High Correlation (high + correlation)

Distribution by Scientific Domains
Distribution within Medical Sciences

Kinds of High Correlation

  • very high correlation

  • Terms modified by High Correlation

  • high correlation coefficient

  • Selected Abstracts


    Development of an Artificial Lipid-Based Membrane Sensor with High Selectivity and Sensitivity to the Bitterness of Drugs and with High Correlation with Sensory Score

    IEEJ TRANSACTIONS ON ELECTRICAL AND ELECTRONIC ENGINEERING, Issue 6 2009
    Yoshikazu Kobayashi Non-member
    Abstract This paper reports the development of membrane sensors based on an artificial lipid and plasticizers with high selectivity and sensitivity to drug bitterness by using bis(1-butylpentyl) adipate (BBPA), bis(2-ethylhexyl) sebacate (BEHS), phosphoric acid tris(2-ethylhexyl) ester (PTEH), and tributyl o-acetylcitrate (TBAC) as a plasticizer and phosphoric acid di-n-decyl ester (PADE) as an artificial lipid to optimize surface hydrophobicity of the sensors. In addition, a sensor with highly correlated bitterness sensory score was developed by blending BBPA and TBAC to detect the bitterness suppression effect of sucrose, and other bitter-masking materials. Therefore, this sensor can be used to evaluate the bitterness of various drug formulations with high accuracy. Copyright © 2009 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc. [source]


    Perfusional evaluation of postesophagectomy gastroplasty with a radioisotopic study

    DISEASES OF THE ESOPHAGUS, Issue 6 2008
    G. Gabiatti
    SUMMARY., Anastomotic fistula represents one of the frequent causes of postoperative morbidity and mortality following transhiatal esophageal resections. The main etiological factor is the ischemia of the gastric tube created for digestive transit reconstruction. Evidence suggests that per operative hypoperfusion can be maintained or even impaired after the surgery. Several methods have been employed in an attempt to assess the blood perfusion of the gastric flap, but they all pose limitations. However, there is a chronological relationship between perfusion assessments, which are almost exclusively performed per operatively, and the occurrence of a leak, which commonly appears several days after the surgery. The authors have developed a method of gastric perfusion evaluation by single photon emission computed tomography scintigraphy, which corrects that temporal matter, allowing the estimation of postoperative gastric perfusion. It is noninvasive, low cost, and may be applied by the time frame when most fistulas occur. High correlation between the event fistula and the low radiotracer uptake in the group of studied patients could be demonstrated. A role in the research of perfusion evaluation of different types of esophageal reconstruction is suggested. [source]


    STORAGE STABILITY OF STRAWBERRY JAM COLOR ENHANCED WITH BLACK CARROT JUICE CONCENTRATE

    JOURNAL OF FOOD PROCESSING AND PRESERVATION, Issue 5 2007
    EGÜL KIRCA
    ABSTRACT Black carrot juice concentrate was added to enhance the color of strawberry jams prepared from two locally grown cultivars, Osmanl, and Kara. Compared to other cultivars processed to jams, these two cultivars are lightly colored but very aromatic. Color and pigment stability of colored and noncolored (control) strawberry jams were studied during storage. The use of black carrot concentrate as a source of natural colorant stabilized the color of strawberry jam. The stabilization was more noticeable for jams prepared from Osmanl, cultivar. Monomeric anthocyanin degradation was fitted to a first-order reaction model. Storage temperature had a strong influence on anthocyanin degradation. As the storage temperature increased, the stability of anthocyanins decreased significantly in both colored and noncolored jams. Parallel to decrease in monomeric anthocyanins, hue (h°) values of all jam samples increased throughout the storage. However, increase in h° values was much smaller in colored samples than in noncolored samples. High correlation was found between h° value and anthocyanin concentration at 22C (r = 0.910,0.978) and 37C (r = 0.931,0.981). [source]


    Validation of a brief symptom questionnaire (ReQuest in Practice) for patients with gastro-oesophageal reflux disease

    ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 9 2008
    G. RUBIN
    Summary Background, A clinical need exists for a means of assessing symptom control in patients with gastro-oesophageal reflux disease. The ReQuest questionnaire has been extensively validated for symptom assessment in both erosive and non-erosive gastro-oesophageal reflux disease but was designed for research purposes. We derived a shorter version (ReQuest in Practice) that would be more convenient for clinical practice. Aim, To validate ReQuest in Practice in patients suffering from gastro-oesophageal reflux disease. Methods, Multicentre, non-interventional, crossover comparison. Patients completed ReQuest in Practice followed by ReQuest or vice versa. Before and after a planned endoscopy, patients completed the health-related quality of life questionnaire GERDyzer. Internal consistency and the Intraclass Correlation Coefficient were calculated. Construct validity was evaluated by correlation with ReQuest and GERDyzer. Results, There was high internal consistency of ReQuest in Practice (Cronbach's alpha: 0.9) and a high Intraclass Correlation Coefficient of 0.99. The measurement error of ReQuest in Practice was 4.1. High correlation between ReQuest in Practice and ReQuest (Spearman correlation coefficient: 0.9) and GERDyzer (Spearman correlation coefficient: 0.8) demonstrated construct validity. Conclusions, ReQuest in Practice was proven to be valid and reliable. Its close correlation with ReQuest makes it a promising tool to guide the clinical management of patients across the full spectrum of both erosive and non-erosive gastro-oesophageal reflux disease. [source]


    Protein stability indicates divergent evolution of PD-(D/E)XK type II restriction endonucleases

    PROTEIN SCIENCE, Issue 8 2002
    Monika Fuxreiter
    SC, stabilization center; PDB, Protein Data Bank Abstract Type II restriction endonucleases recognize 4,8 base-pair-long DNA sequences and catalyze their cleavage with remarkable specificity. Crystal structures of the PD-(DE)XK superfamily revealed a common ,/, core motif and similar active site. In contrast, these enzymes show little sequence similarity and use different strategies to interact with their substrate DNA. The intriguing question is whether this enzyme family could have evolved from a common origin. In our present work, protein structure stability elements were analyzed and compared in three parts of PD-(DE)XK type II restriction endonucleases: (1) core motif, (2) active-site residues, and (3) residues playing role in DNA recognition. High correlation was found between the active-site residues and those stabilization factors that contribute to preventing structural decay. DNA recognition sites were also observed to participate in stabilization centers. It indicates that recognition motifs and active sites in PD-(DE)XK type II restriction endonucleases should have been evolutionary more conserved than other parts of the structure. Based on this observation it is proposed that PD-(DE)XK type II restriction endonucleases have developed from a common ancestor with divergent evolution. [source]


    Validity and responsiveness of the Osnabrück Hand Eczema Severity Index (OHSI): a methodological study

    BRITISH JOURNAL OF DERMATOLOGY, Issue 1 2009
    M. Dulon
    Summary Background, The Osnabrück Hand Eczema Severity Index (OHSI) is a scoring system for the assessment of the severity of hand eczema (HE). Objective, To assess the clinimetric value of the OHSI and to validate the longitudinal responsiveness of the OHSI using the Manuscore as a gold standard. Methods, OHSI and Manuscore scores were compared before and after 3 weeks' inpatient treatment of 62 patients with occupational HE. Correlation coefficients and 95% limits of agreement were calculated and the ability of OHSI to identify severe HE was analysed. The responsiveness of the OHSI in monitoring skin changes over time was evaluated by calculating effect sizes. Results, High correlation was found between the OHSI and Manuscore at both scoring occasions (around rs = 0·77). Differences between both measurements were within the 95% limits of agreement for 94% of patients, with a tendency for the OHSI to underestimate the severity at very low and at very high values compared with the Manuscore. Responsiveness to change was good. Both instruments showed significant improvement between the scoring occasions. Using the OHSI values, the proportion of classification to the correct tertile of score change was 69%. Effect size from untreated to treated was 0·6 for the Manuscore and 1·1 for the OHSI, with higher effect sizes in individuals with severe HE. Conclusions, Even though the OHSI allows less differentiation than the Manuscore, it shows adequate validity and responsiveness to change. Thus the OHSI is suitable for both monitoring the severity of HE and the effects of treatment. [source]


    Behavioral profile of Alzheimer's disease in Chinese elderly , a validation study of the Chinese version of the Alzheimer's disease behavioral pathology rating scale

    INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 4 2001
    Linda C. W. Lam
    Abstract Objectives This study aims to examine the psychometric properties of the Chinese version of the Alzheimer's disease behavioral pathology rating scale (CBehave-AD) and the behavioral profile of Chinese patients with AD. Methods Seventy-one subjects with NINCDS-ADRDA diagnosis of probable and possible AD were assessed for validation of the CBehave-AD. A behavioral symptom frequency checklist, the Chinese version of the Blessed Roth dementia scale (CDS) and the Cantonese version of the Mini-Mental State Examination (CMMSE) were used for comparison. An extended sample of 120 AD patients was then evaluated with the CBehave-AD. Results High correlations between the CBehave-AD and checklist scores were found (paranoid and delusional ideation, hallucinations, activity disturbances, aggressiveness and diurnal rhythm disturbances). The scale also demonstrated satisfactory inter-rater and test-retest reliabilities. The mean (SD) CMMSE score of the 120 patients was 9.4 (7.1). Among them, 32% have delusions, 15% had hallucinations, 54% had activity disturbances, 61% had aggressive behavior, 44% had sleep disturbance, 24% had affective disturbances, 19% had anxiety and phobias. Delusional ideation was significantly associated with hallucinations, aggressiveness, and affective disturbances. Diurnal rhythm disturbances were associated with activity disturbances and aggressiveness. CBehave-AD total scores were not significantly correlated with severity of AD, but individual symptom categories showed different pattern of correlation. Delusions, hallucinations, anxiety and phobias were significantly correlated with dementia staging. Conclusion The findings suggest that the CBehave-AD is a valid assessment tool for behavioral disturbances in patients with AD. Variable associations between different symptom categories and dementia staging suggest a need for further exploration of the complex interactions between behavioral and cognitive disturbances in dementia. Copyright © 2001 John Wiley & Sons, Ltd. [source]


    Radio-transmitted electromyogram signals as indicators of swimming speed in lake trout and brown trout

    JOURNAL OF FISH BIOLOGY, Issue 3 2000
    E. B. Thorstad
    Swimming speed and average electromyogram (EMG) pulse intervals were highly correlated in individual lake trout Salvelinus namaycush (r2=0·52,0·89) and brown trout Salmo trutta (r2=0·45,0·96). High correlations were found also for pooled data in both lake trout (r2=0·90) and brown trout of the Emå stock (r2=0·96) and Lærdal stock (r2=0·96). The linear relationship between swimming speed and average EMG pulse intervals differed significantly among lake trout and the brown trout stocks. This successful calibration of EMGs to swimming speed opens the possibility of recording swimming speed of free swimming lake trout and brown trout in situ. EMGs can also be calibrated to oxygen consumption to record energy expenditure. [source]


    Nondestructive Assessment of Lipid Oxidation in Minced Poultry Meat by Autofluorescence Spectroscopy

    JOURNAL OF FOOD SCIENCE, Issue 1 2000
    J.P. Wold
    ABSTRACT: To develop a rapid method to assess lipid oxidation, autofluorescence spectra (excitation wavelengths 365, 380, and 400 nm) from large samples (17 cm2) of minced poultry meat were collected by an optical system to determine directly lipid oxidation level. The same samples were also measured by 2-thiobarbituric acid method (TBARS). High correlations could be made between the TBARS method and autofluorescence spectra, especially those from 380 nm excitation. Partial least squares regression resulted in a root mean square error of 0.15 (R = 0.87) for chicken meat and 0.24 (R = 0.80) for mechanically recovered turkey meat. Classification analysis between fresh (TBARS < 0.25) and rancid (TBARS > 0.25) samples was done with high success rates. Autofluorescence spectroscopy might be well suited for rapid on-line determination of lipid oxidation level in minced poultry meat. [source]


