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Second Approach (second + approach)
Selected AbstractsAn integrated perception for autonomous virtual agents: active and predictive perceptionCOMPUTER ANIMATION AND VIRTUAL WORLDS (PREV: JNL OF VISUALISATION & COMPUTER ANIMATION), Issue 3-4 2006Toni Conde Abstract This paper presents an original model with methodologies that integrate in a novel way different types of an autonomous virtual agent's perception in a virtual environment. Our first new approach permits the coherent management of the shared virtual environment for the simulations of an autonomous virtual agent (AVA). Our second approach allows the prediction or the estimation of both the orientation and the attention of an AVA in a virtual environment. By means of a test application with a ,virtual goalkeeper', we demonstrate the speed and the robustness of our technique. Copyright © 2006 John Wiley & Sons, Ltd. [source] Accounting for uncertainty in DEMs from repeat topographic surveys: improved sediment budgetsEARTH SURFACE PROCESSES AND LANDFORMS, Issue 2 2010Joseph M. Wheaton Abstract Repeat topographic surveys are increasingly becoming more affordable, and possible at higher spatial resolutions and over greater spatial extents. Digital elevation models (DEMs) built from such surveys can be used to produce DEM of Difference (DoD) maps and estimate the net change in storage terms for morphological sediment budgets. While these products are extremely useful for monitoring and geomorphic interpretation, data and model uncertainties render them prone to misinterpretation. Two new methods are presented, which allow for more robust and spatially variable estimation of DEM uncertainties and propagate these forward to evaluate the consequences for estimates of geomorphic change. The first relies on a fuzzy inference system to estimate the spatial variability of elevation uncertainty in individual DEMs while the second approach modifies this estimate on the basis of the spatial coherence of erosion and deposition units. Both techniques allow for probabilistic representation of uncertainty on a cell-by-cell basis and thresholding of the sediment budget at a user-specified confidence interval. The application of these new techniques is illustrated with 5 years of high resolution survey data from a 1,km long braided reach of the River Feshie in the Highlands of Scotland. The reach was found to be consistently degradational, with between 570 and 1970,m3 of net erosion per annum, despite the fact that spatially, deposition covered more surface area than erosion. In the two wetter periods with extensive braid-plain inundation, the uncertainty analysis thresholded at a 95% confidence interval resulted in a larger percentage (57% for 2004,2005 and 59% for 2006,2007) of volumetric change being excluded from the budget than the drier years (24% for 2003,2004 and 31% for 2005,2006). For these data, the new uncertainty analysis is generally more conservative volumetrically than a standard spatially-uniform minimum level of detection analysis, but also produces more plausible and physically meaningful results. The tools are packaged in a wizard-driven Matlab software application available for download with this paper, and can be calibrated and extended for application to any topographic point cloud (x,y,z). Copyright © 2009 John Wiley & Sons, Ltd. [source] Seismic reliability of V-braced frames: Influence of design methodologiesEARTHQUAKE ENGINEERING AND STRUCTURAL DYNAMICS, Issue 14 2009Alessandra Longo Abstract According to the most modern trend, performance-based seismic design is aimed at the evaluation of the seismic structural reliability defined as the mean annual frequency (MAF) of exceeding a threshold level of damage, i.e. a limit state. The methodology for the evaluation of the MAF of exceeding a limit state is herein applied with reference to concentrically ,V'-braced steel frames designed according to different criteria. In particular, two design approaches are examined. The first approach corresponds to the provisions suggested by Eurocode 8 (prEN 1998,Eurocode 8: design of structures for earthquake resistance. Part 1: general rules, seismic actions and rules for buildings), while the second approach is based on a rigorous application of capacity design criteria aiming at the control of the failure mode (J. Earthquake Eng. 2008; 12:1246,1266; J. Earthquake Eng. 2008; 12:728,759). The aim of the presented work is to focus on the seismic reliability obtained through these design methodologies. The probabilistic performance evaluation is based on an appropriate combination of probabilistic seismic hazard analysis, probabilistic seismic demand analysis (PSDA) and probabilistic seismic capacity analysis. Regarding PSDA, nonlinear dynamic analyses have been carried out in order to obtain the parameters describing the probability distribution laws of demand, conditioned to given values of the earthquake intensity measure. Copyright © 2009 John Wiley & Sons, Ltd. [source] Increased urinary excretion of nitric oxide metabolites in longitudinally monitored migraine patientsEUROPEAN JOURNAL OF NEUROLOGY, Issue 12 2006K. Rejdak This study evaluated a relationship between nitric oxide (NO) and migraine attacks in order to gain insight into migraine pathomechanism. The study groups consisted of 12 migraineurs and eight controls. All subjects collected morning urine samples for 40 consecutive days. Urinary NO metabolites, nitrite/nitrate (NOx) levels were measured with the vanadium-based assay, whilst creatinine (Cr) and neopterin were determined with high-performance liquid chromatography. The mean urinary NOx/Cr ratio and number of NOx peaks was significantly greater in the migraine group compared with controls (P = 0.01 and P = 0.007, respectively). In the second approach, high NOx values were re-assessed in relation to raised neopterin, a marker of systemic infection or inflammation, and were excluded. The excretion of NOx persisted being pulsatile, and migraineurs had more peaks compared with controls (P = 0.01). In seven patients, NOx peaks coincided with headache days. This was more frequent than expected by random association in four patients (Monte-Carlo simulation; odds ratios: 2.16,7.77; no overlap of 95% CI). In four patients, NOx peaks preceded or followed headache days. Although there is a difference in the pattern of urinary NOx excretion between control and migraine populations, the variable temporal association of NOx peaks and headaches suggests a complex role of NO in this condition. [source] Analytical Modelling of the Radiative Properties of Metallic Foams: Contribution of X-Ray TomographyADVANCED ENGINEERING MATERIALS, Issue 4 2008M. Loretz Two metallic foams exhibiting a similar porosity but different cell sizes have been characterized using X-ray tomography. The images have been processed and analysed to retrieve the morphological properties required for the calculation of the radiative properties such as the extinction coefficient. The multiple possibilities of using the X-ray tomography method rather than conventional optical methods like SEM have been quantified. The extinction coefficient has then been determined from two approaches. First, the resulting morphological properties have been used as the input data of the conventional independent scattering theory. A special emphasis is put on the determination of morphological properties and their influence on the results. In the second approach, an original method is also proposed in order to determine the extinction coefficient of highly porous open cell metal foams, from the tomographic images and without any calculation or hypothesis. Results show a good agreement with the extinction coefficient obtained from experimental measurements. Our novel method enables to reduce uncertainties considerably. [source] Quantification of Grafting Densities Achieved via Modular "Grafting-to" Approaches onto Divinylbenzene MicrospheresADVANCED FUNCTIONAL MATERIALS, Issue 12 2010Leena Nebhani Abstract The surface modification of divinylbenzene (DVB)-based microspheres is performed via a combination of reversible addition fragmentation chain transfer (RAFT) polymerization and rapid hetero-Diels,Alder (HDA) chemistry with the aim of quantifying the grafting densities achieved using this "grafting-to" method. Two variants of the RAFT-HDA concept are employed to achieve the functionalization of the microspheres. In the first approach, the microspheres are functionalized with a highly reactive diene, i.e., cyclopentadiene, and are subsequently reacted with polystyrene chains (number-averaged molecular weight, Mn,=,4200,g,mol,1; polydispersity index, PDI,=,1.12.) that carry a thiocarbonyl moiety functioning as a dienophile. The functionalization of the microspheres is achieved rapidly under ambient conditions, without the aid of an external catalyst. The surface grafting densities obtained are close to 1.2,×,1020 chains per gram of microspheres. In the second approach, the functionalization proceeds via the double bonds inherently available on the microspheres, which are reacted with poly(isobornyl acrylate) chains carrying a highly dienophilic thiocarbonyl functionality; two molecular weights (Mn,=,6000,g,mol,1, PDI,=,1.25; Mn,=,26,000,g,mol,1, PDI,=,1.26) are used. Due to the less reactive nature of the dienes in the second approach, functionalization is carried out at elevated temperatures (T,=,60,°C) yet in the absence of a catalyst. In this case the surface grafting density is close to 7,chains,nm,2 for Mn,=,6000,g,mol,1 and 4,chains,nm,2 for Mn,=,26,000,g,mol,1, or 2.82,×,1019 and 1.38,×,1019,chains g,1, respectively. The characterization of the microspheres at various functionalization stages is performed via elemental analysis for the quantification of the grafting densities and attenuated total reflectance (ATR) IR spectroscopy as well as confocal microscopy for the analysis of the surface chemistry. [source] Why are species' body size distributions usually skewed to the right?FUNCTIONAL ECOLOGY, Issue 4 2002Jan Koz, owski Summary 1.,Species' body size distributions are right-skewed, symmetric or left-skewed, but right-skewness strongly prevails. 2.,Skewness changes with taxonomic level, with a tendency to high right-skewness in classes and diverse skewness in orders within a class. Where the number of lower taxa allows for analysis, skewness coefficients have normal distributions, with the majority of taxa being right-skewed. 3.,Skewness changes with geographical scale. For a broad range, distributions in a class are usually right-skewed. For a narrower scale, distributions remain right-skewed or become symmetric or even close to uniform. 4.,The prevailing right-skewness of species' body size distributions is explained with macroevolutionary models, the fractal character of the environment, or body size optimization. 5.,Macroevolutionary models assume either size-biased speciation and extinction, or the existence of a constraint on small size. Macroevolutionary mechanisms seem insufficient to explain the pattern of species' body size distributions, but they may operate together with other mechanisms. 6.,Optimization models assume that directional and then stabilizing selection works after speciation events. There are two kinds of optimization approaches to study species' body size distributions. Under the first approach, it is assumed that a single energetic optimum exists for an entire taxon, and that species are distributed around this optimum. Under the second approach, each species has a separate optimum, and the species' body size distribution reflects the distribution of optimal values. 7.,Because not only energetic properties but also mortality are important in determining optimal sizes, only the second approach, that is, seeking the distribution of optimal values, seems appropriate in the context of life-history evolution. This approach predicts diverse shapes of body size distributions, with right-skewness prevailing. [source] Formation of Metal Nano- and Micropatterns on Self-Assembled Monolayers by Pulsed Laser Deposition Through Nanostencils and Electroless Deposition,ADVANCED FUNCTIONAL MATERIALS, Issue 10 2006A. Speets Abstract Patterns of noble-metal structures on top of self-assembled monolayers (SAMs) on Au and SiO2 substrates have been prepared following two approaches. The first approach consists of pulsed laser deposition (PLD) of Pt, Pd, Au, or Cu through nano- and microstencils. In the second approach, noble-metal cluster patterns deposited through nano- and microstencils are used as catalysts for selective electroless deposition (ELD) of Cu. Cu structures are grown on SAMs on both Au and SiO2 substrates and are subsequently analyzed using X-ray photoelectron spectroscopy element mapping, atomic force microscopy, and optical microscopy. The combination of PLD through stencils on SAMs followed by ELD is a new method for the creation of (sub)-micrometer-sized metal structures on top of SAMs. This method minimizes the gas-phase deposition step, which is often responsible for damage to, or electrical shorts through, the SAM. [source] Effective Methods for the Synthesis of N -Methyl , -Amino Acids from All Twenty Common , -Amino Acids Using 1,3-Oxazolidin-5-ones and 1,3-Oxazinan-6-onesHELVETICA CHIMICA ACTA, Issue 11 2006Andrew Abstract N -Methyl , -amino acids are generally required for application in the synthesis of potentially bioactive modified peptides and other oligomers. Previous work highlighted the reductive cleavage of 1,3-oxazolidin-5-ones to synthesise N -methyl , -amino acids. Starting from , -amino acids, two approaches were used to prepare the corresponding N -methyl , -amino acids. First, , -amino acids were converted to N -methyl , -amino acids by the so-called ,1,3-oxazolidin-5-one strategy', and these were then homologated by the Arndt,Eistert procedure to afford N -protected N -methyl , -amino acids derived from the 20 common , -amino acids. These compounds were prepared in yields of 23,57% (relative to N -methyl , -amino acid). In a second approach, twelve N -protected , -amino acids could be directly homologated by the Arndt,Eistert procedure, and the resulting , -amino