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Selected AbstractsEvaluating the validities of different DSM-IV-based conceptual constructs of tobacco dependence,ADDICTION, Issue 7 2008Peter S. Hendricks ABSTRACT Aim To compare the concurrent and predictive validities of two subsets of DSM-IV criteria for nicotine dependence (tolerance and withdrawal; withdrawal; difficulty controlling use; and use despite harm) to the concurrent and predictive validity of the full DSM-IV criteria. Design Analysis of baseline and outcome data from three randomized clinical trials of cigarette smoking treatment. Setting San Francisco, California. Participants Two samples of cigarette smokers (n = 810 and 322), differing with regard to baseline characteristics and treatment received, derived from three randomized clinical trials. Measurements DSM-IV nicotine dependence criteria were measured at baseline with a computerized version of the Diagnostic Interview Schedule for DSM-IV (DIS-IV). Additional baseline measures included the Fagerström Test of Nicotine Dependence (FTND), number of cigarettes smoked per day, breath carbon monoxide (CO) level, the Minnesota Nicotine Withdrawal Scale (MNWS), the Michigan Nicotine Reinforcement Questionnaire (M-NRQ) and the Profile of Mood States (POMS). Seven-day point-prevalence abstinence was assessed at week 12. Findings Full DSM-IV criteria displayed greater concurrent validity than either of the two subsets of criteria. However, DSM-IV symptoms accounted for only a nominal amount of the variance in baseline smoking-related characteristics and were unrelated to smoking abstinence at week 12. Cigarettes smoked per day was the only significant predictor of abstinence at week 12. Conclusions Although the findings do not provide a compelling alternative to the full set of DSM-IV nicotine dependence criteria, its poor psychometric properties and low predictive power limit its clinical and research utility. [source] The missing piece: Measuring portfolio salience in Western European parliamentary democraciesEUROPEAN JOURNAL OF POLITICAL RESEARCH, Issue 1 2005JAMES N. DRUCKMAN Portfolios constitute an important payoff, not just because they provide access to patronage, but because influence over policy decisions tends to go with control over the key government portfolios. It is easy to discover which and how many portfolios each party holds in any government, but what is missing is accurate measurement of the value or salience of these portfolios. Some attempts have been made to measure portfolio salience, but they have lacked one or more of the following properties: cross-national scope, country-specific measurement, coverage of the full set of postwar portfolios, measurement by multiple experts and measurement at the interval level. In this article, we present a new data contribution: a set of portfolio salience scores that possesses all of these properties for 14 Western European countries derived from an expert survey. We demonstrate the comprehensiveness and reliability of the ratings, and undertake some preliminary analyses that show what the ratings reveal about parliamentary government in Western Europe. [source] A Framework for Valuing Derivative SecuritiesFINANCIAL MARKETS, INSTITUTIONS & INSTRUMENTS, Issue 5 2001Philip Gray This paper develops a general framework for valuing a wide range of derivative securities. Rather than focusing on the stochastic process of the underlying security and developing an instantaneously-riskless hedge portfolio, we focus on the terminal distribution of the underlying security. This enables the derivative security to be valued as the weighted sum of a number of component pieces. The component pieces are simply the different payoffs that the security generates in different states of the world, and they are weighted by the probability of the particular state of the world occurring. A full set of derivations is provided. To illustrate its use, the valuation framework is applied to plain-vanilla call and put options, as well as a range of derivatives including caps, floors, collars, supershares, and digital options. [source] Ex vivo microscopic assessment of factors affecting the quality of apical seal created by root-end fillingsINTERNATIONAL ENDODONTIC JOURNAL, Issue 8 2007S. I. Tobón-Arroyave Abstract Aim, (i) To evaluate the incidence of microcracks around root-end preparations completed with ultrasonic tips and their relationship with the root filling technique and thickness of surrounding dentine. (ii) To investigate the effect of rapid exposure to a water-soluble dye of Intermediate Restorative Material (IRM), Super Ethoxybenzoic Acid (sEBA) and Mineral Trioxide Aggregate (MTA), on the marginal adaptation and microleakage of root-end fillings. (iii) To describe the microstructure of the surface of root-end filling materials. Methodology, Ninety-two single-rooted teeth were divided into two groups (n = 46) according to the root canal instrumentation/filling techniques. Group 1 consisted of specimens in which canal preparation was completed using a crown-down technique and then filled with the Thermafil system (TF group); Group 2 consisted of specimens in which canal preparation was completed using a step-back technique and lateral condensation (LC group). Following root-end resection and ultrasonic cavity preparation, the samples were further divided into three subgroups (n = 24) for root-end filling with IRM, sEBA or MTA. The ultrasonic preparation time was recorded. Eight teeth were kept as positive and 12 as negative controls. Following immersion in Indian