigree. [source] Toward a Theology of Scientific Endeavour: The Descent of Science.THE HEYTHROP JOURNAL, Issue 4 2008By Christopher B. Kaiser No abstract is available for this article. [source] Cognitive-Behavioural Work with Offenders in the UK: A History of Influential EndeavourTHE HOWARD JOURNAL OF CRIMINAL JUSTICE, Issue 2 2000Maurice Vanstone Programmes premised on the cognitive-behavioural theoretical model have become an important feature of work with people who offend, and the model itself has become a cornerstone of the ,what works' enterprise in the United Kingdom. This has not occurred without critical attention from commentators in both the academic and practice worlds. This article attempts to draw together the strands of that debate, and provide a critical account of the recent history of the model's development and application within the criminal justice system that accords more significance to pioneering work in the United Kingdom than has been hitherto recognised. It is argued that one of the features of the response of the probation service to the pessimistic conclusions of research into the impact of community supervision in the 1970s was a divergence of policy and practice, the former redirecting the efforts of the service towards diversion from custody and the latter retaining its commitment to rehabilitation. While acknowledging the limitations of the cognitive-behavioural model, it is argued that by contributing positively to evidence-based, rehabilitative effort it has given impetus to a reunification of the focus of policy and practice. [source] Glandular prediction: the pride and the prejudiceCYTOPATHOLOGY, Issue 4 2004C. Waddell For the cytologist and clinician alike, glandular lesions pose possibly the greatest challenge in cervical screening. Worldwide, with increasing confidence in cytological prediction, terminology is evolving. In the UK, with the adoption of liquid based methods, the technical aspects of cervical cytology are being addressed, it is now time to standardise our terminology in glandular reporting. Consideration of the cytological complexity, clinical needs and international protocols is essential in this endeavour. [source] Partitioned Nature, Privileged Knowledge: Community-based Conservation in TanzaniaDEVELOPMENT AND CHANGE, Issue 5 2003Mara Goldman Community Based Conservation (CBC) has become the catch,all solution to the social and ecological problems plaguing traditional top,down, protectionist conservation approaches. CBC has been particularly popular throughout Africa as a way to gain local support for wildlife conservation measures that have previously excluded local people and their development needs. This article shows that, despite the rhetoric of devolution and participation associated with new CBC models, conservation planning in Tanzania remains a top,down endeavour, with communities and their specialized socio,ecological knowledge delegated to the margins. In addition to the difficulties associated with the transfer of power from state to community hands, CBC also poses complex challenges to the culture or institution of conservation. Using the example of the Tarangire,Manyara ecosystem, the author shows how local knowledge and the complexities of ecological processes challenge the conventional zone,based conservation models, and argues that the insights of local Maasai knowledge claims could better reflect the ecological and social goals of the new CBC rhetoric. [source] Pro-Poor Modes of Technical Integration into the Global EconomDEVELOPMENT AND CHANGE, Issue 4 2000Jeffrey James Recent evidence indicates that globalization based on technical advances in information technology is creating a dualistic situation in the world economy, whereby the benefits tend to accrue to a narrow group of relatively affluent countries, while the majority lag behind. The purpose of this article is to suggest a framework within which to assess an alternative, pro-poor form of technical integration into the global economy , in other words, a form of globalization that benefits the poor as well as the rich. The article focuses particularly on the role that can be played by NGOs, aid donors and national governments in this endeavour. [source] Research into the glomerular podocyte,is it relevant to diabetic nephropathy?DIABETIC MEDICINE, Issue 7 2006K. E. White Abstract The cause of proteinuria in renal disease is the subject of intensive research and, latterly, the podocyte, a specialized epithelial cell of the kidney glomerulus, has been the focus of much of this endeavour. It is a complex cell with functions and structural features that have an important role in the development of proteinuria. This review explores some of the characteristics of the podocyte and how abnormalities of its structure and function may have particular relevance to the development and progression of clinical diabetic nephropathy. [source] Misunderstanding Gödel: New Arguments about Wittgenstein and New Remarks by WittgensteinDIALECTICA, Issue 3 2003Victor Rodych The long-standing issue of Wittgenstein's controversial remarks on Gödel's Theorem has recently heated up in a number of different and interesting directions [(Floyd and Putnam. 2000), (Steiner, 2001), (Floyd, 2001)]. In their (2000), Juliet Floyd and Hilary Putnam purport to argue that Wittgenstein's,notorious'(RFM App. III, §8) "Contains a philosophical claim of great interest," namely, "if one assumed. that ,P is provable in Russell's system one should, give up the "translation" of P by the English sentence ,P is not provable'," because if ,P is provable in PM, PM is , -inconsistent, and if PM is ,-inconsistent, we cannot translate ,P'as 'P is not provable in PM'because the predicate,NaturalNo.