acids were converted to the 1,3-oxazinan-6-ones in 30,45% yield. Finally, reductive cleavage afforded the desired N -methyl , -amino acids in 41,63% yield. One sterically congested , -amino acid, 3-methyl-3-aminobutanoic acid, did give a high yield (95%) of the 1,3-oxazinan-6-one (65), and subsequent reductive cleavage gave the corresponding AIBN-derived N -methyl , -amino acid 61 in 71% yield (Scheme,2). Thus, our protocols allow the ready preparation of all N -methyl , -amino acids derived from the 20 proteinogenic , -amino acids. [source] Highly accurate solutions of the bifurcation structure of mixed-convection heat transfer using spectral methodINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN FLUIDS, Issue 5 2002M. Selmi Abstract This paper is concerned with producing highly accurate solution and bifurcation structure using the pseudo-spectral method for the two-dimensional pressure-driven flow through a horizontal duct of a square cross-section that is heated by a uniform flux in the axial direction with a uniform temperature on the periphery. Two approaches are presented. In one approach, the streamwise vorticity, streamwise momentum and energy equations are solved for the stream function, axial velocity, and temperature. In the second approach, the streamwise vorticity and a combination of the energy and momentum equations are solved for stream function and temperature only. While the second approach solves less number of equations than the first approach, a grid sensitivity analysis has shown no distinct advantage of one method over the other. The overall solution structure composed of two symmetric and four asymmetric branches in the range of Grashof number (Gr) of 0,2 × 106 for a Prandtl number (Pr) of 0.73 has been computed using the first approach. The computed structure is comparable to that found by Nandakumar and Weinitschke (1991) using a finite difference scheme for Grashof numbers in the range of 0,1×106. The stability properties of some solution branches; however, are different. In particular, the two-cell structure of the isolated symmetric branch that has been found to be unstable by the study of Nandakumar and Weinitschke is found to be stable by the current study. Copyright © 2002 John Wiley & Sons, Ltd. [source] Composite adaptive and input observer-based approaches to the cylinder flow estimation in spark ignition automotive enginesINTERNATIONAL JOURNAL OF ADAPTIVE CONTROL AND SIGNAL PROCESSING, Issue 2 2004A. Stotsky Abstract The performance of air charge estimation algorithms in spark ignition automotive engines can be enhanced using advanced estimation techniques available in the controls literature. This paper illustrates two approaches of this kind that can improve the cylinder flow estimation for gasoline engines without external exhaust gas recirculation (EGR). The first approach is based on an input observer, while the second approach relies on an adaptive estimator. Assuming that the cylinder flow is nominally estimated via a speed-density calculation, and that the uncertainty is additive to the volumetric efficiency, the straightforward application of an input observer provides an easy to implement algorithm that corrects the nominal air flow estimate. The experimental results that we report in the paper point to a sufficiently good transient behaviour of the estimator. The signal quality may deteriorate, however, for extremely fast transients. This motivates the development of an adaptive estimator that relies mostly on the feedforward speed-density calculation during transients, while during engine operation close to steady-state conditions, it relies mostly on the adaptation. In our derivation of the adaptive estimator, the uncertainty is modelled as an unknown parameter multiplying the intake manifold temperature. We use the tracking error between the measured and modelled intake manifold pressure together with an appropriately defined prediction error estimate to develop an adaptation algorithm with improved identifiability and convergence rate. A robustness enhancement, via a ,-modification with the ,-factor depending on the prediction error estimate, ensures that in transients the parameter estimate converges to a pre-determined a priori value. In close to steady-state conditions, the ,-modification is rendered inactive and the evolution of the parameter estimate is determined by both tracking error and prediction error estimate. Further enhancements are made by incorporating a functional dependence of the a priori value on the engine operating conditions such as the intake manifold pressure. The coefficients of this function can be learned during engine operation from the values to which the parameter estimate converges in close to steady-state conditions. This feedforward learning functionality improves transient estimation accuracy and reduces the convergence time of the parameter estimate. Copyright © 2004 John Wiley & Sons, Ltd. [source] A robust approach to the UAV task assignment problemINTERNATIONAL JOURNAL OF ROBUST AND NONLINEAR CONTROL, Issue 2 2008Mehdi Alighanbari Abstract This paper presents a new robust approach to the task assignment of unmanned aerial vehicles (UAVs) operating in uncertain dynamic environments for which the optimization data, such as target cost and target,UAV distances, are time varying and uncertain. The impact of this uncertainty in the data is mitigated by tightly integrating two approaches for improving the robustness of the assignment algorithm. One approach is to design task assignment plans that are robust to the uncertainty in the data, which reduces the sensitivity to errors in the situational awareness (SA), but can be overly conservative for long duration plans. A second approach is to replan as the SA is updated, which results in the best plan given the current information, but can lead to a churning type of instability if the updates are performed too rapidly. The strategy proposed in this paper combines robust planning with the techniques developed to eliminate churning. This combination results in the robust filter-embedded task assignment algorithm that uses both proactive techniques that hedge against the uncertainty, and reactive approaches that limit churning behavior by the vehicles. Numerous simulations are shown to demonstrate the performance benefits of this new algorithm. Copyright © 2007 John Wiley & Sons, Ltd. [source] A new multiplex assay allowing simultaneous detection of the inhibition of cell proliferation and induction of cell deathJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2005Józefa W, sierska-G Abstract The efficacy of distinct anti-cancer drugs used in the chemotherapy of human malignancies varies between tumor tissues and depends largely on the ability of the therapeutic agents to simultaneously inhibit cell proliferation and to eliminate malignant cells by apoptosis. Especially, detection of early apoptotic changes seems to be important because early stages of apoptosis differ from those of necrosis. Therefore, the development of a novel test allowing fast and concomitant screening of the anti-proliferative and pro-apoptotic action of a number of anti-cancer drugs is of great interest. For this purpose, we choose as an experimental model a well characterized anti-proliferative and pro-apoptotic effect of cisplatin (CP) on human cervical carcinoma HeLaS3 cells. As previously reported, exposure of HeLaS3 to CP resulted in a concomitant inhibition of cell proliferation and induction of apoptosis in a dose- and time-dependent manner. In the present study we performed two independent approaches. In the first approach, we examined the cell proliferation and activity of caspases-3/7 in two separate microtiter plates using the CellTiter-GloÔ Luminescent Cell Viability Assay and the Caspase-GloÔ 3/7 Assay, respectively. In the second approach, we determined the same parameters sequentially in one microtiter plate by a mutiplexing assay using CellTiter-BlueÔ Cell Viability Assay and Caspase-GloÔ 3/7 Assay. The both approaches gave very similar results indicating that this new multiplexing assay offers an important advantage for simultaneous detection of cell number and activation of caspases-3/7. The new multiplexing assay offers a range of benefits over standard assays. © 2005 Wiley-Liss, Inc. [source] Project AURORA: Infrastructure and flight control experiments for a robotic airshipJOURNAL OF FIELD ROBOTICS (FORMERLY JOURNAL OF ROBOTIC SYSTEMS), Issue 3-4 2006Ely Carneiro de Paiva Project AURORA aims at the development of unmanned robotic airships capable of autonomous flight over user-defined locations for aerial inspection and environmental monitoring missions. In this article, the authors report a successful control and navigation scheme for a robotic airship flight path following. First, the AURORA airship, software environment, onboard system, and ground station infrastructures are described. Then, two main approaches for the automatic control and navigation system of the airship are presented. The first one shows the design of dedicated controllers based on the linearized dynamics of the vehicle. Following this methodology, experimental results for the airship flight path following through a set of predefined points in latitude/longitude, along with automatic altitude control are presented. A second approach considers the design of a single global nonlinear control scheme, covering all of the aerodynamic operational range in a sole formulation. Nonlinear control solutions under investigation for the AURORA airship are briefly described, along with some preliminary simulation results. © 2006 Wiley Periodicals, Inc. [source] A Product-Level Approach to Historical Material Flow AnalysisJOURNAL OF INDUSTRIAL ECOLOGY, Issue 5-6 2008Tungsten as a Case Study Summary Studies of material cycles, which have a solid history in biogeochemistry, include characterization of technological materials cycles that quantify the way in which materials move through the economy and environment of a region. One of the most important aspects of historical technological materials cycles is determining how much material goes into various uses over time and modeling its lifetime in each use. A material flow analysis methodology is presented by which a historical (i.e., 1975 to 2000) study of tungsten use in the United States was constructed. The approach utilized in this study is twofold: the traditional approach by which material going into end-use sectors is approximated (the "end-use sector model"), and a second approach by which end-use products are specifically addressed (the "finished product model"). By virtue of the latter method, a detailed historical account of a material's end uses was developed. This study shows that (1) both models present a detailed treatment of trade of finished products over time for a variety of highly disaggregated products, (2) the end-use sector model provides a method to combine quantitative and qualitative data about products in various sectors to estimate domestic production for a metal about which little is known in terms of its end uses, and (3) the finished product model produces detailed estimates of domestic production for a large number of highly disaggregated products. [source] High-resolution H/D exchange studies on the HET-s218,295 prion proteinJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 5 2005Alexis Nazabal Abstract In a search for improved resolution of hydrogen/deuterium (H/D) exchange experiments analyzed by mass spectrometry (HXMS), we evaluated two methodologies for a detailed structural study of solvent accessibility in the case of the HET-s218,295 prion protein. For the first approach, after incubation in the deuterated solvent, aggregated HET-s218,295 was digested with pepsin and the generated peptides were analyzed by nanospray mass spectrometry in an ion trap, with and without collision-induced dissociation (CID). We compared deuterium incorporation in peptides as determined on peptide pseudomolecular ions and on b and y fragments produced by longer peptides under CID conditions. For both b and y fragment ions, an extensive H/D scrambling phenomenon was observed, in contrast with previous studies comparing CID-MS experiments and 1H NMR data. Thus, the spatial resolution of HXMS experiments could not be improved by means of MS/MS data generated by an ion trap mass spectrometer. In a second approach, the incorporation of deuterium was analyzed by MS for 76 peptides of the HET-s218,289 peptide mass fingerprint, and the use of shared boundaries among peptic peptides allowed us to determine deuteration levels of small regions ranging from one to four amino acids. This methodology led to evidence of highly protected regions along the HET-s218,295 sequence. Copyright © 2005 John Wiley & Sons, Ltd. [source] Estimating water retention curves of forest soils from soil texture and bulk densityJOURNAL OF PLANT NUTRITION AND SOIL SCIENCE, Issue 1 2003Robert Teepe Abstract Forest soils differ significantly from the arable land in their distribution of the soil bulk density and humus content, but the water retention parameters are primarily derived from the data of agricultural soils. Thus, there is a need to relate physical parameters of forest soils with their water retention characteristics and compare them with those of agricultural soils. Using 1850 water retention curves from forest soils, we related the following soil physical parameters to soil texture, bulk density, and C content: air capacity (AC), available water capacity (AWC), and the permanent wilting point (PWP). The ACs of forest soils were significantly higher than those of agricultural soils which were related to the low bulk densities of the forest soils, whereas differences in AWCs were small. Therefore, for a proper evaluation of the water retention curves (WRCs) and the parameters derived from them, further subdivisions of the lowest (< 1.45 g cm -3) of the three bulk density classes was undertaken to the wide range of low soil densities in forest soils (giving a total of 5 bulk density classes). In Germany, 31 soil texture classes are used for the estimation of soil physical parameters. Such a detailed classification is not required