ink for 7 days, all resected root surfaces were evaluated for the presence of microcracks and the cross-sectional area of root-end surface and root-end filling were measured to evaluate the thickness of the dentinal walls. Thereafter, the samples were sectioned longitudinally so as to assess the depth of dye penetration and marginal adaptation of root-end fillings. Negative controls longitudinally sectioned were used to describe microstructural characteristics of the root-end filling materials using scanning electron microscopic (SEM) techniques. Results, Although the thickness of dentinal walls between groups 1 and 2 was similar, the ultrasonic preparation time and number of microcracks were significantly higher (P < 0.001) in the TF group. Both groups had a significant correlation between microcracks and ultrasonic preparation time (P < 0.001). sEBA and IRM had better adaptation and less leakage compared with MTA. A SEM analysis displayed microstructural differences between the root-end filling materials. Conclusion, Microcracks can occur independently of the thickness of dentinal walls and may be associated with the prolonged ultrasonic preparation time required for the removal of the root filling during root-end cavity preparation. Although sEBA and IRM had better behaviour than MTA regarding microleakage and marginal adaptation, it is possible that exposure of MTA to a water-soluble dye before achieving full set and its porous microstructure contributed to the results. [source] Dynamic reduction of a CH4/air chemical mechanism appropriate for investigating vortex,flame interactionsINTERNATIONAL JOURNAL OF CHEMICAL KINETICS, Issue 4 2007Shaheen R. Tonse This paper describes two methods, piecewise reusable implementation of solution mapping (PRISM) and dynamic steady-state approximation (DYSSA), in which chemistry is reduced dynamically to reduce the computational burden in combustion simulations. Each method utilizes the large range in species timescales to reduce the dimensionality to the number of species with slow timescales. The methods are applied within a framework that uses hypercubes to partition multidimensional chemical composition space, where each chemical species concentration, plus temperature, is represented by an axis in space. The dimensionality of the problem is reduced uniquely in each hypercube, but the dimensionality of chemical composition space is not reduced. The dimensionality reduction is dynamic and is different for different hypercubes, thereby escaping the restrictions of global methods in which reductions must be valid for all chemical mixtures. PRISM constructs polynomial equations in each hypercube, replacing the chemical kinetic ordinary differential equation (ODE) system with a set of quadratic polynomials with terms related to the number of species with slow timescales. Earlier versions of PRISM were applied to smaller chemical mechanisms and used all chemical species concentrations as terms. DYSSA is a dynamic treatment of the steady-state approximation and uses the fast,slow timescale separation to determine the set of steady-state species in each hypercube. A reduced number of chemical kinetic ODEs are integrated rather than the original full set. PRISM and DYSSA are evaluated for simulations of a pair of counterrotating vortices interacting with a premixed CH4/air laminar flame. DYSSA is sufficiently accurate for use in combustion simulations, and when relative errors are less than 1.0%, speedups on the order of 3 are observed. PRISM does not perform as well as DYSSA with respect to accuracy and efficiency. Although the polynomial evaluation that replaces the ODE solver is sufficiently fast, polynomials are not reused sufficiently to enable their construction cost to be recovered. © 2007 Wiley Periodicals, Inc. 39: 204,220, 2007 [source] On the design of gain-scheduled trajectory tracking controllersINTERNATIONAL JOURNAL OF ROBUST AND NONLINEAR CONTROL, Issue 9 2002Carlos Silvestre Abstract A new methodology is proposed for the design of trajectory tracking controllers for autonomous vehicles. The design technique builds on gain scheduling control theory. An application is made to the design of a trajectory tracking controller for a prototype autonomous underwater vehicle (AUV). The effectiveness and advantages of the new control laws derived are illustrated in simulation using a full set of non-linear equations of motion of the vehicle. Copyright © 2002 John Wiley & Sons, Ltd. [source] A Cross-Atlantic Dialogue: The Progress of Research and Theory in the Study of International MigrationINTERNATIONAL MIGRATION REVIEW, Issue 3 2004Alejandro Portes The articles included in this issue were originally presented at a conference on Conceptual and Methodological Developments in the Study of International Migration held at Princeton University in May 2003. The conference was jointly sponsored by the Committee on International Migration of the Social Science Research Council (SSRC), the Center for Migration and Development (CMD) at Princeton, and this journal. Its purpose was to review recent innovations in this field, both in theory and empirical research, across both sides of the Atlantic. The conference was deliberately organized as a sequel to a similar event convened by the SSRC on Sanibel Island in January 1996 in order to assess the state of international migration studies within the United States from an inter-disciplinary perspective. A selection of articles from that conference was published as a special issue of International Migration Review (Vol. 31, No. 4, Winter), and the