(x)'in ,P'"cannot be,interpreted" as "x is a natural number." Though Floyd and Putnam do not clearly distinguish the two tasks, they also argue for "The Floyd-Putnam Thesis," namely, that in the 1930's Wittgenstein had a particular (correct) understanding of Gödel's First Incompleteness Theorem. In this paper, I endeavour to show, first, that the most natural and most defensible interpretation of Wittgenstein's (RFM App. III, §8) and the rest of (RFM App. III) is incompatible with the Floyd-Putnam attribution and, second, that evidence from Wittgenstein's Nachla (i.e., a hitherto unknown "proof sketch" of Gödel's reasoning, Wittgenstein's only mention of ,-inconsistency, and Wittgenstein's only mention of "K provable") strongly indicates that the Floyd- Putnam attribution and the Floyd-Putnam Thesis are false. By way of this examination, we shall see that despite a failure to properly understand Gödel's proof,perhaps because, as Kreisel says, Wittgenstein did not read Gödel's 1931 paper prior to 1942-Wittgenstein's 1937,38, 1941 and 1944 remarks indicate that Gödel's result makes no sense from Wittgenstein's own (idiosyncratic) perspective. [source] Complexity and Educational Research: A critical reflectionEDUCATIONAL PHILOSOPHY AND THEORY, Issue 1 2008Lesley Kuhn Abstract Judgements concerning proper or appropriate educational endeavour, methods of investigation and philosophising about education necessarily implicate perspectives, values, assumptions and beliefs. In recent years ideas from the complexity sciences have been utilised in many domains including psychology, economics, architecture, social science and education. This paper addresses questions concerning the appropriateness of utilising complexity science in educational research as well as issues relating to the ways in which complexity might be engaged. I suggest that, just like all human endeavour, approaches to research emerge out of discursive communities and can be understood as self-organising, dynamic and emergent over time. In this formulation, complexity represents one such newly emergent approach. I argue that it is important that researchers partake in critical and reflective discourse about the nature of education and conceptual frameworks, as well as about impacts and legacies of utilising complexity, so as to participate in and influence the ongoing emergence of educational endeavour. I conclude by suggesting a series of caveats for researchers considering using complexity in educational research. [source] Visiting America: notes from an alcohol-focused study tour made in 1961ADDICTION, Issue 12 2008Griffith Edwards ABSTRACT Aims This paper has as its focus a study tour made by the author in 1961. Diary notes are used to capture a historical moment in the evolution of alcohol studies. The paper will argue for the continuing value today of such experiences in support of career development and the building of ,the field'. Data sources Diary notes and personal recollection. Findings The United States was at the time more active than the United Kingdom in its response to alcohol problems. There was, however, a disjunction between the elite American research world and the world of action, which was not informed greatly by research. For the most part, treatment services and prevention strategies seemed driven by opinion rather than by evidence. But at the level of serious scientific endeavour there was opportunity to meet influential figures including Seldon Bacon, Morris Chafetz, Milton Gross, Ebbe Curtis Hoff, Harris Isbell, E. M. Jellinek, Mark Keller, Benjamin Kissen, Robert Strauss, Wolf Schmidt and Abraham Wikler, who generously made their time available. Conclusions These diary notes provide a snapshot of a field of endeavour at a critical stage of transition from uninformed assumptions towards establishment of a research base which can inform public action. The visit was of tangible value to the visitor in several different identified ways. Such an experience is inevitably time-bound and personal, but there are general conclusions to be drawn as to the benefits which will be derived from early travel opportunities in a field such as alcohol studies, which is all too easily culture-bound in its horizons and assumptions. Alcohol science needs to be more reflective on its history and the mechanisms that help to make it happen. [source] Development Section, April 2008GEOGRAPHY COMPASS (ELECTRONIC), Issue 3 2008Cheryl McEwan EDITORIAL It is a great privilege to serve as Editor for the Development section of Geography Compass. The journal is an exciting new venture in electronic publishing that aims to publish state-of-the-art peer-reviewed surveys of key contemporary issues in geographical scholarship. As the first Editor of this section, it is my responsibility to establish the key aims and innovations for this section of the journal. These include: publishing reviews of scholarship on topics of contemporary relevance that are accessible and useful to researchers, teachers, students and practitioners; developing the range of topics covered across the spectrum of development geography; helping to set agendas in development geography by identifying gaps in existing empirical and conceptual research; commissioning articles from both established and graduate/early career researchers who are working at the frontiers of development geography; and communicating the distinctiveness of Geography Compass. Part of this distinctiveness is in publishing articles that are both of scholarly excellence and accessible to a wide audience. The first volume of Geography Compass was published in 2007, covering a wide range of topics (e.g. migration, children, technology, grassroots women's organizations, civil society, biodiversity, tourism, inequality, agrarian