because of insignificant differences in WRCs for a large number of these classes. Based on cluster analysis of AC, AWC, and PWP parameters, 10 texture collectives were obtained. Using 5 classes of bulk densities, we further calculated the ACs, AWCs, and the PWPs for these 10 classes. Furthermore, "van Genuchten parameters" (, r, , s, ,, and n) were derived which described the average WRC for each designated class. In a second approach using multiple regression analysis, regression functions for AC, AWC, and PWP and for the van Genuchten parameter were calculated. Abschätzung der Wasser-Retentionskurven von Waldböden anhand der Bodenart und Bodendichte Obwohl sich Waldböden in der Verteilung der Bodendichte und Humusgehalte deutlich von Ackerböden unterscheiden, basiert die Ableitung ihrer bodenphysikalischen Kenngrößen in der Kartieranleitung auf Erhebungen landwirtschaftlich genutzter Böden. Die Abschätzung physikalischer Eigenschaften von Waldböden ist daher weiterhin als unzureichend anzusehen. In dieser Arbeit wurde auf Grundlage von 1850 an Waldböden ermittelten Wasser-Retentionskurven die Luftkapazität, die nutzbare Wasserspeicherkapazität und der Wassergehalt am permanenten Welkepunkt aus der Bodenart, der Bodendichte und dem C-Gehalt hergeleitet. Im Vergleich zu Ackerböden lagen die berechneten Luftkapazitäten aufgrund der unterschiedlichen vertikalen Verteilung der Bodendichten und Humusgehalte von Wald- und Ackerböden in Waldböden deutlich höher, Unterschiede in der nutzbaren Wasserspeicherkapazität hingegen waren gering. Die Ergebnisse zeigen, dass für Waldböden eine differenziertere Unterteilung der Dichteklassen notwendig ist, um die große Streuung im Bereich der unteren Bodendichte adäquat zu berücksichtigen. Andererseits basiert in Deutschland die Abschätzung physikalischer Bodeneigenschaften auf einer detaillierten Einteilung von 31 Texturklassen (Kartieranleitung und Forstliche Standortaufnahme). Da die Unterschiede zwischen vielen Texturklassen häufig sehr gering und statistisch nicht zu trennen sind, wurde unser Datensatz mit Hilfe einer Clusteranalyse auf 10 Texturklassen reduziert. Für diese Texturklassen wurden, unterteilt in jeweils 5 Dichteklassen, die Luftkapazitäten, die nutzbaren Wasserspeicherkapazitäten und der permanente Welkepunkt sowie die van Genuchten Parameter , r, , s, ,, und n berechnet. In einem zweiten Ansatz wurde eine Abschätzung dieser Kenngrößen mit Hilfe der multiplen Regression vorgenommen. [source] End-functionalization of semiconducting species with dendronized terpyridine,Ru(II),terpyridine complexesJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 7 2009Elefterios K. Pefkianakis Abstract Semiconducting oligomers and polymers decorated with two or one dendronized tpy-Ru(II)-tpy metallocomplexes are presented. Initially, free terpyridine end-functionalized semiconducting oligomers (distyrylanthracene, quinquephenylene, mono- and trifluorenes) were prepared while in a second approach, atom transfer radical polymerization was employed for the preparation of side-chain oligomeric and polymeric (oxadiazole)s using a terpyridine initiator. These terpyridine-bearing oligomers and polymers were complexated with a Percec-type first-generation (G1) dendronized terpyridine,Ru(III)Cl3 monocomplex, having two dodecyloxy groups. All oligomeric and polymeric metallocomplexes were characterized via NMR spectroscopies for their structural perfection and via UV-Vis and PL spectroscopies for their optical properties. The existence of the organic semiconducting blocks in combination with the terpyridine,Ru(II),terpyridine groups afforded hybrid metallo-semiconducting species presenting the optical features of both their components. Moreover, their thin-film morphologies were investigated through atomic force microscopy, revealing, in some cases, an organization tendency in the nanometer scale. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1939,1952, 2009 [source] Standard errors for EM estimationJOURNAL OF THE ROYAL STATISTICAL SOCIETY: SERIES B (STATISTICAL METHODOLOGY), Issue 2 2000M. Jamshidian The EM algorithm is a popular method for computing maximum likelihood estimates. One of its drawbacks is that it does not produce standard errors as a by-product. We consider obtaining standard errors by numerical differentiation. Two approaches are considered. The first differentiates the Fisher score vector to yield the Hessian of the log-likelihood. The second differentiates the EM operator and uses an identity that relates its derivative to the Hessian of the log-likelihood. The well-known SEM algorithm uses the second approach. We consider three additional algorithms: one that uses the first approach and two that use the second. We evaluate the complexity and precision of these three and the SEM in algorithm seven examples. The first is a single-parameter example used to give insight. The others are three examples in each of two areas of EM application: Poisson mixture models and the estimation of covariance from incomplete data. The examples show that there are algorithms that are much simpler and more accurate than the SEM algorithm. Hopefully their simplicity will increase the availability of standard error estimates in EM applications. It is shown that, as previously conjectured, a symmetry diagnostic can accurately estimate errors arising from numerical differentiation. Some issues related to the speed of the EM algorithm and algorithms that differentiate the EM operator are identified. [source] PVC modification through polymerization of a monomer absorbed in porous suspension-type PVC particlesJOURNAL OF VINYL & ADDITIVE TECHNOLOGY, Issue 3 2004M. Narkis In-situ polymerization is the polymerization of one monomer in the presence of another polymer. It can be performed by sequential emulsion polymerization, or by reactions in the melt, in the solid phase, or in solution. The current report describes two methods to obtain poly(vinyl chloride) (PVC) modification through polymerization of a monomer absorbed in commercial porous suspension-type PVC particles. The generated modified PVC products differ significantly in their structure and properties. The first approach includes absorption of a monomer/peroxide solution within porous suspension-type PVC particles, followed by polymerization/crosslinking in the solid state at 80°C in an aqueous stabilizer-free dispersion. The monomer/crosslinker pairs selected are styrene/DVB (divinyl benzene), methylmethacrylate/EGDMA (ethylene glycol dimethacrylate), butyl acrylate/EGDMA, and ethylhexyl acrylate/EGDMA. The influence of composition and nature of the polymerizing/crosslinking constituents on the modified PVC particle structure was studied by microscopy methods, porosity measurements, and dynamic mechanical behavior (DMTA). The level of molecular grafting between PVC and the modifying polymer was determined by solvent extraction experiments. This work shows that the different monomers used represent distinct courses of monomer transport through the PVC particles. The characteristics of the modified PVC particle indicate that the polymerization/crosslinking process occurs in both the PVC bulk, i.e., within the walls constituting a particle, and in the PVC pores. No indication of chemical intermolecular interaction within the modified PVC particles was found. In the second approach, a solution of monomer, initiator, and a crosslinking agent is absorbed in commercial suspension-type porous PVC particles, thus forming a dry blend. This dry blend is subsequently reactively polymerized in a twin-screw extruder at an elevated temperature, 180°C, in the molten state. The properties of the reactively extruded PVC/PMMA blends are compared with those of physical blends at similar compositions. Owing to the high polymerization temperature, short-chain polymers are formed in the reactive polymerization process. Reactively extruded PVC/PMMA blends are transparent, form single-phase morphology, have a single Tg, and show mechanical properties comparable with those of the neat PVC. The resulting reactively extruded PVC/PMMA blends have high compatibility. J. Vinyl Addit. Technol. 10:109,120, 2004. © 2004 Society of Plastics Engineers. [source] Algorithms for vector field generation in mass consistent modelsNUMERICAL METHODS FOR PARTIAL DIFFERENTIAL EQUATIONS, Issue 4 2010Ciro Flores Abstract Diagnostic models in meteorology are based on the fulfillment of some time independent physical constraints as, for instance, mass conservation. A successful method to generate an adjusted wind field, based on mass conservation equation, was proposed by Sasaki and leads to the solution of an elliptic problem for the multiplier. Here we study the problem of generating an adjusted wind field from given horizontal initial velocity data, by two ways. The first one is based on orthogonal projection in Hilbert spaces and leads to the same elliptic problem but with natural boundary conditions for the multiplier. We derive from this approach the so called E,algorithm. An innovative alternative proposal is obtained from a second approach where we consider the saddle,point formulation of the problem,avoiding boundary conditions for the multiplier, and solving this problem by iterative conjugate gradient methods. This leads to an algorithm that we call the CG,algorithm, which is inspired from Glowinsk's approach to solve Stokes,like problems in computational fluid dynamics. Finally, the introduction of new boundary conditions for the multiplier in the elliptic problem generates better adjusted fields than those obtained with the original boundary conditions. © 2009 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 2010 [source] Optimal portion control using variable cutter-blade spacing in can-fillingPACKAGING TECHNOLOGY AND SCIENCE, Issue 4 2001F. Omar Abstract In the present context, optimal portion control refers to the process of preparing can-filling portions so that the deviation of the portion weight from a specified target weight is minimized. An approach has been developed for achieving this where a batch of objects is placed in a linearly overlapped optimal arrangement and then cut into portions using a series of parallel blades. The parameters of optimization are the arrangement order, orientation and degree of overlap of the objects. The approach has been demonstrated to produce impressive improvements in the application of fish canning. For this application, two approaches of optimal cutting are compared in the present paper. In one approach, the blade spacing is kept fixed and constant at a predetermined value. In the second approach, the blade spacing is varied for each portion after the objects are placed according to the optimal arrangement, where the target weight distribution is allowed to vary within a tolerance interval. The results presented in this paper indicate that the second approach produces a significantly higher percentage of acceptable portions than the first approach. What is presented are results from computer simulations, utilizing true data as measured from actual batches of fish. The paper demonstrates the potential benefit of the optimal portion control approach when applied in an industrial fish-canning process. Copyright © 2001 John Wiley & Sons, Ltd. [source] Glucocorticoids enhance interleukin-4 production to neo-antigen (hyaluronidase) in children immunocompromised with cytostatic drugsPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 5 2002Monika Edelbauer Immunoglobulin E (IgE)-mediated immediate-type allergic reactions to hyaluronidase have been observed in children with central nervous system (CNS) tumors. Glucocorticoids, used as therapy for brain edema, are discussed controversially as T helper 2 (Th2) stimulatory factors. In this study we investigated the role of glucocorticoids on a Th2 cytokine-promoting effect in children with CNS tumors. Peripheral blood mononuclear cells (PBMCs) from: 29 children suffering from malignant brain tumors, of whom 23 received short-term glucocorticoid treatment (for 3,4 days) during the course of chemotherapy; 18 children with nephrotic syndrome or renal transplantation receiving long-term glucocorticoid treatment; and 13 healthy children, were incubated with phytohemagglutinin (PHA) and/or anti-CD28 monoclonal antibody (mAb) and, in a second approach, with hyaluronidase. The concentrations of Th cell-mediated cytokines , interleukin (IL)-4, IL-10, and interferon-, (IFN-,) , were measured in supernatants. The IL-4 production of PBMCs incubated with PHA/anti-CD28 mAb from children with repeated co-administration of glucocorticoids, hyaluronidase, and cytostatic drugs (median: 249.9 pg/ml; range: 234.4,261.7) was significantly higher (p < 0.0001) than IL-4 production of PBMC from children of all the other groups (median: 86.18; range: 16.0,212.5). There was no significant difference in the levels of IL-10 and IFN-, within the groups. PBMCs stimulated only with hyaluronidase failed to produce detectable levels of cytokines. The results of this study indicate that repeated co-administration of glucocorticoids and hyaluronidase (a neo-antigen) enhance IL-4 production in vitro and thus may induce the production of specific IgE antibodies in children immunocompromised with cytostatic drugs. Hyaluronidase itself does not stimulate in vitro IL-4 synthesis in PBMCs of children receiving cytostatic drugs. [source] Accounting for periods of wetness in displacement of Fusarium pseudograminearum from cereal strawANNALS OF APPLIED BIOLOGY, Issue 1 2010D.P.S. Lakhesar Displacement of pathogenic Fusarium species from cereal residues by other fungi is an important mechanism for the effectiveness of fallows and crop rotations on disease management, as well as in potential biological control. The effect of fluctuating environmental conditions on the rate of displacement was assessed using two different approaches. In the first, wetness durations between 4 and 10 h were simulated by spraying water onto straw inoculated with Fusarium pseudograminearum and antagonists in a greenhouse. For a given cumulative period of wetness, displacement of F. pseudograminearum was generally higher for short (4 h) than longer (10 h) wetting durations, indicating that it was the