full set of articles was published as the Handbook of International Migration: The American Experience (Hirschman, Kasinitz and DeWind, 1999). [source] Accruals Management, Investor Sophistication, and Equity Valuation: Evidence from 10,Q FilingsJOURNAL OF ACCOUNTING RESEARCH, Issue 4 2002Steven Balsam The release of the full set of financial statements in Form 10,Q provides investors with the data necessary to estimate the discretionary portion of earnings, thereby allowing them to better assess the integrity of reported quarterly earnings. We thus expect a negative association between unexpected discretionary accruals estimated using 10,Q disclosures and stock returns around 10,Q filing dates. Consistent with our expectations, we document a negative association between unexpected discretionary accruals and cumulative abnormal returns over a short window around the 10,Q filing date. Furthermore, this association varies systematically with investor sophistication. Finally, results from portfolio tests indicate that this association is economically as well as statistically significant. One interpretation of our findings is that accruals management has substantial valuation consequences, which are quickly impounded into stock prices. [source] Scheduling considerations for a branching transit routeJOURNAL OF ADVANCED TRANSPORTATION, Issue 3 2004Aichong Sun This paper addresses the impacts of different scheduling alternatives for a branching transit route. It examines different schedule alternatives that might be used to optimize the route performance in terms of the passenger traveling time distributed among branch passengers and trunk-line passengers. The schedule alternatives considered include transit vehicle allocation to different branches, offset shifting across vehicles on different branches, and vehicle holding (slack time) in the transit vehicle schedule. With these variables, several vehicle schedules are devised and examined based on a wide variety of possible passenger boarding scenarios using deterministic service models. Test outcomes provide general conclusions about the performance of the strategies. Vehicle assignment leading to even headways among branches is generally preferred for the case of low passenger demand. However, when passenger demand is high, or the differences between the passenger demands on branches are significant, unequal vehicle assignment will be helpful to improve the overall route performance. Holding, as a proactive strategy in scheduling, has the potential to be embedded into the schedule as a type of slack time, but needs further evidence and study to determine the full set of conditions where it may be beneficial. Offset shifting does not show sufficient evidence to be an efficient strategy to improve route performance in the case of low or high passenger demand. [source] Variable selection in random calibration of near-infrared instruments: ridge regression and partial least squares regression settingsJOURNAL OF CHEMOMETRICS, Issue 3 2003Arief Gusnanto Abstract Standard methods for calibration of near-infrared instruments, such as partial least-squares (PLS) and ridge regression (RR), typically use the full set of wavelengths in the model. In this paper we investigate the effect of variable (wavelength) selection for these two methods on the model prediction. For RR the selection is optimized with respect to the ridge parameter, the number of variables and the configuration of the variables in the model. A fast iterative computational algorithm is developed for the purpose of this optimization. For PLS the selection is optimized with respect to the number of components, the number of variables and the configuration of the variables. We use three real data sets in this study: processed milk from the market, milk from a dairy farm and milk from the production line of a milk processing factory. The quantity of interest is the concentration of fat in the milk. The observations are randomly split into estimation and validation sets. Optimization is based on the mean square prediction error computed on the validation set. The results indicate that the wavelength selection will not always give better prediction than using all of the available wavelengths. Investigation of the information in the spectra is necessary to determine whether all of them are relevant to the objective of the model. Copyright © 2003 John Wiley & Sons, Ltd. [source] Accuracy of free energies of hydration using CM1 and CM3 atomic chargesJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 11 2004Blagovi, Marina Udier Abstract Absolute free energies of hydration (,Ghyd) have been computed for 25 diverse organic molecules using partial atomic charges derived from AM1 and PM3 wave functions via the CM1 and CM3 procedures of Cramer, Truhlar, and coworkers. Comparisons are made with results using charges fit to the electrostatic potential surface (EPS) from ab initio 6-31G* wave functions and from the OPLS-AA force field. OPLS Lennard,Jones parameters for the organic molecules were used together with the TIP4P water model in Monte Carlo simulations with free energy perturbation theory. Absolute free energies of hydration were computed for OPLS united-atom and all-atom methane by annihilating the solutes in water and in the gas phase, and absolute ,Ghyd values for all other molecules were computed via transformation to one of these references. Optimal charge scaling factors were determined by minimizing the unsigned average error between experimental and calculated hydration free energies. The PM3-based charge models do not lead to lower average errors than obtained with the EPS charges for the subset of 13 molecules in the original study. However, improvement is obtained by scaling the CM1A partial charges by 1.14 and the CM3A charges by 1.15, which leads to average errors of 1.0 and 1.1 kcal/mol for the full set of 25 molecules. The scaled CM1A charges also yield the best results for the hydration of amides including the E/Z free-energy difference for N -methylacetamide in water. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1322,1332, 2004 [source] The lissamphibian humerus and elbow joint, and the origins of modern amphibiansJOURNAL OF MORPHOLOGY, Issue 12 2009Trond Sigurdsen Abstract The origins and evolution of the three major clades of modern amphibians are still a source of controversy, and no general consensus exists as to their relationship to the various known Paleozoic taxa. This may indicate that additional character complexes should be studied to resolve their phylogenetic relationship. The salamander elbow joint has been fundamentally misinterpreted in previous morphological descriptions. In caudates and anurans, both the radius and ulna (fused in anurans) articulate with the characteristically large capitulum (radial condyle), although part of the ulnar articulating surface fits into to the smooth trochlear region. The salamander "ulnar condyle" of previous descriptions is in fact the entepicondyle. The condition seen in batrachians (i.e., salamanders and frogs) may be a lissamphibian synapomorphy because the elbow region of the primitive fossil caecilian Eocaecilia resembles those of frogs and salamanders. In addition to the large and bulbous capitulum, all lissamphibian humeri lack an entepicondylar foramen, and possess a distally pointing entepicondyle, a low and rounded ectepicondyle, and an elongated shaft. These characters are identified in key fossil forms to assess the support for the different hypotheses proposed for the evolutionary origins of lissamphibians. Temnospondyli is the only group of early tetrapods that shows a progressive evolution of lissamphibian traits in the humerus and elbow joint. Furthermore, among Paleozoic taxa, the dissorophoid temnospondyl Doleserpeton annectens is the only taxon that has the full set of humeral features shared by all lissamphibians. These results add support for the theory of a monophyletic origin of lissamphibians from dissorophoidtemnospondyls. J. Morphol., 2009. © 2009 Wiley-Liss, Inc. [source] Expression studies on a novel type 2B variant of the von Willebrand factor gene (R1308L) characterized by defective collagen bindingJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2005L. BARONCIANI Summary., A novel mutation, R1308L (3923G > T) was present in the heterozygous state in five members of a family with type 2B von Willebrand disease (VWD) characterized by a full set of von Willebrand factor (VWF) multimers in plasma and by the absence of thrombocytopenia before and after desmopressin (DDAVP). The defect (R1308L) was located at the same amino acid position of one of the most common mutations associated with type 2B VWD (R1308C), which is characterized by the loss of high molecular weight VWF multimers (HMWM) in plasma and the occurrence of thrombocytopenia. To understand the mechanisms of this defect, the novel (R1308L) and ,common' (R1308C) mutations were expressed in COS-7 cells, either alone or, to mimic the patients' heterozygous state, together with wild-type VWF. R1308L recombinant VWF (rVWF) had a higher affinity for the platelet glycoprotein Ib, (GPIb,) receptor than wild-type rVWF, R1308C rVWF showing an even higher affinity. A novel finding was that both mutant rVWFs showed a similarly reduced binding to collagen type I and type III in comparison with wild-type rVWF. The latter finding suggests a more important role than recognized so far for the VWF A1 domain in VWF binding to collagen, which may contribute to the in vivo hemostatic defect associated with type 2B VWD. [source] Lakes and society: The contribution of lakes to sustainable societiesLAKES & RESERVOIRS: RESEARCH AND MANAGEMENT, Issue 2 2001Lowell L. Klessig Abstract Lake management is typically approached from a biophysical perspective. Lake managers ask how lakes can be managed to sustain their ecological functions. The social value of lakes is usually given less attention. The present paper begins the analysis at the other end of the lake and society connection by posing the question: what social needs must be met to sustain society? The primary social needs of sustainable societies are outlined and then the contribution of lakes to each need is discussed. Lakes can only provide optimal social benefits if management decisions recognize the full set of potential contributions lakes can make to society and those management decisions are integrated to provided balanced attention to all values that lakes provide. The present paper expands the domain of values beyond the traditional environmental and recreational contributions of lake management to also include aesthetics, education, economic opportunity, emotional security, cultural opportunity, individual freedom and spirituality. Citizen involvement is essential in broadening the conceptualization of the lake values and in implementing integrated management plans. [source] How much does simplification of probability forecasts reduce forecast quality?METEOROLOGICAL APPLICATIONS, Issue 1 2008F. J. Doblas-Reyes Abstract Probability forecasts from an ensemble are often discretized into a small set of categories before being distributed