change, participatory development, disability, spirituality) in a number of specific geographical areas (e.g. Africa/southern Africa, Caribbean, China, Peru). Forthcoming in 2008/2009 are articles on the Gambia, Latin America, the Philippines, Southeast Asia, Bangladesh and South Africa, focusing on topics such as food security, comparative post-socialism, foreign aid and fair trade. Building on these diverse and excellent articles, I plan to communicate the distinctiveness of Development in a number of ways. First, I encourage an ecumenical approach to the notion of ,development geography' and welcome contributions from scholars across a range of social science disciplines whose work would be useful to a geography audience. This is important, not least because both development and geography, in disciplinary terms, are largely European inventions. Many scholars in Latin America, Africa and Asia, for example, do not refer to themselves as either development specialists or geographers but are producing important research in areas of direct relevance to students and researchers of ,development geography'. As the first editions illustrate, I also seek to publish articles that reflect ,development' in its broadest sense, encompassing economic, (geo)political, social, cultural and environmental issues. 2008 will be an interesting year for development, with a number of important issues and events shaping discourse and policy. These include: the Beijing Olympics and increasing focus on China's role in international development; political change in a number of African countries (Kenya, Zimbabwe, South Africa); the US presidential elections and potential shifts in policy on climate change, trade and security; the impacts of the Bali roadmap on climate change in the current economic context; the increasing number of impoverished people in Asia (notably China and India), sub-Saharan Africa and Latin America (notably Brazil) that even the World Bank has acknowledged; the implications of the increasing role of philanthropic foundations (e.g. the Gates Foundation and those emerging in India and Russia) in international development. I hope to see some of these issues covered in this journal. Second, I am keen to break down the association between ,development' and parts of the world variously categorized as ,Third World', ,Global South' or ,Developing World' by publishing articles that cut across North and South, East and West. The intellectual and disciplinary practices within (Western) geography that separate those researching issues in the South and post-socialist contexts from those researching similar issues in advanced capitalist economies are, it seems, no longer sustainable or sensible. Moreover, while studies of transnational and ethical trade, neoliberalism, household economies and ,commodity chains', for example, incorporate a multitude of case studies from across the world, these tend to be understood through conceptual lenses that almost always have their theoretical antecedents in Western theorization. The notion of ,learning from' debates, policy and practice in other parts of the world is still relatively alien within the discipline. There are thus issues in how we research and teach ethically and responsibly in and about different parts of the world, and in which this journal might make a contribution. Third, and related, part of my responsibility is to ensure that Compass reflects the breadth of debate about ,development' by publishing articles written by a truly international range of scholars. This has proved to be a challenge to date, in part reflecting the newness of the journal and the difficulties posed by English language publication. However, an immediate aim is to publish the work and ideas of scholars based outside of Anglophone contexts, in the Global South and in post-socialist contexts, and to use international referees who are able to provide valuable commentaries on the articles. A longer-term aim is to also further internationalize the Editorial Board. Currently, one-third of the Editorial Board is non-UK and I plan to increase this to at least 50% in future. Fourth, I plan to ensure that the Development section takes full advantage of electronic publication and the opportunities this offers. Thus, while I am keen to retain a word limit in the interest of publishing accessible articles, the lack of constraint regarding page space enables authors to include a wide range of illustrative and other material that is impossible in print journals. I plan to encourage authors to make greater use of visual materials (maps, photographs/photo-essays, video, sound recordings, model simulations and datasets) alongside text as well as more innovative forms of presentation where this might be appropriate. Finally, in the coming year, I intend to work more closely with other Compass section Editors to realize the potential for fostering debate that cuts across subdisciplinary and even disciplinary boundaries. The journal publishes across the full spectrum of the discipline and there is thus scope for publishing articles and/or special issues on development-related topics that might best be approached through dialogue between the natural and social sciences. Such topics might include resources (e.g. water, oil, bio-fuels), hazard and risk (from environmental issues to human and state security), and sustainability and quality of life (planned for 2008). Part of the distinctiveness of Compass is that electronic-only publication ensures that articles are published in relatively quick time , in some cases less than 3 months from initial submission to publication. It thus provides an important outlet for researchers working in fast-changing contexts and for