number of wetting events, rather than their individual durations, that determined the rate of displacement. In the second approach, exponential decay models using thermal time adjusted for rainfall were fitted to published data on survival of Fusarium species in residues. Heat sums calculated from the mean temperature of days on which rain fell, or rainday-degrees (RDD), gave good fits to data from short-term experiments on displacement of F. pseudograminearum by antagonists under natural conditions. RDD and two other indices, decomposition days (DCD) and corrected degree-days (CDD), were equally satisfactory for modelling straw decomposition and mortality of Fusarium in longer term data sets. Such models could be useful for predicting the effects of environmental variation on rotations and biocontrol for Fusarium management in cereals. [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 Bonaïti-Pellié 1 , Emmanuelle Génin 12 INSERM UMR-S535 and Université Paris Sud, Villejuif, 94817, France Keywords: Gene-environment interaction, sibling recurrence risk, exposure correlation Gene-environment interactions may play important roles in complex disease susceptibility but their detection is often difficult. Here we show how gene-environment interactions can be detected by investigating the degree of familial aggregation according to the exposure of the probands. In case of gene-environment interaction, the distribution of genotypes of affected individuals, and consequently the risk in relatives, depends on their exposure. We developed a test comparing the risks in sibs according to the proband exposure. To evaluate the properties of this new test, we derived the formulas for calculating the expected risks in sibs according to the exposure of probands for various values of exposure frequency, relative risk due to exposure alone, frequencies of latent susceptibility genotypes, genetic relative risks and interaction coefficients. We find that the ratio of risks when the proband is exposed and not exposed is a good indicator of the interaction effect. We evaluate the power of the test for various sample sizes of affected individuals. We conclude that this test is valuable for diseases with moderate familial aggregation, only when the role of the exposure has been clearly evidenced. Since a correlation for exposure among sibs might lead to a difference in risks among sibs in the different proband exposure strata, we also add an exposure correlation coefficient in the model. Interestingly, we find that when this correlation is correctly accounted for, the power of the test is not decreased and might even be significantly increased. Andrea Callegaro 1 , Hans J.C. Van Houwelingen 1 , Jeanine Houwing-Duistermaat 13 Dept. of Medical Statistics and Bioinformatics, Leiden University Medical Center, The Netherlands Keywords: Survival analysis, age at onset, score test, linkage analysis Non parametric linkage (NPL) analysis compares the identical by descent (IBD) sharing in sibling pairs to the expected IBD sharing under the hypothesis of no linkage. Often information is available on the marginal cumulative hazards (for example breast cancer incidence curves). Our aim is to extend the NPL methods by taking into account the age at onset of selected sibling pairs using these known marginal hazards. Li and Zhong (2002) proposed a (retrospective) likelihood ratio test based on an additive frailty model for genetic linkage analysis. From their model we derive a score statistic for selected samples which turns out to be a weighed NPL method. The weights depend on the marginal cumulative hazards and on the frailty parameter. A second approach is based on a simple gamma shared frailty model. Here, we simply test whether the score function of the frailty parameter depends on the excess IBD. We compare the performance of these methods using simulated data. Céline Bellenguez 1 , Carole Ober 2 , Catherine Bourgain 14 INSERM U535 and University Paris Sud, Villejuif, France 5 Department of Human Genetics, The University of Chicago, USA Keywords: Linkage analysis, linkage disequilibrium, high density SNP data Compared with microsatellite markers, high density SNP maps should be more informative for linkage analyses. However, because they are much closer, SNPs present important linkage disequilibrium (LD), which biases classical nonparametric multipoint analyses. This problem is even stronger in population isolates where LD extends over larger regions with a more stochastic pattern. We investigate the issue of linkage analysis with a 500K SNP map in a large and inbred 1840-member Hutterite pedigree, phenotyped for asthma. Using an efficient pedigree breaking strategy, we first identified linked regions with a 5cM microsatellite map, on which we focused to evaluate the SNP map. The only method that models LD in the NPL analysis is limited in both the pedigree size and the number of markers (Abecasis and Wigginton, 2005) and therefore could not be used. Instead, we studied methods that identify sets of SNPs with maximum linkage information content in our pedigree and no LD-driven bias. Both algorithms that directly remove pairs of SNPs in high LD and clustering methods were evaluated. Null simulations were performed to control that Zlr calculated with the SNP sets were not falsely inflated. Preliminary results suggest that although LD is strong in such populations, linkage information content slightly better than that of microsatellite maps can be extracted from dense SNP maps, provided that a careful marker selection is conducted. In particular, we show that the specific LD pattern requires considering LD between a wide range of marker pairs rather than only in predefined blocks. Peter Van Loo 1,2,3 , Stein Aerts 1,2 , Diether Lambrechts 4,5 , Bernard Thienpont 2 , Sunit Maity 4,5 , Bert Coessens 3 , Frederik De Smet 4,5 , Leon-Charles Tranchevent 3 , Bart De Moor 2 , Koen Devriendt 3 , Peter Marynen 1,2 , Bassem Hassan 1,2 , Peter Carmeliet 4,5 , Yves Moreau 36 Department of Molecular and Developmental Genetics, VIB, Belgium 7 Department of Human Genetics, University of Leuven, Belgium 8 Bioinformatics group, Department of Electrical Engineering, University of Leuven, Belgium 9 Department of Transgene Technology and Gene Therapy, VIB, Belgium 10 Center for Transgene Technology and Gene Therapy, University of Leuven, Belgium Keywords: Bioinformatics, gene prioritization, data fusion The identification of genes involved in health and disease remains a formidable challenge. Here, we describe a novel bioinformatics method to prioritize candidate genes underlying pathways or diseases, based on their similarity to genes known to be involved in these processes. It is freely accessible as an interactive software tool, ENDEAVOUR, at http://www.esat.kuleuven.be/endeavour. Unlike previous methods, ENDEAVOUR generates distinct prioritizations from multiple heterogeneous data sources, which are then integrated, or fused, into one global ranking using order statistics. ENDEAVOUR prioritizes candidate genes in a three-step process. First, information about a disease or pathway is gathered from a set of known "training" genes by consulting multiple data sources. Next, the candidate genes are ranked based on similarity with the training properties obtained in the first step, resulting in one prioritized list for each data source. Finally, ENDEAVOUR fuses each of these rankings into a single global ranking, providing an overall prioritization of the candidate genes. Validation of ENDEAVOUR revealed it was able to efficiently prioritize 627 genes in disease data sets and 76 genes in biological pathway sets, identify candidates of 16 mono- or polygenic diseases, and discover regulatory genes of myeloid differentiation. Furthermore, the approach identified YPEL1 as a novel gene involved in craniofacial development from a 2-Mb chromosomal region, deleted in some patients with DiGeorge-like birth defects. Finally, we are currently evaluating a pipeline combining array-CGH, ENDEAVOUR and in vivo validation in zebrafish to identify novel genes involved in congenital heart defects. Mark Broom 1 , Graeme Ruxton 2 , Rebecca Kilner 311 Mathematics Dept., University of Sussex, UK 12 Division of Environmental and Evolutionary Biology, University of Glasgow, UK 13 Department of Zoology, University of Cambridge, UK Keywords: Evolutionarily stable strategy, parasitism, asymmetric game Brood parasites chicks vary in the harm that they do to their companions in the nest. In this presentation we use game-theoretic methods to model this variation. Our model considers hosts which potentially abandon single nestlings and instead choose to re-allocate their reproductive effort to future breeding, irrespective of whether the abandoned chick is the host's young or a brood parasite's. The parasite chick must decide whether or not to kill host young by balancing the benefits from reduced competition in the nest against the risk of desertion by host parents. The model predicts that three different types of evolutionarily stable strategies can exist. (1) Hosts routinely rear depleted broods, the brood parasite always kills host young and the host never then abandons the nest. (2) When adult survival after deserting single offspring is very high, hosts always abandon broods of a single nestling and the parasite never kills host offspring, effectively holding them as hostages to prevent nest desertion. (3) Intermediate strategies, in which parasites sometimes kill their nest-mates and host parents sometimes desert nests that contain only a single chick, can also be evolutionarily stable. We provide quantitative descriptions of how the values given to ecological and behavioral parameters of the host-parasite system influence the likelihood of each strategy and compare our results with real host-brood parasite associations in nature. Martin Harrison 114 Mathematics Dept, University of Sussex, UK Keywords: Brood parasitism, games, host, parasite The interaction between hosts and parasites in bird populations has been studied extensively. Game theoretical methods have been used to model this interaction previously, but this has not been studied extensively taking into account the sequential nature of this game. We consider a model allowing the host and parasite to make a number of decisions, which depend on a number of natural factors. The host lays an egg, a parasite bird will arrive at the nest with a certain probability and then chooses to destroy a number of the host eggs and lay one of it's own. With some destruction occurring, either natural or through the actions of the parasite, the host chooses to continue, eject an egg (hoping to eject the parasite) or abandon the nest. Once the eggs have hatched the game then falls to the parasite chick versus the host. The chick chooses to destroy or eject a number of eggs. The final decision is made by the host, choosing whether to raise or abandon the chicks that are in the nest. We consider various natural parameters and probabilities which influence these decisions. We then use this model to look at real-world situations of the interactions of the Reed Warbler and two different parasites, the Common Cuckoo and the Brown-Headed Cowbird. These two parasites have different methods in the way that they parasitize the nests of their hosts. The hosts in turn have a different reaction to these parasites. Arne Jochens 1 , Amke Caliebe 2 , Uwe Roesler 1 , Michael Krawczak 215 Mathematical Seminar, University of Kiel, Germany 16 Institute of Medical Informatics and Statistics, University of Kiel, Germany Keywords: Stepwise mutation model, microsatellite, recursion equation, temporal behaviour We consider the stepwise mutation model which occurs, e.g., in microsatellite loci. Let X(t,i) denote the allelic state of individual i at time t. We compute expectation, variance and covariance of X(t,i), i=1,,,N, and provide a recursion equation for P(X(t,i)=z). Because the variance of X(t,i) goes to infinity as t grows, for the description of the temporal behaviour, we regard the scaled process X(t,i)-X(t,1). The results furnish a better understanding of the behaviour of the stepwise mutation model and may in future be used to derive tests for neutrality under this model. Paul O'Reilly 1 , Ewan Birney 2 , David Balding 117 Statistical Genetics, Department of Epidemiology and Public Health, Imperial, College London, UK 18 European Bioinformatics Institute, EMBL, Cambridge, UK Keywords: Positive selection, Recombination rate, LD, Genome-wide, Natural Selection In recent years efforts to develop population genetics methods that estimate rates of recombination and levels of natural selection in the human genome have intensified. However, since the two processes have an intimately related impact on genetic variation their inference is vulnerable to confounding. Genomic regions subject to recent selection are likely to have a relatively recent common ancestor and consequently less opportunity for historical recombinations that are detectable in contemporary populations. Here we show that selection can reduce the population-based recombination rate estimate substantially. In genome-wide studies for detecting selection we observe a tendency to highlight loci that are subject to low levels of recombination. We find that the outlier approach commonly adopted in such studies may have low power unless variable recombination is accounted for. We introduce a new genome-wide method for detecting selection that exploits the sensitivity to recent selection of methods for estimating recombination rates, while accounting for variable recombination using pedigree data. Through simulations we demonstrate the high power of the Ped/Pop approach to discriminate between neutral and adaptive evolution, particularly in the context of choosing outliers from a genome-wide distribution. Although methods have been developed showing good power to detect selection ,in action', the corresponding window of opportunity is small. In contrast, the power of the Ped/Pop method is maintained for many generations after the fixation of an advantageous variant Sarah Griffiths 1 , Frank Dudbridge 120 MRC Biostatistics Unit, Cambridge, UK Keywords: Genetic