to the users. This study investigates how such simplification can affect the forecast quality of probabilistic predictions as measured by the Brier score (BS). An example from the European Centre for Medium-Range Weather Forecasts (ECMWF) operational seasonal ensemble forecast system is used to show that the simplification of the forecast probabilities reduces the Brier skill score (BSS) by as much as 57% with respect to the skill score obtained with the full set of probabilities issued from the ensemble. This is more obvious for a small number of probability categories and is mainly due to a decrease in forecast resolution of up to 36%. The impact of the simplification as a function of the ensemble size is also discussed. The results suggest that forecast quality should be made available for the set of probabilities that the forecast user has access to as well as for the complete set of probabilities issued by the ensemble forecasting system. Copyright © 2008 Royal Meteorological Society [source] Patterns of population subdivision and gene flow in the ant Nothomyrmecia macrops reflected in microsatellite and mitochondrial DNA markersMOLECULAR ECOLOGY, Issue 9 2003M. Sanetra Abstract The Australian endemic ant Nothomyrmecia macrops is renowned for having retained a large proportion of ,primitive' morphological and behavioural characters. Another less studied peculiarity of this species is the production of short-winged (brachypterous) female sexuals, which presumably are poor dispersers. The males, in contrast, bear a full set of normally developed wings and thus may disperse widely. We investigated patterns of genetic differentiation within and among three distantly separated populations in South Australia using nine polymorphic microsatellite loci and four regions of mitochondrial DNA (COI, COII, Cytb, lrRNA). We sampled eight subpopulations, one in the Lake Gilles CP, two near Penong and five around Poochera where distances ranged from 360 km to sites separated by 2,10 km. Only little differentiation was found at the local scale (within the assumed dispersal distance of males) using nuclear markers, whereas the three distant locations were moderately differentiated (FST = 0.06). Mitochondrial DNA genetic structure was much more pronounced on all scales (,ST = 0.98), with regular differences in both haplotype composition and frequency even occurring among closely located sites. This lack of congruence between nuclear and mitochondrial markers strongly suggests limited female dispersal and male-biased gene flow among populations. As to the conservation status of the species there is no evidence for severe population reductions in the recent past, which would have left populations genetically depauperate. [source] Statistical evaluation of time-dependent metabolite concentrations: estimation of post-mortem intervals based on in situ1H-MRS of the brainNMR IN BIOMEDICINE, Issue 3 2005Eva Scheurer Abstract Knowledge of the time interval from death (post-mortem interval, PMI) has an enormous legal, criminological and psychological impact. Aiming to find an objective method for the determination of PMIs in forensic medicine, 1H-MR spectroscopy (1H-MRS) was used in a sheep head model to follow changes in brain metabolite concentrations after death. Following the characterization of newly observed metabolites (Ith et al., Magn. Reson. Med. 2002; 5: 915,920), the full set of acquired spectra was analyzed statistically to provide a quantitative estimation of PMIs with their respective confidence limits. In a first step, analytical mathematical functions are proposed to describe the time courses of 10 metabolites in the decomposing brain up to 3 weeks post-mortem. Subsequently, the inverted functions are used to predict PMIs based on the measured metabolite concentrations. Individual PMIs calculated from five different metabolites are then pooled, being weighted by their inverse variances. The predicted PMIs from all individual examinations in the sheep model are compared with known true times. In addition, four human cases with forensically estimated PMIs are compared with predictions based on single in situ MRS measurements. Interpretation of the individual sheep examinations gave a good correlation up to 250,h post-mortem, demonstrating that the predicted PMIs are consistent with the data used to generate the model. Comparison of the estimated PMIs with the forensically determined PMIs in the four human cases shows an adequate correlation. Current PMI estimations based on forensic methods typically suffer from uncertainties in the order of days to weeks without mathematically defined confidence information. In turn, a single 1H-MRS measurement of brain tissue in situ results in PMIs with defined and favorable confidence intervals in the range of hours, thus offering a quantitative and objective method for the determination of PMIs. Copyright © 2004 John Wiley & Sons, Ltd. [source] Accuracy, confidence and consistency in diagnosing Class III malocclusion with diagnostic records: a two-center studyORTHODONTICS & CRANIOFACIAL RESEARCH, Issue 3 2000Peter Ngan The objective of this study was to determine the accuracy, confidence and consistency in diagnosing the Class III malocclusion in children by diagnostic records. Ten orthodontists from the state of West Virginia and 20 from the state of Ohio were asked to classify the dental and skeletal occlusion of eight patients. Six of the cases were patients with Class III malocclusion. Two cases, one with a Class II division 1 malocclusion and one with a Class I malocclusion, were used