those, such as graduate and early-career researchers, who might require swift publication for career purposes. Of course, as Editor I am reliant on referees both engaging with Manuscript Central and providing reports on articles in a relatively short space of time to fully expedite the process. My experience so far has been generally very positive and I would like to thank the referees for working within the spirit of the journal. Editing a journal is, of course, a collaborative and shared endeavour. The Development Editorial Board has been central to the successful launch of Development by working so generously to highlight topics and potential authors and to review articles; I would like to take this opportunity to thank Tony Bebbington, Reg Cline-Cole, Sara Kindon, Claire Mercer, Giles Mohan, Warwick Murray, Richa Nagar, Rob Potter, Saraswati Raju, Jonathan Rigg, Jenny Robinson and Alison Stenning. The Editors-in-Chief , Mike Bradshaw and Basil Gomez , have provided invaluable advice while adding humour (and colour) to the editorial process. Colleagues at Wiley-Blackwell have provided superb support, in particular, Helen Ashton who is constantly on hand to provide advice and assistance. I look forward to working closely with these people again in the coming year, as well as with the authors and readers who are vital to ensuring that Geography Compass fulfils its remit. [source] The Caledonides of East Greenland,tales of the birth and death of oceansGEOLOGY TODAY, Issue 3 2009Kent Brooks In Geology Today (2008, v.24, no.1,) I traced the history of geological research in northeast Greenland, research that has culminated in the new and impressive map of the region produced by the Geological Survey of Denmark and Greenland. But what did all this endeavour, spread over more than 150 years, and involving hundreds of geologists and costing perhaps hundreds of millions of dollars, achieve? Here I summarize the results: the understanding of the evolution of this region over billions of years. [source] The Artist in Contemplation: Love and Creation in Schiller's Philosophische BriefeGERMAN LIFE AND LETTERS, Issue 1 2007Jennifer Driscoll Colosimo ABSTRACT In addition to documenting the development of the author's philosophical world-view from his student days to his first years as an independent artist, Schiller's Philosophische Briefe provide a unique view into his continued endeavour to define and defend the artist's role in society. The examination of the artistic nature forms a remarkable subtext throughout the entire Philosophische Briefe project. It is certainly not Schiller's conscious intent to expose his own doubts and insecurities regarding the moral tendency of his profession. Indeed, his stance in the foreword to the work is so urgently self-assured that he betrays himself primarily by protesting too much. However, the frame narrative and the internal philosophical essay, the Theosophie des Julius, reveal just how much his early philosophy centres on the justification of the artist, and how tenuous this justification is. This article addresses the representation of the artist in each of the three sections that compose the Philosophische Briefe, with reference to other works of the same period that relate thematically. Taken together, these representations illuminate some of the key reasons why Schiller felt compelled to defend his life's pursuit, and against what or whom. [source] A Critique of Schopenhauer's MetaphysicGERMAN LIFE AND LETTERS, Issue 3 2006G.A. Wells Schopenhauer's metaphysic is not more credible than the systems of his contemporaries Fichte, Schelling and Hegel, all of whom he criticised so severely. But as his writings, unlike theirs, are so lucid, they illustrate very clearly the metaphysician's endeavour to reach knowledge that is immediate and indubitable, not mediated by the sense organs and the brain, as is knowledge of the external world. He argues that ,das Einzige wirklich und unbedingt Gegebene ist das Selbstbewußtsein', which alone can yield ,die letzten und wichtigsten Aufschlüsse über das Wesen der Dinge'. He himself was not religious, but this doctrine has appealed to theologians seeking a basis for their belief that is independent of external (historical) testimony. In this connection, Albert Schweitzer expressly urged a return to the German metaphysical tradition, in particular to Schopenhauer's view of the will as the transcendent reality at the basis of self-consciousness. The present article argues, in the British empirical tradition, that there is really no reason to distinguish self-consciousness and experiences attributable to will from other kinds of experience. The practical distinction is that the idea of self depends largely not on the sensations provided by readily observable senses such as sight and hearing, but on muscular, articular and visceral receptors which constitute a less accessible internal sensorium. [source] Developing research capacity in health librarians: a review of the evidenceHEALTH INFORMATION & LIBRARIES JOURNAL, Issue 3 2008Hannah Rossall This critical review considers current issues of research capacity development in UK health care and the role of health librarianship in this context, placing particular focus on the use of research networks. There is a growing literature base recognising the need for librarians to engage more with research. The concepts of evidence-based health librarianship and clinical librarianship are discussed in the context of research and examples of existing good practice are reviewed. It is suggested that librarians should build on this through better consideration of evidence based methodologies, hierarchies of evidence, improvement of research skills, and a collective endeavour to identify