association, multimarker tag, haplotype, likelihood analysis In association studies it is generally too expensive to genotype all variants in all subjects. We can exploit linkage disequilibrium between SNPs to select a subset that captures the variation in a training data set obtained either through direct resequencing or a public resource such as the HapMap. These ,tag SNPs' are then genotyped in the whole sample. Multimarker tagging is a more aggressive adaptation of pairwise tagging that allows for combinations of two or more tag SNPs to predict an untyped SNP. Here we describe a new method for directly testing the association of an untyped SNP using a multimarker tag. Previously, other investigators have suggested testing a specific tag haplotype, or performing a weighted analysis using weights derived from the training data. However these approaches do not properly account for the imperfect correlation between the tag haplotype and the untyped SNP. Here we describe a straightforward approach to testing untyped SNPs using a missing-data likelihood analysis, including the tag markers as nuisance parameters. The training data is stacked on top of the main body of genotype data so there is information on how the tag markers predict the genotype of the untyped SNP. The uncertainty in this prediction is automatically taken into account in the likelihood analysis. This approach yields more power and also a more accurate prediction of the odds ratio of the untyped SNP. Anke Schulz 1 , Christine Fischer 2 , Jenny Chang-Claude 1 , Lars Beckmann 121 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany 22 Institute of Human Genetics, University of Heidelberg, Germany Keywords: Haplotype, haplotype sharing, entropy, Mantel statistics, marker selection We previously introduced a new method to map genes involved in complex diseases, using haplotype sharing-based Mantel statistics to correlate genetic and phenotypic similarity. Although the Mantel statistic is powerful in narrowing down candidate regions, the precise localization of a gene is hampered in genomic regions where linkage disequilibrium is so high that neighboring markers are found to be significant at similar magnitude and we are not able to discriminate between them. Here, we present a new approach to localize susceptibility genes by combining haplotype sharing-based Mantel statistics with an iterative entropy-based marker selection algorithm. For each marker at which the Mantel statistic is evaluated, the algorithm selects a subset of surrounding markers. The subset is chosen to maximize multilocus linkage disequilibrium, which is measured by the normalized entropy difference introduced by Nothnagel et al. (2002). We evaluated the algorithm with respect to type I error and power. Its ability to localize the disease variant was compared to the localization (i) without marker selection and (ii) considering haplotype block structure. Case-control samples were simulated from a set of 18 haplotypes, consisting of 15 SNPs in two haplotype blocks. The new algorithm gave correct type I error and yielded similar power to detect the disease locus compared to the alternative approaches. The neighboring markers were clearly less often significant than the causal locus, and also less often significant compared to the alternative approaches. Thus the new algorithm improved the precision of the localization of susceptibility genes. Mark M. Iles 123 Section of Epidemiology and Biostatistics, LIMM, University of Leeds, UK Keywords: tSNP, tagging, association, HapMap Tagging SNPs (tSNPs) are commonly used to capture genetic diversity cost-effectively. However, it is important that the efficacy of tSNPs is correctly estimated, otherwise coverage may be insufficient. If the pilot sample from which tSNPs are chosen is too small or the initial marker map too sparse, tSNP efficacy may be overestimated. An existing estimation method based on bootstrapping goes some way to correct for insufficient sample size and overfitting, but does not completely solve the problem. We describe a novel method, based on exclusion of haplotypes, that improves on the bootstrap approach. Using simulated data, the extent of the sample size problem is investigated and the performance of the bootstrap and the novel method are compared. We incorporate an existing method adjusting for marker density by ,SNP-dropping'. We find that insufficient sample size can cause large overestimates in tSNP efficacy, even with as many as 100 individuals, and the problem worsens as the region studied increases in size. Both the bootstrap and novel method correct much of this overestimate, with our novel method consistently outperforming the bootstrap method. We conclude that a combination of insufficient sample size and overfitting may lead to overestimation of tSNP efficacy and underpowering of studies based on tSNPs. Our novel approach corrects for much of this bias and is superior to the previous method. Sample sizes larger than previously suggested may still be required for accurate estimation of tSNP efficacy. This has obvious ramifications for the selection of tSNPs from HapMap data. Claudio Verzilli 1 , Juliet Chapman 1 , Aroon Hingorani 2 , Juan Pablo-Casas 1 , Tina Shah 2 , Liam Smeeth 1 , John Whittaker 124 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, UK 25 Division of Medicine, University College London, UK Keywords: Meta-analysis, Genetic association studies We present a Bayesian hierarchical model for the meta-analysis of candidate gene studies with a continuous outcome. Such studies often report results from association tests for different, possibly study-specific and non-overlapping markers (typically SNPs) in the same genetic region. Meta analyses of the results at each marker in isolation are seldom appropriate as they ignore the correlation that may exist between markers due to linkage disequlibrium (LD) and cannot assess the relative importance of variants at each marker. Also such marker-wise meta analyses are restricted to only those studies that have typed the marker in question, with a potential loss of power. A better strategy is one which incorporates information about the LD between markers so that any combined estimate of the effect of each variant is corrected for the effect of other variants, as in multiple regression. Here we develop a Bayesian hierarchical linear regression that models the observed genotype group means and uses pairwise LD measurements between markers as prior information to make posterior inference on adjusted effects. The approach is applied to the meta analysis of 24 studies assessing the effect of 7 variants in the C-reactive protein (CRP) gene region on plasma CRP levels, an inflammatory biomarker shown in observational studies to be positively associated with cardiovascular disease. Cathryn M. Lewis 1 , Christopher G. Mathew 1 , Theresa M. Marteau 226 Dept. of Medical and Molecular Genetics, King's College London, UK 27 Department of Psychology, King's College London, UK Keywords: Risk, genetics, CARD15, smoking, model Recently progress has been made in identifying mutations that confer susceptibility to complex diseases, with the potential to use these mutations in determining disease risk. We developed methods to estimate disease risk based on genotype relative risks (for a gene G), exposure to an environmental factor (E), and family history (with recurrence risk ,R for a relative of type R). ,R must be partitioned into the risk due to G (which is modelled independently) and the residual risk. The risk model was then applied to Crohn's disease (CD), a severe gastrointestinal disease for which smoking increases disease risk approximately 2-fold, and mutations in CARD15 confer increased risks of 2.25 (for carriers of a single mutation) and 9.3 (for carriers of two mutations). CARD15 accounts for only a small proportion of the genetic component of CD, with a gene-specific ,S, CARD15 of 1.16, from a total sibling relative risk of ,S= 27. CD risks were estimated for high-risk individuals who are siblings of a CD case, and who also smoke. The CD risk to such individuals who carry two CARD15 mutations is approximately 0.34, and for those carrying a single CARD15 mutation the risk is 0.08, compared to a population prevalence of approximately 0.001. These results imply that complex disease genes may be valuable in estimating with greater precision than has hitherto been possible disease risks in specific, easily identified subgroups of the population with a view to prevention. Yurii Aulchenko 128 Department of Epidemiology & Biostatistics, Erasmus Medical Centre Rotterdam, The Netherlands Keywords: Compression, information, bzip2, genome-wide SNP data, statistical genetics With advances in molecular technology, studies accessing millions of genetic polymorphisms in thousands of study subjects will soon become common. Such studies generate large amounts of data, whose effective storage and management is a challenge to the modern statistical genetics. Standard file compression utilities, such as Zip, Gzip and Bzip2, may be helpful to minimise the storage requirements. Less obvious is the fact that the data compression techniques may be also used in the analysis of genetic data. It is known that the efficiency of a particular compression algorithm depends on the probability structure of the data. In this work, we compared different standard and customised tools using the data from human HapMap project. Secondly, we investigate the potential uses of data compression techniques for the analysis of linkage, association and linkage disequilibrium Suzanne Leal 1 , Bingshan Li 129 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA Keywords: Consanguineous pedigrees, missing genotype data Missing genotype data can increase false-positive evidence for linkage when either parametric or nonparametric analysis is carried out ignoring intermarker linkage disequilibrium (LD). Previously it was demonstrated by Huang et al (2005) that no bias occurs in this situation for affected sib-pairs with unrelated parents when either both parents are genotyped or genotype data is available for two additional unaffected siblings when parental genotypes are missing. However, this is not the case for consanguineous pedigrees, where missing genotype data for any pedigree member within a consanguinity loop can increase false-positive evidence of linkage. The false-positive evidence for linkage is further increased when cryptic consanguinity is present. The amount of false-positive evidence for linkage is highly dependent on which family members are genotyped. When parental genotype data is available, the false-positive evidence for linkage is usually not as strong as when parental genotype data is unavailable. Which family members will aid in the reduction of false-positive evidence of linkage is highly dependent on which other family members are genotyped. For a pedigree with an affected proband whose first-cousin parents have been genotyped, further reduction in the false-positive evidence of linkage can be obtained by including genotype data from additional affected siblings of the proband or genotype data from the proband's sibling-grandparents. When parental genotypes are not available, false-positive evidence for linkage can be reduced by including in the analysis genotype data from either unaffected siblings of the proband or the proband's married-in-grandparents. Najaf Amin 1 , Yurii Aulchenko 130 Department of Epidemiology & Biostatistics, Erasmus Medical Centre Rotterdam, The Netherlands Keywords: Genomic Control, pedigree structure, quantitative traits The Genomic Control (GC) method was originally developed to control for population stratification and cryptic relatedness in association studies. This method assumes that the effect of population substructure on the test statistics is essentially constant across the genome, and therefore unassociated markers can be used to estimate the effect of confounding onto the test statistic. The properties of GC method were extensively investigated for different stratification scenarios, and compared to alternative methods, such as the transmission-disequilibrium test. The potential of this method to correct not for occasional cryptic relations, but for regular pedigree structure, however, was not investigated before. In this work we investigate the potential of the GC method for pedigree-based association analysis of quantitative traits. The power and type one error of the method was compared to standard methods, such as the measured genotype (MG) approach and quantitative trait transmission-disequilibrium test. In human pedigrees, with trait heritability varying from 30 to 80%, the power of MG and GC approach was always higher than that of TDT. GC had correct type 1 error and its power was close to that of MG under moderate heritability (30%), but decreased with higher heritability. William Astle 1 , Chris Holmes 2 , David Balding 131 Department of Epidemiology and Public Health, Imperial College London, UK 32 Department of Statistics, University of Oxford, UK Keywords: Population structure, association studies, genetic epidemiology, statistical genetics In the analysis of population association studies, Genomic Control (Devlin & Roeder, 1999) (GC) adjusts the Armitage test statistic to correct the type I error for the effects of population substructure, but its power is often sub-optimal. Turbo Genomic Control (TGC) generalises GC to incorporate co-variation of relatedness and phenotype, retaining control over type I error while improving power. TGC is similar to the method of Yu et al. (2006), but we extend it to binary (case-control) in addition to quantitative phenotypes, we implement improved estimation of relatedness coefficients, and we derive an explicit statistic that generalizes the Armitage test statistic and is fast to compute. TGC also has similarities to EIGENSTRAT (Price et al., 2006) which is a new method based on principle components analysis. The problems of population structure(Clayton et al., 2005) and cryptic relatedness (Voight & Pritchard, 2005) are essentially the same: if patterns of shared ancestry differ between cases and controls, whether distant (coancestry) or recent (cryptic