as distractors. Diagnosis of these cases was established by four published cephalometric analyses, which served as the ,gold standard', to determine the number of correct responses from the participants. Four faculty members were employed to confirm the cephalometric and clinical diagnosis of these cases with a full set of records. Participants were asked to diagnose the cases using only study casts and facial profile photographs for the first time. After an interval of 30 days, the procedure was repeated with the addition of lateral cephalograms and tracings. The accuracy in diagnosing malocclusion was determined by the percentage of correct responses. The level of confidence was determined by calculating the median of a 5-point graded response utilizing the following confidence values: 1=not at all, 2=slightly, 3=moderately, 4=very, 5=absolutely. Differences between ,with' and ,without' lateral cephalograms were analyzed non-parametrically using the Wilcoxon matched-pairs signed-ranks test. The results from both centers show the accuracy in dental classification of Class III malocclusion was quite good (83%±17.1% in the West Virginia group and 93%±14.1% in the Ohio group). The accuracy in skeletal classification was poor (72%±16.3 in the West Virginia group and 53%±7.03 in the Ohio group). The addition of lateral cephalograms and tracings did not improve the accuracy of dental or skeletal classification. However, clinicians felt more confident in their diagnoses with the information provided by lateral cephalograms and tracings. The consistency in dental and skeletal classification was fair and poor, respectively. These results suggest that clinicians are not consistent in diagnosing the Class III malocclusion and that skeletal classification of Class III malocclusion in children could be difficult. The addition of lateral cephalograms and tracings do not contribute to the accuracy of diagnosis. [source] Raman tensor analysis of baddeleyite single-crystal and its application to define crystallographic domains in polycrystalline zirconiaPHYSICA STATUS SOLIDI (B) BASIC SOLID STATE PHYSICS, Issue 2 2010Kyoju Fukatsu Abstract The angular dependence of polarized Raman intensity for the Ag and Bg modes was investigated and the full set of Raman tensor elements defined for a baddeleyite single-crystal, namely the monoclinic polymorph of zirconia (ZrO2). Based on the quantitative knowledge of the tensor elements, a method has been proposed for the determination of unknown crystallographic textures in monoclinic zirconia. An application of this method is also shown, which consists of a Raman analysis of crystal orientation on the microscopic scale in polycrystalline ZrO2 after its tetragonal-to-monoclinic (t,m) polymorphic transformation (i.e., occurred under an externally applied stress field). This working example not only confirms the well-known phenomenon of stress-induced phase transformation in polycrystalline zirconia, but also proves the existence of textured domain patterns in the monoclinic phase on a scale larger than that of individual grains. This finding might suggest that the structural and functional properties of polycrystalline zirconia after partial phase transformation should be reinterpreted with taking into account a crystallographic reorientation effect. [source] Contributions of disease resistance and escape to the control of septoria tritici blotch of wheatPLANT PATHOLOGY, Issue 5 2009L. S. Arraiano The contributions of disease escape and disease resistance to the responses of wheat to septoria tritici leaf blotch (STB) were analysed in a set of 226 lines, including modern cultivars, breeding lines and their progenitors dating back to the origin of scientific wheat breeding. Field trials were located in the important wheat-growing region of eastern England and were subject to natural infection by Mycosphaerella graminicola. STB scores were related to disease-escape traits, notably height, leaf spacing, leaf morphology and heading date, and to the presence of known Stb resistance genes and isolate-specific resistances. The Stb6 resistance gene was associated with a reduction of 19% in the level of STB in the complete set of 226 lines and with a 33% reduction in a subset of 139 lines of semidwarf stature. Greater plant height was strongly associated with reduced STB in the full set of lines, but only weakly in the semidwarf lines. Shorter leaf length was also associated with reduced STB, but, in contrast to earlier reports, lines with more prostrate leaves had more STB on average, probably because they tended to have longer leaves. Several lines, notably cvs Pastiche and Exsept, had low mean levels of STB which could not be explained by either escape traits or specific resistance genes, implying that they have unknown genes for partial resistance to STB. [source] Genetic diversity in populations of the fungi Phaeomoniella chlamydospora and Phaeoacremonium aleophilum on grapevine in FrancePLANT PATHOLOGY, Issue 1 2002B. Borie Isolates of Phaeomoniella chlamydospora (Phc) and Phaeoacremonium aleophilum (Pha), two haploid, deuteromycetous fungi, were obtained from vines showing symptoms of esca disease in different localities in two French regions, and within a single vineyard in one of these regions. The population genetic structure was determined in both fungi using random amplified polymorphic DNA (RAPD) analysis. Populations of Phc showed similar levels of diversity at local and regional levels. The most frequent Phc haplotypes were found in every population, and the frequencies of positive alleles of