research priorities. The importance research capacity is being given in the Department of Health R&D strategy and the use of networks in achieving this is discussed, and it is suggested that the utilisation of networks and collaboration should be undertaken and explored in more depth in developing research capacity in health librarianship. Areas where librarians currently engage with research and use networks and collaborative practices to contribute to the research base are reviewed. A co-ordinated approach to developing research capacity is called for and it is argued that the use of networks would be beneficial in assisting the process. [source] The provincial social survey in Edwardian BritainHISTORICAL RESEARCH, Issue 187 2002Mark Freeman This article examines three social surveys carried out in English provincial towns after Seebohm Rowntree's study of York and before A. L. Bowley's sample surveys of five towns. The authors emphasized specific local circumstances and suggested local voluntary and municipal remedies for the social problems they described. Their focus was on the community, and although informed by the discourses of ,national efficiency' that also lay behind Rowntree's researches, the solutions to the problems of juvenile life and casual labour that compromised national efficiency were to be found in local endeavour. Poverty was viewed in the context of its impact on the community rather than on the individual. [source] Intrinsic and extrinsic factors in skin ageing: a reviewINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 2 2008M. A. Farage Synopsis As the proportion of the ageing population in industrialized countries continues to increase, the dermatological concerns of the aged grow in medical importance. Intrinsic structural changes occur as a natural consequence of ageing and are genetically determined. The rate of ageing is significantly different among different populations, as well as among different anatomical sites even within a single individual. The intrinsic rate of skin ageing in any individual can also be dramatically influenced by personal and environmental factors, particularly the amount of exposure to ultraviolet light. Photodamage, which considerably accelerates the visible ageing of skin, also greatly increases the risk of cutaneous neoplasms. As the population ages, dermatological focus must shift from ameliorating the cosmetic consequences of skin ageing to decreasing the genuine morbidity associated with problems of the ageing skin. A better understanding of both the intrinsic and extrinsic influences on the ageing of the skin, as well as distinguishing the retractable aspects of cutaneous ageing (primarily hormonal and lifestyle influences) from the irretractable (primarily intrinsic ageing), is crucial to this endeavour. Résumé Comme le pourcentage de la population vieillissante dans les pays industrialisés s'accroît, les préoccupations dermatologiques des personnes âgées augmentent en importance sur le plan médical. Les modifications structurelles intrinsèques sont une conséquence naturelle du vieillissement et sont génétiquement déterminées. La vitesse de vieillissement diffère significativement selon les différentes populations et selon les différents sites anatomiques, même pour un seul individu. La vitesse intrinsèque du vieillissement de la peau pour un individu peut être aussi très influencée par les facteurs personnels et environnementaux, en particulier le taux d'exposition à la lumière ultra-violette. La photodégradation qui accélère considérablement le vieillissement visible de la peau augmente également beaucoup le risque de formation de néoplasme cutané. Au fur et à mesure que la population vieillit, il faut davantage se préoccuper de diminuer la morbidité réelle associée au vieillissement de la peau, plutôt que de palier à ses conséquences cosmétiques. Il est donc crucial de s'efforcer à mieux comprendre les facteurs intrinsèques et extrinsèques qui agissent sur le vieillissement de la peau et aussi de faire la distinction entre les aspects réversibles du vieillissement cutané (facteurs essentiellement hormonaux et mode de vie) et les aspects irréversibles (principalement le vieillissement intrinsèque). [source] Effect of thermal treatment of incubated potato juice on the formation of Maillard volatilesINTERNATIONAL JOURNAL OF FOOD SCIENCE & TECHNOLOGY, Issue 8 2003Stephen J. Davids Summary Potato juice samples, obtained from potatoes stored at different temperatures (0,24 °C) and times (8,20 weeks), were incubated (45,57 °C for 42 h) with or without commercial proteases. The samples were then used for thermal browning experiments by placing in either a heated oven at 125 °C overnight or in an autoclave at 132 or 121 °C for 1 h, these experiments promoted the occurrence of the Maillard reaction. After the heat treatment step, all samples were extracted with methylene chloride and analysed by gas chromatography/mass spectrometry. The data indicated that, by subjecting the potato juice to thermal treatments, a wide variety of volatiles generated by the Maillard were produced and these are known to be associated with specific flavour notes, examples are alkyl and acetyl pyrazines, piperazinediones, furans and pyrroles. These findings suggest that the study of potato juice extract as a new medium for flavour development, in particular in those applications which presently use malt, coffee, soybean, meat and yeast extracts, is a worthwhile endeavour. [source] Challenging behaviours in nursing home residents with dementia: a randomized controlled trial of multidisciplinary interventionsINTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 1 2002Janet Opie Abstract Objectives To test the premise that individually tailored