relatedness), false positives can arise and power can be diminished. With large numbers of widely-spaced genetic markers, coancestry can now be measured accurately for each pair of individuals via patterns of allele-sharing. Instead of modelling subpopulations, we work instead with a coancestry coefficient for each pair of individuals in the study. We explain the relationships between TGC, GC and EIGENSTRAT. We present simulation studies and real data analyses to illustrate the power advantage of TGC in a range of scenarios incorporating both substructure and cryptic relatedness. References Clayton, D. G.et al. (2005) Population structure, differential bias and genomic control in a large-scale case-control association study. Nature Genetics37(11) November 2005. Devlin, B. & Roeder, K. (1999) Genomic control for association studies. Biometics55(4) December 1999. Price, A. L.et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics38(8) (August 2006). Voight, B. J. & Pritchard, J. K. (2005) Confounding from cryptic relatedness in case-control association studies. Public Library of Science Genetics1(3) September 2005. Yu, J.et al. (2006) A unified mixed-model method for association mapping that accounts for multiple levels of relatedness. Nature Genetics38(2) February 2006. Hervé Perdry 1 , Marie-Claude Babron 1 , Françoise Clerget-Darpoux 133 INSERM U535 and Univ. Paris Sud, UMR-S 535, Villejuif, France Keywords: Modifier genes, case-parents trios, ordered transmission disequilibrium test A modifying locus is a polymorphic locus, distinct from the disease locus, which leads to differences in the disease phenotype, either by modifying the penetrance of the disease allele, or by modifying the expression of the disease. The effect of such a locus is a clinical heterogeneity that can be reflected by the values of an appropriate covariate, such as the age of onset, or the severity of the disease. We designed the Ordered Transmission Disequilibrium Test (OTDT) to test for a relation between the clinical heterogeneity, expressed by the covariate, and marker genotypes of a candidate gene. The method applies to trio families with one affected child and his parents. Each family member is genotyped at a bi-allelic marker M of a candidate gene. To each of the families is associated a covariate value; the families are ordered on the values of this covariate. As the TDT (Spielman et al. 1993), the OTDT is based on the observation of the transmission rate T of a given allele at M. The OTDT aims to find a critical value of the covariate which separates the sample of families in two subsamples in which the transmission rates are significantly different. We investigate the power of the method by simulations under various genetic models and covariate distributions. Acknowledgments H Perdry is funded by ARSEP. Pascal Croiseau 1 , Heather Cordell 2 , Emmanuelle Génin 134 INSERM U535 and University Paris Sud, UMR-S535, Villejuif, France 35 Institute of Human Genetics, Newcastle University, UK Keywords: Association, missing data, conditionnal logistic regression Missing data is an important problem in association studies. Several methods used to test for association need that individuals be genotyped at the full set of markers. Individuals with missing data need to be excluded from the analysis. This could involve an important decrease in sample size and a loss of information. If the disease susceptibility locus (DSL) is poorly typed, it is also possible that a marker in linkage disequilibrium gives a stronger association signal than the DSL. One may then falsely conclude that the marker is more likely to be the DSL. We recently developed a Multiple Imputation method to infer missing data on case-parent trios Starting from the observed data, a few number of complete data sets are generated by Markov-Chain Monte Carlo approach. These complete datasets are analysed using standard statistical package and the results are combined as described in Little & Rubin (2002). Here we report the results of simulations performed to examine, for different patterns of missing data, how often the true DSL gives the highest association score among different loci in LD. We found that multiple imputation usually correctly detect the DSL site even if the percentage of missing data is high. This is not the case for the naïve approach that consists in discarding trios with missing data. In conclusion, Multiple imputation presents the advantage of being easy to use and flexible and is therefore a promising tool in the search for DSL involved in complex diseases. Salma Kotti 1 , Heike Bickeböller 2 , Françoise Clerget-Darpoux 136 University Paris Sud, UMR-S535, Villejuif, France 37 Department of Genetic Epidemiology, Medical School, University of Göttingen, Germany Keywords: Genotype relative risk, internal controls, Family based analyses Family based analyses using internal controls are very popular both for detecting the effect of a genetic factor and for estimating the relative disease risk on the corresponding genotypes. Two different procedures are often applied to reconstitute internal controls. The first one considers one pseudocontrol genotype formed by the parental non-transmitted alleles called also 1:1 matching of alleles, while the second corresponds to three pseudocontrols corresponding to all genotypes formed by the parental alleles except the one of the case (1:3 matching). Many studies have compared between the two procedures in terms of the power and have concluded that the difference depends on the underlying genetic model and the allele frequencies. However, the estimation of the Genotype Relative Risk (GRR) under the two procedures has not been studied. Based on the fact that on the 1:1 matching, the control group is composed of the alleles untransmitted to the affected child and on the 1:3 matching, the control group is composed amongst alleles already transmitted to the affected child, we expect a difference on the GRR estimation. In fact, we suspect that the second procedure leads to biased estimation of the GRRs. We will analytically derive the GRR estimators for the 1:1 and 1:3 matching and will present the results at the meeting. Family based analyses using internal controls are very popular both for detecting the effect of a genetic factor and for estimating the relative disease risk on the corresponding genotypes. Two different procedures are often applied to reconstitute internal controls. The first one considers one pseudocontrol genotype formed by the parental non-transmitted alleles called also 1:1 matching of alleles, while the second corresponds to three pseudocontrols corresponding to all genotypes formed by the parental alleles except the one of the case (1:3 matching). Many studies have compared between the two procedures in terms of the power and have concluded that the difference depends on the underlying genetic model and the allele frequencies. However, the estimation of the Genotype Relative Risk (GRR) under the two procedures has not been studied. Based on the fact that on the 1:1 matching, the control group is composed of the alleles untransmitted to the affected child and on the 1:3 matching, the control group is composed amongst alleles already transmitted to the affected child, we expect a difference on the GRR estimation. In fact, we suspect that the second procedure leads to biased estimation of the GRR. We will analytically derive the GRR estimator for the 1:1 and 1:3 matching and will present the results at the meeting. Luigi Palla 1 , David Siegmund 239 Department of Mathematics,Free University Amsterdam, The Netherlands 40 Department of Statistics, Stanford University, California, USA Keywords: TDT, assortative mating, inbreeding, statistical power A substantial amount of Assortative Mating (AM) is often recorded on physical and psychological, dichotomous as well as quantitative traits that are supposed to have a multifactorial genetic component. In particular AM has the effect of increasing the genetic variance, even more than inbreeding because it acts across loci beside within loci, when the trait has a multifactorial origin. Under the assumption of a polygenic model for AM dating back to Wright (1921) and refined by Crow and Felsenstein (1968,1982), the effect of assortative mating on the power to detect genetic association in the Transmission Disequilibrium Test (TDT) is explored as parameters, such as the effective number of genes and the allelic frequency vary. The power is reflected by the non centrality parameter of the TDT and is expressed as a function of the number of trios, the relative risk of the heterozygous genotype and the allele frequency (Siegmund and Yakir, 2007). The noncentrality parameter of the relevant score statistic is updated considering the effect of AM which is expressed in terms of an ,effective' inbreeding coefficient. In particular, for dichotomous traits it is apparent that the higher the number of genes involved in the trait, the lower the loss in power due to AM. Finally an attempt is made to extend this relation to the Q-TDT (Rabinowitz, 1997), which involves considering the effect of AM also on the phenotypic variance of the trait of interest, under the assumption that AM affects only its additive genetic component. References Crow, & Felsenstein, (1968). The effect of assortative mating on the genetic composition of a population. Eugen.Quart.15, 87,97. Rabinowitz,, 1997. A Transmission Disequilibrium Test for Quantitative Trait Loci. Human Heredity47, 342,350. Siegmund, & Yakir, (2007) Statistics of gene mapping, Springer. Wright, (1921). System of mating.III. Assortative mating based on somatic resemblance. Genetics6, 144,161. Jérémie Nsengimana 1 , Ben D Brown 2 , Alistair S Hall 2 , Jenny H Barrett 141 Leeds Institute of Molecular Medicine, University of Leeds, UK 42 Leeds Institute for Genetics, Health and Therapeutics, University of Leeds, UK Keywords: Inflammatory genes, haplotype, coronary artery disease Genetic Risk of Acute Coronary Events (GRACE) is an initiative to collect cases of coronary artery disease (CAD) and their unaffected siblings in the UK and to use them to map genetic variants increasing disease risk. The aim of the present study was to test the association between CAD and 51 single nucleotide polymorphisms (SNPs) and their haplotypes from 35 inflammatory genes. Genotype data were available for 1154 persons affected before age 66 (including 48% before age 50) and their 1545 unaffected siblings (891 discordant families). Each SNP was tested for association to CAD, and haplotypes within genes or gene clusters were tested using FBAT (Rabinowitz & Laird, 2000). For the most significant results, genetic effect size was estimated using conditional logistic regression (CLR) within STATA adjusting for other risk factors. Haplotypes were assigned using HAPLORE (Zhang et al., 2005), which considers all parental mating types consistent with offspring genotypes and assigns them a probability of occurence. This probability was used in CLR to weight the haplotypes. In the single SNP analysis, several SNPs showed some evidence for association, including one SNP in the interleukin-1A gene. Analysing haplotypes in the interleukin-1 gene cluster, a common 3-SNP haplotype was found to increase the risk of CAD (P = 0.009). In an additive genetic model adjusting for covariates the odds ratio (OR) for this haplotype is 1.56 (95% CI: 1.16-2.10, p = 0.004) for early-onset CAD (before age 50). This study illustrates the utility of haplotype analysis in family-based association studies to investigate candidate genes. References Rabinowitz, D. & Laird, N. M. (2000) Hum Hered50, 211,223. Zhang, K., Sun, F. & Zhao, H. (2005) Bioinformatics21, 90,103. Andrea Foulkes 1 , Recai Yucel 1 , Xiaohong Li 143 Division of Biostatistics, University of Massachusetts, USA Keywords: Haploytpe, high-dimensional, mixed modeling The explosion of molecular level information coupled with large epidemiological studies presents an exciting opportunity to uncover the genetic underpinnings of complex diseases; however, several analytical challenges remain to be addressed. Characterizing the components to complex diseases inevitably requires consideration of synergies across multiple genetic loci and environmental and demographic factors. In addition, it is critical to capture information on allelic phase, that is whether alleles within a gene are in cis (on the same chromosome) or in trans (on different chromosomes.) In associations studies of unrelated individuals, this alignment of alleles within a chromosomal copy is generally not observed. We address the potential ambiguity in allelic phase in this high dimensional data setting using mixed effects models. Both a semi-parametric and fully likelihood-based approach to estimation are considered to account for missingness in cluster identifiers. In the first case, we apply a multiple imputation procedure coupled with a first stage expectation maximization algorithm for parameter estimation. A bootstrap approach is employed to assess sensitivity to variability induced by parameter estimation. Secondly, a fully likelihood-based approach using an expectation conditional maximization algorithm is described. Notably, these models allow for characterizing high-order gene-gene interactions while providing a flexible statistical framework to account for the confounding or mediating role of person specific covariates. The proposed method is applied to data arising from a cohort of human immunodeficiency virus type-1 (HIV-1) infected individuals at risk for therapy associated dyslipidemia. Simulation studies demonstrate reasonable power and control of family-wise type 1 error rates. Vivien Marquard 1 , Lars Beckmann 1 , Jenny Chang-Claude 144 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany Keywords: Genotyping errors, type I error, haplotype-based association methods It has been shown in several simulation studies that genotyping errors may have a great impact on the type I error of statistical methods used in genetic association analysis of complex diseases. Our aim was to investigate type I error rates in a case-control study, when differential and non-differential genotyping errors were introduced in