markers were similar across populations. The hypothesis that recombination had occurred was rejected for the full set of samples, but not for the samples reduced to haplotypes, indicating that Phc may be a recombining species. Different features were identified in Pha populations. First, the southern population of Pha appeared more diverse than the south-western populations. Second, genetic differentiation was identified between Pha populations from southern and south-western regions for several RAPDs. Finally, in the southern population of Pha no evidence for recombination was obtained, even by reducing the sample to haplotypes. Within the single vineyard surveyed, several haplotypes of both fungi were recovered and randomly distributed. Thus different infection events appeared to have occurred on a low spatial scale. Data from this study showed that haplotypes of both fungi were distributed over long distances geographically, and that most of the vineyards surveyed were infested by more than one haplotype of Phc and Pha. [source] Justice and Culture: Rawls, Sen, Nussbaum and O'NeillPOLITICAL STUDIES REVIEW, Issue 1 2003Cécile Fabre Is it possible, in a multicultural world, to hold all societies to a common standard of decency that is both high enough to protect basic human interests, and yet not biased in the direction of particular cultural values? We examine the recent work of four liberals , John Rawls, Amartya Sen, Martha Nussbaum and Onora O'Neill , to see whether any of them has given a successful answer to this question. For Rawls, the decency standard is set by reference to an idea of basic human rights that we argue offers too little protection to members of non-liberal societies. Sen and Nussbaum both employ the idea of human capabilities, but in interestingly different ways: for Sen the problems are how to weight different capabilities, and how to decide which are basic, whereas for Nussbaum the difficulty is that her favoured list of capabilities depends on an appeal to autonomy that is unlikely to be acceptable to non-liberal cultures. O'Neill rejects a rights-based approach in favour of a neo-Kantian position that asks which principles of action people everywhere could consent to, but this also may be too weak in the face of cultural diversity. We conclude that liberals need to argue both for a minimum decency standard and for the full set of liberal rights as the best guarantors of that standard over time. [source] An exact sinusoidal beam finite elementPROCEEDINGS IN APPLIED MATHEMATICS & MECHANICS, Issue 1 2008Zdzislaw Pawlak The purpose of the paper is to derive an efficient sinusoidal thick beam finite element for the static analysis of 2D structures. A two,node, 6,DOF curved, sine,shape element of a constant cross,section is considered. Effects of flexural, axial and shear deformations are taken into account. Contrary to commonly used curvilinear co,ordinates, a rectangular co,ordinates system is used in the present analysis. First, an auxiliary problem is solved: a symmetric clamped,clamped sinusoidal arch subjected to unit nodal displacements of both supports is considered using the flexibility method. The exact stiffness matrix for the shear,flexible and compressible element is derived. Introduction of two parameters "n" and "t" enables the identification of shear and membrane influences in the element stiffness matrix. Basing on the principle of virtual work a full set of 18 shape functions related to unit support displacements is derived (total rotations of cross,sections, tangential and normal displacements along the element). The functions are found analytically in the closed form. They are functions of one linear dimensionless coordinate of x,axis and depend on one geometrical parameter of sinusoidal arch, height/span ratio "c" and on physical and geometrical properties of the element cross,section. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Strong opinions are no substitute for balanced arguments: Comments on Cicchetti, Kaufman, and Sparrow's critical appraisal of PCB cohort studiesPSYCHOLOGY IN THE SCHOOLS, Issue 6 2004Gerhard Winneke This paper comments on a critical review of cohort studies on PCB-related neurodevelopmental deficit in young children by D.V. Cicchetti, A.S. Kaufman, and S.S. Sparrow (CKS). Major points of criticism of CKS, namely alleged violation of statistical principles, presumed lack of clinical significance of findings, and alleged insufficient control of confounding are dealt with in appropriate detail. It is argued that much of this criticism is inappropriate and biased, and that, in particular, arguments dealing with basic rules of statistical inference rely too heavily on the narrow principles of Neyman-Pearson testing which are discussed controversially in modern epidemiology. Other critical arguments concerning the presumed lack of validity of assessment instruments, the apparent lack of reliability checks in some studies, and the presumed inappropriate treatment of longitudinal data are also discussed as being poorly founded. It is finally concluded that, although there are inconsistencies and weaknesses both within and between individual PCB-studies, the almost unconditional rejection of the full set of cohort studies by CKS is in no way supported by good reasoning. © 2004 Wiley Periodicals, Inc. Psychol Schs 41: 655,663, 2004. [source] New insights into plant transaldolaseTHE PLANT JOURNAL, Issue 1 2005Maxime Caillau Summary The oxidative pentose phosphate pathway (OPPP) provides plants with important substrates for both primary and secondary metabolism