psychosocial, nursing and medical interventions to nursing home residents with dementia will reduce the frequency and severity of behavioural symptoms. Methods A four-member team comprising a psychiatrist, psychologist and nurses conducted detailed assessments of 99 nursing home residents with advanced dementia who were rated by staff as having frequent, severe behavioural disturbances. Residents were then randomly assigned to an ,early' or ,late' intervention group and observed for four weeks. Interventions encompassed psychosocial strategies, nursing approaches, psychotropic medications and management of pain. Outcome measures included the frequency and severity of disruptive behaviours and assessments of change by senior nursing home staff. Results While improvements in behaviour were noted in both groups from the outset of observations, pointing to a powerful Hawthorne effect, consultancies were associated with a modest but statistically significant decrease in challenging behaviours. Staff assessments of the interventions were highly favourable. Conclusions The consultancies were effective and well received by staff. The change-inducing nature of any new endeavour is an integral part of research in a long-term setting. Copyright © 2002 John Wiley & Sons, Ltd. [source] The relationship between healthcare professionals and the parents of chronically ill children: negotiating the boundaries between dependence and expertiseINTERNATIONAL JOURNAL OF PHARMACY PRACTICE, Issue 1 2007Alda Hummelinck senior clinical pharmacist Objective Mutual respect and understanding between parents and healthcare professionals are fundamental to the realisation of a partnership in the provision of care to chronically ill children. The aim of this study was an exploration of parents' perspectives on their relationship with healthcare professionals and their involvement in decisions about their child's care. Setting The paediatric department of a district general hospital in the West Midlands, England. Method Qualitative methodology using semi-structured interviews with 27 parents from 20 families with a chronically ill child. Key findings In the time following the child's diagnosis, parents' attitudes towards healthcare professionals often moved from reliance and trust to scepticism and suspicion. This change in attitude derived from their experience of inadequate communication and perception of professionals' failure to understand the reality of the intense and relentless demands and challenges that confront families providing care for a chronically ill child. Parents tended to be initially accepting and deferential to professional expertise. Over time, however, as their experience and confidence increased, they often desired a greater involvement in decisions about treatment and care. This transition, between initial, or episodic, dependency and active partnership, was often not recognised or accommodated by professionals. It was difficult for both parties to negotiate the transition from parents' dependency on health professionals to becoming more independent managers of care. Conclusions Professionals should be aware of parents' preferred and changing level of involvement in care and decision making, and endeavour to accommodate these throughout the process of providing care for chronically ill children. [source] PDB_REDO: automated re-refinement of X-ray structure models in the PDBJOURNAL OF APPLIED CRYSTALLOGRAPHY, Issue 3 2009Robbie P. Joosten Structural biology, homology modelling and rational drug design require accurate three-dimensional macromolecular coordinates. However, the coordinates in the Protein Data Bank (PDB) have not all been obtained using the latest experimental and computational methods. In this study a method is presented for automated re-refinement of existing structure models in the PDB. A large-scale benchmark with 16,807 PDB entries showed that they can be improved in terms of fit to the deposited experimental X-ray data as well as in terms of geometric quality. The re-refinement protocol uses TLS models to describe concerted atom movement. The resulting structure models are made available through the PDB_REDO databank (http://www.cmbi.ru.nl/pdb_redo/). Grid computing techniques were used to overcome the computational requirements of this endeavour. [source] Literature review: decision-making regarding slow resuscitationJOURNAL OF CLINICAL NURSING, Issue 11 2007H Dip, Jacinta Kelly MSc Aims and objectives., Applying ethical principles as a framework, a review of the literature will be presented regarding the decision-making process of slow codes. Background., Slow codes are cardiopulmonary resuscitative efforts intentionally conducted too slowly for resuscitation to occur. While some authors argue that a slow code is a non-maleficent and beneficent act towards the hopelessly ill patient, others believe that this practice is harmful and deceptive, that it disregards patient and surrogate autonomy and deprives the patient of a peaceful death. Method., Literature review. Results., Decision-making surrounding cardiopulmonary resuscitation receives considerable attention in the literature. However, data relating to the decision-making process in slow codes is sparse. One ethnographic study described the practice of slow codes as doing good and preventing harm to the patient. Conclusions., It was evident from the literature review that slow codes, even in the most limited form, are invasive and undignified and that they prolong death and suffering. Further research is needed to examine why slow codes happen despite the availability of a do-not-resuscitate order. Relevance to clinical practice., Decision-making regarding cardiopulmonary resuscitation is increasingly problematic