realistic scenarios. We simulated case-control data sets, where individual genotypes were drawn from a haplotype distribution of 18 haplotypes with 15 markers in the APM1 gene. Genotyping errors were introduced following the unrestricted and symmetric with 0 edges error models described by Heid et al. (2006). In six scenarios, errors resulted from changes of one allele to another with predefined probabilities of 1%, 2.5% or 10%, respectively. A multiple number of errors per haplotype was possible and could vary between 0 and 15, the number of markers investigated. We examined three association methods: Mantel statistics using haplotype-sharing; a haplotype-specific score test; and Armitage trend test for single markers. The type I error rates were not influenced for any of all the three methods for a genotyping error rate of less than 1%. For higher error rates and differential errors, the type I error of the Mantel statistic was only slightly and of the Armitage trend test moderately increased. The type I error rates of the score test were highly increased. The type I error rates were correct for all three methods for non-differential errors. Further investigations will be carried out with different frequencies of differential error rates and focus on power. Arne Neumann 1 , Dörthe Malzahn 1 , Martina Müller 2 , Heike Bickeböller 145 Department of Genetic Epidemiology, Medical School, University of Göttingen, Germany 46 GSF-National Research Center for Environment and Health, Neuherberg & IBE-Institute of Epidemiology, Ludwig-Maximilians University München, Germany Keywords: Interaction, longitudinal, nonparametric Longitudinal data show the time dependent course of phenotypic traits. In this contribution, we consider longitudinal cohort studies and investigate the association between two candidate genes and a dependent quantitative longitudinal phenotype. The set-up defines a factorial design which allows us to test simultaneously for the overall gene effect of the loci as well as for possible gene-gene and gene time interaction. The latter would induce genetically based time-profile differences in the longitudinal phenotype. We adopt a non-parametric statistical test to genetic epidemiological cohort studies and investigate its performance by simulation studies. The statistical test was originally developed for longitudinal clinical studies (Brunner, Munzel, Puri, 1999 J Multivariate Anal 70:286-317). It is non-parametric in the sense that no assumptions are made about the underlying distribution of the quantitative phenotype. Longitudinal observations belonging to the same individual can be arbitrarily dependent on one another for the different time points whereas trait observations of different individuals are independent. The two loci are assumed to be statistically independent. Our simulations show that the nonparametric test is comparable with ANOVA in terms of power of detecting gene-gene and gene-time interaction in an ANOVA favourable setting. Rebecca Hein 1 , Lars Beckmann 1 , Jenny Chang-Claude 147 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany Keywords: Indirect association studies, interaction effects, linkage disequilibrium, marker allele frequency Association studies accounting for gene-environment interactions (GxE) may be useful for detecting genetic effects and identifying important environmental effect modifiers. Current technology facilitates very dense marker spacing in genetic association studies; however, the true disease variant(s) may not be genotyped. In this situation, an association between a gene and a phenotype may still be detectable, using genetic markers associated with the true disease variant(s) (indirect association). Zondervan and Cardon [2004] showed that the odds ratios (OR) of markers which are associated with the disease variant depend highly on the linkage disequilibrium (LD) between the variant and the markers, and whether the allele frequencies match and thereby influence the sample size needed to detect genetic association. We examined the influence of LD and allele frequencies on the sample size needed to detect GxE in indirect association studies, and provide tables for sample size estimation. For discordant allele frequencies and incomplete LD, sample sizes can be unfeasibly large. The influence of both factors is stronger for disease loci with small rather than moderate to high disease allele frequencies. A decline in D' of e.g. 5% has less impact on sample size than increasing the difference in allele frequencies by the same percentage. Assuming 80% power, large interaction effects can be detected using smaller sample sizes than those needed for the detection of main effects. The detection of interaction effects involving rare alleles may not be possible. Focussing only on marker density can be a limited strategy in indirect association studies for GxE. Cyril Dalmasso 1 , Emmanuelle Génin 2 , Catherine Bourgain 2 , Philippe Broët 148 JE 2492 , Univ. Paris-Sud, France 49 INSERM UMR-S 535 and University Paris Sud, Villejuif, France Keywords: Linkage analysis, Multiple testing, False Discovery Rate, Mixture model In the context of genome-wide linkage analyses, where a large number of statistical tests are simultaneously performed, the False Discovery Rate (FDR) that is defined as the expected proportion of false discoveries among all discoveries is nowadays widely used for taking into account the multiple testing problem. Other related criteria have been considered such as the local False Discovery Rate (lFDR) that is a variant of the FDR giving to each test its own measure of significance. The lFDR is defined as the posterior probability that a null hypothesis is true. Most of the proposed methods for estimating the lFDR or the FDR rely on distributional assumption under the null hypothesis. However, in observational studies, the empirical null distribution may be very different from the theoretical one. In this work, we propose a mixture model based approach that provides estimates of the lFDR and the FDR in the context of large-scale variance component linkage analyses. In particular, this approach allows estimating the empirical null distribution, this latter being a key quantity for any simultaneous inference procedure. The proposed method is applied on a real dataset. Arief Gusnanto 1 , Frank Dudbridge 150 MRC Biostatistics Unit, Cambridge UK Keywords: Significance, genome-wide, association, permutation, multiplicity Genome-wide association scans have introduced statistical challenges, mainly in the multiplicity of thousands of tests. The question of what constitutes a significant finding remains somewhat unresolved. Permutation testing is very time-consuming, whereas Bayesian arguments struggle to distinguish direct from indirect association. It seems attractive to summarise the multiplicity in a simple form that allows users to avoid time-consuming permutations. A standard significance level would facilitate reporting of results and reduce the need for permutation tests. This is potentially important because current scans do not have full coverage of the whole genome, and yet, the implicit multiplicity is genome-wide. We discuss some proposed summaries, with reference to the empirical null distribution of the multiple tests, approximated through a large number of random permutations. Using genome-wide data from the Wellcome Trust Case-Control Consortium, we use a sub-sampling approach with increasing density to estimate the nominal p-value to obtain family-wise significance of 5%. The results indicate that the significance level is converging to about 1e-7 as the marker spacing becomes infinitely dense. We considered the concept of an effective number of independent tests, and showed that when used in a Bonferroni correction, the number varies with the overall significance level, but is roughly constant in the region of interest. We compared several estimators of the effective number of tests, and showed that in the region of significance of interest, Patterson's eigenvalue based estimator gives approximately the right family-wise error rate. Michael Nothnagel 1 , Amke Caliebe 1 , Michael Krawczak 151 Institute of Medical Informatics and Statistics, University Clinic Schleswig-Holstein, University of Kiel, Germany Keywords: Association scans, Bayesian framework, posterior odds, genetic risk, multiplicative model Whole-genome association scans have been suggested to be a cost-efficient way to survey genetic variation and to map genetic disease factors. We used a Bayesian framework to investigate the posterior odds of a genuine association under multiplicative disease models. We demonstrate that the p value alone is not a sufficient means to evaluate the findings in association studies. We suggest that likelihood ratios should accompany p values in association reports. We argue, that, given the reported results of whole-genome scans, more associations should have been successfully replicated if the consistently made assumptions about considerable genetic risks were correct. We conclude that it is very likely that the vast majority of relative genetic risks are only of the order of 1.2 or lower. Clive Hoggart 1 , Maria De Iorio 1 , John Whittakker 2 , David Balding 152 Department of Epidemiology and Public Health, Imperial College London, UK 53 Department of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, UK Keywords: Genome-wide association analyses, shrinkage priors, Lasso Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants of small effect, which is a plausible scenario for many complex diseases. Moreover, many simulation studies assume a single causal variant and so more complex realities are ignored. Analysing large numbers of variants simultaneously is now becoming feasible, thanks to developments in Bayesian stochastic search methods. We pose the problem of SNP selection as variable selection in a regression model. In contrast to single SNP tests this approach simultaneously models the effect of all SNPs. SNPs are selected by a Bayesian interpretation of the lasso (Tibshirani, 1996); the maximum a posterior (MAP) estimate of the regression coefficients, which have been given independent, double exponential prior distributions. The double exponential distribution is an example of a shrinkage prior, MAP estimates with shrinkage priors can be zero, thus all SNPs with non zero regression coefficients are selected. In addition to the commonly-used double exponential (Laplace) prior, we also implement the normal exponential gamma prior distribution. We show that use of the Laplace prior improves SNP selection in comparison with single -SNP tests, and that the normal exponential gamma prior leads to a further improvement. Our method is fast and can handle very large numbers of SNPs: we demonstrate its performance using both simulated and real genome-wide data sets with 500 K SNPs, which can be analysed in 2 hours on a desktop workstation. Mickael Guedj 1,2 , Jerome Wojcik 2 , Gregory Nuel 154 Laboratoire Statistique et Génome, Université d'Evry, Evry France 55 Serono Pharmaceutical Research Institute, Plan-les-Ouates, Switzerland Keywords: Local Replication, Local Score, Association In gene-mapping, replication of initial findings has been put forwards as the approach of choice for filtering false-positives from true signals for underlying loci. In practice, such replications are however too poorly observed. Besides the statistical and technical-related factors (lack of power, multiple-testing, stratification, quality control,) inconsistent conclusions obtained from independent populations might result from real biological differences. In particular, the high degree of variation in the strength of LD among populations of different origins is a major challenge to the discovery of genes. Seeking for Local Replications (defined as the presence of a signal of association in a same genomic region among populations) instead of strict replications (same locus, same risk allele) may lead to more reliable results. Recently, a multi-markers approach based on the Local Score statistic has been proposed as a simple and efficient way to select candidate genomic regions at the first stage of genome-wide association studies. Here we propose an extension of this approach adapted to replicated association studies. Based on simulations, this method appears promising. In particular it outperforms classical simple-marker strategies to detect modest-effect genes. Additionally it constitutes, to our knowledge, a first framework dedicated to the detection of such Local Replications. Juliet Chapman 1 , Claudio Verzilli 1 , John Whittaker 156 Department of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, UK Keywords: FDR, Association studies, Bayesian model selection As genomewide association studies become commonplace there is debate as to how such studies might be analysed and what we might hope to gain from the data. It is clear that standard single locus approaches are limited in that they do not adjust for the effects of other loci and problematic since it is not obvious how to adjust for multiple comparisons. False discovery rates have been suggested, but it is unclear how well these will cope with highly correlated genetic data. We consider the validity of standard false discovery rates in large scale association studies. We also show that a Bayesian procedure has advantages in detecting causal loci amongst a large number of dependant SNPs and investigate properties of a Bayesian FDR. Peter Kraft 157 Harvard School of Public Health, Boston USA Keywords: Gene-environment interaction, genome-wide association scans Appropriately analyzed two-stage designs,where a subset of available subjects are genotyped on a genome-wide panel of markers at the first stage and then a much smaller subset of the most promising markers are genotyped on the remaining subjects,can have nearly as much power as a single-stage study where all subjects are genotyped on the genome-wide panel yet can be much less expensive. Typically, the "most promising" markers are selected based on evidence for a marginal association between genotypes and disease. Subsequently, the few markers found to be associated with disease at the end of the second