via the oxidation of glucose-6-phosphate. The OPPP is also thought to generate large amounts of reducing power to drive various anabolic processes. In animals this major pathway is located within the cytoplasm of cells, but in plants its subcellular compartmentation is far from clear. Although several enzymes of the OPPP were demonstrated to have both cytosolic and plastidic counterparts, there is yet no evidence for a full set of functional enzymes in each compartment. We report here the isolation of two coding sequences from tomato (Lycopersicon esculentum L.) which encode phylogenetically distant sequences (ToTal1 and ToTal2) that putatively encode distinct plastidic TA isoforms. The kinetic characterization of ToTal1 revealed that, unlike other enzymes of the non-oxidative branch of the OPPP, ToTal1 does not follow a Michaelis,Menten mode of catalysis which has implications for its role in regulating carbon flux between primary and secondary metabolism. TA genes appear to be differentially regulated at the level of gene expression in plant tissues and in response to environmental factors which suggests that TA isoforms have a non-overlapping role for plant metabolism. [source] Construction of a ,unigene' cDNA clone set by oligonucleotide fingerprinting allows access to 25 000 potential sugar beet genesTHE PLANT JOURNAL, Issue 5 2002Ralf Herwig Summary Access to the complete gene inventory of an organism is crucial to understanding physiological processes like development, differentiation, pathogenesis, or adaptation to the environment. Transcripts from many active genes are present at low copy numbers. Therefore, procedures that rely on random EST sequencing or on normalisation and subtraction methods have to produce massively redundant data to get access to low-abundance genes. Here, we present an improved oligonucleotide fingerprinting (ofp) approach to the genome of sugar beet (Beta vulgaris), a plant for which practically no molecular information has been available. To identify distinct genes and to provide a representative ,unigene' cDNA set for sugar beet, 159 936 cDNA clones were processed utilizing large-scale, high-throughput data generation and analysis methods. Data analysis yielded 30 444 ofp clusters reflecting the number of different genes in the original cDNA sample. A sample of 10 961 cDNA clones, each representing a different cluster, were selected for sequencing. Standard sequence analysis confirmed that 89% of these EST sequences did represent different genes. These results indicate that the full set of 30 444 ofp clusters represent up to 25 000 genes. We conclude that the ofp analysis pipeline is an accurate and effective way to construct large representative ,unigene' sets for any plant of interest with no requirement for prior molecular sequence data. [source] European 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 Bonaďti-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 naďve 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] Crystallization and preliminary X-ray analysis of inorganic pyrophosphatase from the hyperthermophilic archaeon Pyrococcus horikoshii OT3ACTA CRYSTALLOGRAPHICA SECTION D, Issue 3 2004Binbin Liu Inorganic pyrophosphatase (PPase; EC 3.6.1.1) from the hyperthermophile Pyrococcus horikoshii was crystallized by the hanging-drop vapour-diffusion method at pH 5.0 using polyethyleneglycol 4000 as the precipitant. The crystal belongs to space group P21212, with unit-cell parameters a = 71.7, b = 86.5, c = 92.5,Ĺ, , = , = , = 90°. There are two molecules in the asymmetric unit. The crystals were stable during exposure to X-rays and a full set of X-ray diffraction data was collected to 2.7,Ĺ resolution in-house. [source] Crystallization and preliminary crystallographic data of a leucotoxin S component from Staphylococcus aureusACTA CRYSTALLOGRAPHICA SECTION D, Issue 2 2004Valérie Guillet Class S proteins of staphylococcal bicomponent pore-forming leucotoxins play an important role in membrane targetting and cell specificity. Wild-type and recombinant S components of the Panton,Valentine leucocidin (LukS-PV) were expressed in Staphylococcus aureus and Escherichia coli, respectively, and purified. Both proteins were crystallized in two crystal forms with Jeffamine M-600 as the precipitant at 285,K using the hanging-drop vapour-diffusion method and seeding techniques. Crystals belong to space group P2 (or P21) and P41 (or P43), with unit-cell parameters a = 72.3, b = 95.1, c = 108.1,Ĺ, , = 106.4° and a = b = 94.8, c = 306.2,Ĺ, respectively. A full set of X-ray diffraction data was collected to 2.1,Ĺ from a single tetragonal crystal of the wild-type protein at 100,K. [source] Crystallization and preliminary crystallographic analysis of a partial extracellular fragment of a sperm membrane protein YWK-II/APPH related to the Alzheimer ,A4-amyloid precursor proteinACTA CRYSTALLOGRAPHICA SECTION D, Issue 1 2003Maojun Yang Crystals of a partial extracellular fragment of a human sperm membrane protein YWK-II/APPH have been grown at 291,K using PEG 4000 as precipitant. The diffraction pattern of the crystal extends to 2.8,Ĺ resolution at 100,K using Cu,K, radiation. The crystals belong to space group P212121, with unit-cell parameters a = 46.009, b = 67.387, c = 149.241,Ĺ, , = , = , = 90°. The presence of two molecules per asymmetric unit gives a crystal volume per protein mass (VM) of 3.51,Ĺ3,Da,1 and a solvent content of 64.6% by volume. A full set of X-ray diffraction data were collected to 2.8,Ĺ resolution from the native crystal. [source] | |||||||||||||||||||||||||||||||