in Ireland. The literature review suggests that clinical guidelines regarding decision-making and cardiopulmonary resuscitation should be introduced to reduce the likelihood of slow codes occurring, but also that nurses and doctors endeavour to communicate more effectively with patients and family. [source] Family involvement in perioperative nursing of adult patients undergoing emergency surgeryJOURNAL OF CLINICAL NURSING, Issue 2 2001Eija Paavilainen PhD ,,The purpose of this study was to describe how adult patients undergoing emergency surgery experience family centredness in perioperative nursing practice. The central aim was to generate knowledge to be used while developing the practice, education and management of perioperative nursing. ,,Data were collected using a questionnaire with emergency surgical patients in five regional hospitals in Southern Finland. The number of distributed questionnaires was 132. The response rate was 85% (n=112). ,,The results were mainly described as frequencies and percentages. The open-ended sections of the answers were analysed using qualitative content analysis. The findings from the open-ended questions were used for deepening and complementing the quantitative description of the results. ,,In the preoperative phase, ascertaining the family situation and informing the family member chosen by the patient were not achieved systematically. Family situation was also rarely examined in the intraoperative and postoperative phases, although it is central to coping after surgery, especially in home care. ,,The results support the view of earlier research about the importance of individuality of patients and their families during the perioperative care process and hence enhance the endeavour to develop nursing based on families' real needs. [source] Rhetorical representations of masculinities in South Africa: moving towards a material-discursive understanding of menJOURNAL OF COMMUNITY & APPLIED SOCIAL PSYCHOLOGY, Issue 1 2003Russell Luyt Abstract A material-discursive perspective holds advantage in understanding male realities. It seeks to integrate dominant approaches that appear anaemic in their failure to capture the interplay between the material and discursive realms of human existence. Three dominant metaphorical themes in the rhetorical representation of South African masculinities are described in an attempt to illustrate the complexity of embodied masculine experience. In this sense the discussion seeks to reveal the dynamic nature of masculine debate and lived experience across differing contexts. It serves to underline the importance of adopting a material-discursive perspective in understanding men, which recognizes that they do not exist as a homogeneous social group, and as such experience their masculinities in a variable and changing fashion. The theoretical amalgamation of social representations and rhetoric is argued to provide a useful analytical tool in an endeavour of this nature. It is suggested that the rhetorical approach problematizes an overly consensual view of social reality that social representations theory typically promotes. Copyright © 2003 John Wiley & Sons, Ltd. [source] Theorizing TQM: An Austrian and Evolutionary Economics InterpretationJOURNAL OF MANAGEMENT STUDIES, Issue 2 2000Todd H. Chiles Born out of management practice, the principles of TQM (total quality management) have had a profound and unparalleled impact on modern business history. However, as a body of practical knowledge, TQM has been largely atheoretical. As a consequence, this important management philosophy has remained amorphous and shrouded in considerable conceptual haziness and ambiguity. Recent theorizing, primarily emphasizing the application of organizational behaviour theories to TQM, has begun to provide greater clarity, but much work remains to be done. This paper attempts to contribute to this nascent theory-building literature by employing theory from market process economics (MPE), namely, Austrian and evolutionary economics, which explains how processes of dynamic change, adaptation, and learning are driven by entrepreneurial creativity. We contend that the patterns in this body of theory match, to a remarkable degree, the patterns of practical knowledge contained in the TQM literature. We demonstrate this ,pattern-matching' by showing that MPE effectively provides the theoretical underpinnings of TQM's three main principles , customer focus, continuous improvement and teamwork , as well as the respective TQM topics of customer perceptions, adaptation in dynamic environments, and knowledge creation. Having established MPE as a credible theoretical lens for interpreting TQM, it can be used to clarify fuzzy areas that have remained in the TQM literature with the potential to take us beyond what we know now. We illustrate this with three examples that show how we can resolve debates in TQM over incentive systems, recognize that TQM embraces methodological pluralism in the collection and analysis of data, and highlight hidden dangers that attend benchmarking. While MPE has no monopoly on theoretical interpretations of TQM, it is unique in its ability to comprehensively cover the incredible breadth of this practical body of knowledge, and in its interpretation of TQM as a dynamic economic endeavour. [source] The marketing of industrial real estate: application of Taguchi loss functionsJOURNAL OF MULTI CRITERIA DECISION ANALYSIS, Issue 4 2001Troy A. Festervand Abstract The marketing of industrial real estate is a resource-consuming endeavour for all parties involved consisting of many objectives that, in many cases, may be in conflict with one another. One method of minimizing resource requirements, especially time, while increasing