stage are interrogated for evidence of gene-environment interaction, mainly to understand their impact on disease etiology and public health impact. However, this approach may miss variants which have a sizeable effect restricted to one exposure stratum and therefore only a modest marginal effect. We have proposed to use information on the joint effects of genes and a discrete list of environmental exposures at the initial screening stage to select promising markers for the second stage [Kraft et al Hum Hered 2007]. This approach optimizes power to detect variants that have a sizeable marginal effect and variants that have a small marginal effect but a sizeable effect in a stratum defined by an environmental exposure. As an example, I discuss a proposed genome-wide association scan for Type II diabetes susceptibility variants based in several large nested case-control studies. Beate Glaser 1 , Peter Holmans 158 Biostatistics and Bioinformatics Unit, Cardiff University, School of Medicine, Heath Park, Cardiff, UK Keywords: Combined case-control and trios analysis, Power, False-positive rate, Simulation, Association studies The statistical power of genetic association studies can be enhanced by combining the analysis of case-control with parent-offspring trio samples. Various combined analysis techniques have been recently developed; as yet, there have been no comparisons of their power. This work was performed with the aim of identifying the most powerful method among available combined techniques including test statistics developed by Kazeem and Farrall (2005), Nagelkerke and colleagues (2004) and Dudbridge (2006), as well as a simple combination of ,2-statistics from single samples. Simulation studies were performed to investigate their power under different additive, multiplicative, dominant and recessive disease models. False-positive rates were determined by studying the type I error rates under null models including models with unequal allele frequencies between the single case-control and trios samples. We identified three techniques with equivalent power and false-positive rates, which included modifications of the three main approaches: 1) the unmodified combined Odds ratio estimate by Kazeem & Farrall (2005), 2) a modified approach of the combined risk ratio estimate by Nagelkerke & colleagues (2004) and 3) a modified technique for a combined risk ratio estimate by Dudbridge (2006). Our work highlights the importance of studies investigating test performance criteria of novel methods, as they will help users to select the optimal approach within a range of available analysis techniques. David Almorza 1 , M.V. Kandus 2 , Juan Carlos Salerno 2 , Rafael Boggio 359 Facultad de Ciencias del Trabajo, University of Cádiz, Spain 60 Instituto de Genética IGEAF, Buenos Aires, Argentina 61 Universidad Nacional de La Plata, Buenos Aires, Argentina Keywords: Principal component analysis, maize, ear weight, inbred lines The objective of this work was to evaluate the relationship among different traits of the ear of maize inbred lines and to group genotypes according to its performance. Ten inbred lines developed at IGEAF (INTA Castelar) and five public inbred lines as checks were used. A field trial was carried out in Castelar, Buenos Aires (34° 36' S , 58° 39' W) using a complete randomize design with three replications. At harvest, individual weight (P.E.), diameter (D.E.), row number (N.H.) and length (L.E.) of the ear were assessed. A principal component analysis, PCA, (Infostat 2005) was used, and the variability of the data was depicted with a biplot. Principal components 1 and 2 (CP1 and CP2) explained 90% of the data variability. CP1 was correlated with P.E., L.E. and D.E., meanwhile CP2 was correlated with N.H. We found that individual weight (P.E.) was more correlated with diameter of the ear (D.E.) than with length (L.E). Five groups of inbred lines were distinguished: with high P.E. and mean N.H. (04-70, 04-73, 04-101 and MO17), with high P.E. but less N.H. (04-61 and B14), with mean P.E. and N.H. (B73, 04-123 and 04-96), with high N.H. but less P.E. (LP109, 04-8, 04-91 and 04-76) and with low P.E. and low N.H. (LP521 and 04-104). The use of PCA showed which variables had more incidence in ear weight and how is the correlation among them. Moreover, the different groups found with this analysis allow the evaluation of inbred lines by several traits simultaneously. Sven Knüppel 1 , Anja Bauerfeind 1 , Klaus Rohde 162 Department of Bioinformatics, MDC Berlin, Germany Keywords: Haplotypes, association studies, case-control, nuclear families The area of gene chip technology provides a plethora of phase-unknown SNP genotypes in order to find significant association to some genetic trait. To circumvent possibly low information content of a single SNP one groups successive SNPs and estimates haplotypes. Haplotype estimation, however, may reveal ambiguous haplotype pairs and bias the application of statistical methods. Zaykin et al. (Hum Hered, 53:79-91, 2002) proposed the construction of a design matrix to take this ambiguity into account. Here we present a set of functions written for the Statistical package R, which carries out haplotype estimation on the basis of the EM-algorithm for individuals (case-control) or nuclear families. The construction of a design matrix on basis of estimated haplotypes or haplotype pairs allows application of standard methods for association studies (linear, logistic regression), as well as statistical methods as haplotype sharing statistics and TDT-Test. Applications of these methods to genome-wide association screens will be demonstrated. Manuela Zucknick 1 , Chris Holmes 2 , Sylvia Richardson 163 Department of Epidemiology and Public Health, Imperial College London, UK 64 Department of Statistics, Oxford Center for Gene Function, University of Oxford, UK Keywords: Bayesian, variable selection, MCMC, large p, small n, structured dependence In large-scale genomic applications vast numbers of markers or genes are scanned to find a few candidates which are linked to a particular phenotype. Statistically, this is a variable selection problem in the "large p, small n" situation where many more variables than samples are available. An additional feature is the complex dependence structure which is often observed among the markers/genes due to linkage disequilibrium or their joint involvement in biological processes. Bayesian variable selection methods using indicator variables are well suited to the problem. Binary phenotypes like disease status are common and both Bayesian probit and logistic regression can be applied in this context. We argue that logistic regression models are both easier to tune and to interpret than probit models and implement the approach by Holmes & Held (2006). Because the model space is vast, MCMC methods are used as stochastic search algorithms with the aim to quickly find regions of high posterior probability. In a trade-off between fast-updating but slow-moving single-gene Metropolis-Hastings samplers and computationally expensive full Gibbs sampling, we propose to employ the dependence structure among the genes/markers to help decide which variables to update together. Also, parallel tempering methods are used to aid bold moves and help avoid getting trapped in local optima. Mixing and convergence of the resulting Markov chains are evaluated and compared to standard samplers in both a simulation study and in an application to a gene expression data set. Reference Holmes, C. C. & Held, L. (2006) Bayesian auxiliary variable models for binary and multinomial regression. Bayesian Analysis1, 145,168. Dawn Teare 165 MMGE, University of Sheffield, UK Keywords: CNP, family-based analysis, MCMC Evidence is accumulating that segmental copy number polymorphisms (CNPs) may represent a significant portion of human genetic variation. These highly polymorphic systems require handling as phenotypes rather than co-dominant markers, placing new demands on family-based analyses. We present an integrated approach to meet these challenges in the form of a graphical model, where the underlying discrete CNP phenotype is inferred from the (single or replicate) quantitative measure within the analysis, whilst assuming an allele based system segregating through the pedigree. [source] Current state and prospects of macromolecular crystallographyACTA CRYSTALLOGRAPHICA SECTION D, Issue 1 2006Zbigniew Dauter The current situation and possible future development of macromolecular crystallography are reviewed. The rapid progress and maturation of this field in recent years have to a large extent been made possible by the inspiration and generous support of several active structural genomics initiatives. Two tendencies can be currently observed: one which treats protein crystallography as a highly automatic tool for investigating various biological problems without the need to engage in the intricacies of the technique and a second approach where this method is applied to crystals of difficult, large and complex biological systems, requiring a deeper knowledge of various aspects of crystallography. In the near future it is expected that these two trends will coexist, developing in a parallel fashion. [source] Evaluation and treatment of covert stereotypyBEHAVIORAL INTERVENTIONS, Issue 1 2002Joel E. Ringdahl The treatment of behavior maintained by automatic reinforcement (e.g. stereotypy) can present a unique challenge if practitioners cannot control delivery of the maintaining reinforcer. Further, some individuals might engage in stereotypy only when care providers are absent. In the current evaluation, an adolescent boy's hand flapping was demonstrated to occur in the absence of social contingencies and care providers. To reduce the behavior, two treatment strategies were assessed. In the first approach, verbal reminders to refrain from hand flapping were delivered on time-based schedules. In the second approach (differential reinforcement of other behavior, DRO), we provided access to a preferred item contingent on prespecified time lengths with no hand flapping when the participant was alone in a room. Results of the investigation indicated that the verbal reminders were unsuccessful, whereas the DRO program resulted in near-zero levels of stereotypy. Copyright © 2002 John Wiley & Sons, Ltd. [source] Making use of the primary tumourBIOESSAYS, Issue 1 2003Arnold Baars Surgical resection of a primary tumour is often not sufficient to cure a patient. Even when no residual cancer can be detected at time of surgery, metastases may appear in the following years, which indicates that the primary tumour had apparently spread before surgery. Following surgery, systemic chemotherapy may be used to eradicate micro-metastatic disease. Here we present two unconventional strategies that implement new insights into tumour biology and tumour immunology in the treatment of patients with cancer. Both experimental strategies use the individual characteristics of the patient's primary tumour to optimise the control of life-threatening micro-metastases. We aim to modulate the patient's adaptive immune system, targeting it towards the patient's own tumour cells to eradicate residual disease following local treatment. In one approach, this is done by autologous tumour cell vaccinations as adjuvant treatment for colon cancer patients and, in a second approach, by giving chemo-imunotherapy before local treatment to women with locally advanced breast cancer. BioEssays 25:79,86, 2003. © 2002 Wiley Periodicals, Inc. [source] Exact Log-Rank Tests for Unequal Follow-UpBIOMETRICS, Issue 4 2003Georg Heinze Summary. The asymptotic log-rank and generalized Wilcoxon tests are the standard procedures for comparing samples of possibly censored survival times. For comparison of samples of very different sizes, an exact test is available that is based on a complete permutation of log-rank or Wilcoxon scores. While the asymptotic tests do not keep their nominal sizes if sample sizes differ substantially, the exact complete permutation test requires equal follow-up of the samples. Therefore, we have developed and present two new exact tests also suitable for unequal follow-up. The first of these is an exact analogue of the asymptotic log-rank test and conditions on observed risk sets, whereas the second approach permutes survival times while conditioning on the realized follow-up in each group. In an empirical study, we compare the new procedures with the asymptotic log-rank test, the exact complete permutation test, and an earlier proposed approach that equalizes the follow-up distributions using artificial censoring. Results confirm highly satisfactory performance of the exact procedure conditioning on realized follow-up, particularly in case of unequal follow-up. The advantage of this test over other options of analysis is finally exemplified in the analysis of a breast cancer study. [source] Optimization of Cyclodextrin Glycosyltransferase Production from KlebsiellapneumoniaeAS-22 in Batch, Fed-Batch, and Continuous CulturesBIOTECHNOLOGY PROGRESS, Issue 6 2003Bharat N. Gawande Production of a novel cyclodextrin glycosyltransferase (CGTase) from Klebsiella pneumoniaeAS-22 strain, which converts starch predominantly to ,-CD at high conversion yields, in batch, fed-batch, and continuous cultures, is presented. In batch fermentations, optimization of different operating parameters such as temperature, pH, agitation speed, and carbon-source concentration resulted in more than 6-fold increase in CGTase activity. The enzyme production was further improved by two fed-batch approaches. First, using glucose-based feed to increase cell density, followed by starch-based feed to induce enzyme production, resulted in high cell density of 76 g dry cell weight/L, although the CGTase production was low. Using the second approach of a single dextrin-based feed, 20-fold higher CGTase was produced compared to that in batch fermentations with media containing tapioca starch. In continuous operation, more than 8-fold increase in volumetric CGTase productivity was obtained using dextrin-based media compared to that in batch culture using starch-based media. [source] | |||||||||||||||||||||||||||||||