the probability of a successful match is to select properties for presentation that maximizes buyer utility. Zionts (1992) indicated one area for future research in multiple criteria decision-making (MCDM) is in the development of ,Eclectic Approaches' using old ideas in a new way to help develop MCDM approaches. In this paper Taguchi loss functions, a procedure commonly used in quality control, is proposed as a tool that can be used by industrial real estate professionals to more efficiently determine the property that most closely matches the buyer's needs. Copyright © 2001 John Wiley & Sons, Ltd. [source] Forgiveness, the Moral Law and Education: A Reply to Patricia WhiteJOURNAL OF PHILOSOPHY OF EDUCATION, Issue 4 2002L. Philip Barnes Patricia White has recently attempted to construct an ethically valid notion of forgiveness that will serve educational purposes and contribute to the moral development of pupils in schools. She distinguishes between a strict view that requires repentance before forgiveness, which she rejects, and a relaxed view that does not require repentance, which she endorses. In this reply I defend the strict view of forgiveness against her criticism and challenge the ethical propriety of the relaxed view. I shall argue that her support for the relaxed view both runs counter to our deepest moral intuitions and serves to undermine the moral law and moral endeavour. [source] Efficient estimation of three-dimensional curves and their derivatives by free-knot regression splines, applied to the analysis of inner carotid artery centrelinesJOURNAL OF THE ROYAL STATISTICAL SOCIETY: SERIES C (APPLIED STATISTICS), Issue 3 2009Laura M. Sangalli Summary., We deal with the problem of efficiently estimating a three-dimensional curve and its derivatives, starting from a discrete and noisy observation of the curve. This problem is now arising in many applicative contexts, thanks to the advent of devices that provide three-dimensional images and measures, such as three-dimensional scanners in medical diagnostics. Our research, in particular, stems from the need for accurate estimation of the curvature of an artery, from image reconstructions of three-dimensional angiographies. This need has emerged within the AneuRisk project, a scientific endeavour which aims to investigate the role of vessel morphology, blood fluid dynamics and biomechanical properties of the vascular wall, on the pathogenesis of cerebral aneurysms. We develop a regression technique that exploits free-knot splines in a novel setting, to estimate three-dimensional curves and their derivatives. We thoroughly compare this technique with a classical regression method, local polynomial smoothing, showing that three-dimensional free-knot regression splines yield more accurate and efficient estimates. [source] After Bristol: the healthcare of young children and the lawLEGAL STUDIES, Issue 2 2003Jo Bridgeman This paper considers the written statements provided to the Bristol Inquiry by parents whose children underwent cardiac surgery at the Bristol Royal Infirmary between 1984 and 1995, seeking to learn from their experiences, opinions, feelings and expectations. The law regulating the relationship between healthcare professional, parent and child is considered in light of these accounts. The limitations of the existing law are such that a new legal framework is required which fosters the relationship between healthcare professional, parent and child, supporting them in the shared endeavour of caring for the child. Of central importance within this new framework would be recognition of each child as a distinct individual and of the expertise which parents can contribute to the care of their child. [source] Genetics of personalities: no simple answers for complex traitsMOLECULAR ECOLOGY, Issue 4 2010BARBARA TSCHIRREN Identifying the genes that underlie phenotypic variation in natural populations, and assessing the consequences of polymorphisms at these loci for individual fitness are major objectives in evolutionary biology. Yet, with the exception of a few success stories, little progress has been made, and our understanding of the link between genotype and phenotype is still in its infancy. For example, although body length in humans is largely genetically determined, with heritability estimates greater than 0.8, massive genome-wide association studies (GWAS) have only been able to account for a very small proportion of this variation (Gudbjartsson et al. 2008). If it is so difficult to explain the genetics behind relatively ,simple' traits, can we envision that it will at all be possible to find genes underlying complex behavioural traits in wild non-model organisms? Some notable examples suggest that this can indeed be a worthwhile endeavour. Recently, the circadian rhythm gene Clock has been associated with timing of breeding in a wild blue tit population (Johnsen et al. 2007; Liedvogel et al. 2009) and the Pgi gene to variation in dispersal and flight endurance in Glanville fritillary butterflies (Niitepold et al. 2009). A promising candidate gene for influencing complex animal personality traits, also known as behavioural syndromes (Sih et al. 2004), is the dopamine receptor D4 (DRD4) gene. Within the last decade, polymorphisms in this gene have been associated with variation in novelty seeking and exploration behaviour in a range of species, from humans to great tits (Schinka et al. 2002; Fidler et al. 2007). In this issue, Korsten et al. (2010) attempt to replicate this previously observed association in wild-living birds, and test for the generality of the association between DRD4 and personality across a number of European great tit populations. [source] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||