    MECHANICAL,ACOUSTIC AND SENSORY EVALUATIONS OF CORNSTARCH,WHEY PROTEIN ISOLATE EXTRUDATES

    JOURNAL OF TEXTURE STUDIES, Issue 4 2007
    E.M. CHENG
    ABSTRACT The mechanism relating sensory perception of brittle food foams to their mechanical and acoustic properties during crushing was investigated. Cornstarch was extruded with four levels of whey protein isolate (0, 6, 12 and 18%) and two levels of in-barrel moisture (23 and 27%). Hardness, fracturability and roughness of mass were three main sensory attributes that varied substantially between products. High correlations (r = 0.841,0.998) were observed between sensory attributes and instrumentally determined mechanical properties, including crushing force (11.2,57.9 N) and crispness work (4.6,75.8 N·mm). Based on acoustic data obtained during instrumental crushing, time-domain signal processing and a novel voice recognition technique utilizing frequency spectrograms were successfully employed for understanding the differences in the sensory properties of various products. Microstructure features, including average cell diameter (1.00,2.94 mm), average wall thickness (0.04,0.27 mm) and cell number density (7,193 cell/cm3), were characterized noninvasively using X-ray microtomography, and proved to be critical in relating sensory perception of the cellular extrudates to their mechanical,acoustic signatures. PRACTICAL APPLICATIONS The sensory perception of crispy and crunchy food products is primarily a function of their mechanical response and emission of sounds during fracture. The current study was focused on understanding these relationships in the context of brittle extruded foods. The mechanical,acoustic techniques outlined in this study have the potential of reducing the time, costs and subjectivity involved in evaluation of new foods by human panels, and can be a useful tool in the overall product development cycle. These techniques need not be limited only to food systems, as properties of any rigid, fracturable material can be characterized based on its mechanical,acoustic signature. [source]


    The intake of dietary fiber from grape seeds modifies the antioxidant status in rat cecum

    JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 11 2005
    Isabel Goñi
    Abstract The aim of this study was to measure the antioxidant activity and polyphenolic compounds in cecum and feces of rats fed with a grape seed concentrate. The grape concentrate was rich in indigestible compounds (dietary fiber, polyphenols and other associated compounds) which presented significant antioxidant activity. Polyphenols extracted by aqueous,organic solvents (extractable polyphenols, EPs) and non-extractable polyphenols (NEPs) exhibited high antioxidant capacity as measured by the ABTS method. High correlations were found between antioxidant capacity values and EP (r2 = 0.9608) and NEP content (r2 = 0.9179). EPs and NEPs exhibited considerable antioxidant activity within the large intestine. Significant antioxidant activity was also found in feces derived from excreted EPs and NEPs. The grape fiber concentrate enhanced the antioxidant status in the large intestine. The antioxidant activity in the intestinal content should be considered when assessing the effects of dietary components on bowel diseases. Copyright © 2005 Society of Chemical Industry [source]


    Pulsed Radiofrequency Ablation for Residual and Phantom Limb Pain: A Case Series

    PAIN PRACTICE, Issue 5 2010
    Matt West MD
    Abstract Residual limb pain (RLP) and phantom limb pain (PLP) can be debilitating and can prevent functional gains following amputation. High correlations have been reported between RLP and the stump neuromas following amputation. Many treatment methods including physical therapy, medications, and interventions, have been used with limited success. Pulsed radiofrequency ablation (PRFA) has shown promise in treating neuropathic pain because of the inhibition of evoked synaptic activity. We present 4 amputees who were treated with PRFA after failing conservative management for their RLP and PLP. All 4 patients underwent PRFA and demonstrated at least 80% relief of RLP for over 6 months. One patient reported a complete resolution of phantom sensation while another patient had significantly decreased frequency of spontaneous PLP and resolution of evoked PLP. In addition, all patients reported improved overall function including increased prosthetic tolerance and decreased oral pain medications. This case series suggests that PRFA is a viable treatment option which might be used for long-term relief of intractable RLP and/or PLP. [source]


    Quantitative-genetic analysis of leaf-rust resistance in seedling and adult-plant stages of inbred lines and their testcrosses in winter rye

    PLANT BREEDING, Issue 6 2002
    T. Miedaner
    Abstract Leaf rust is the most frequent leaf disease of winter rye in Germany. All widely grown population and hybrid varieties are susceptible. This study was undertaken to estimate quantitative-genetic parameters of leaf-rust resistance in self-fertile breeding materials with introgressed foreign leaf-rust resistances and to analyze the relative importance of seedling and adult-plant resistance. Forty-four inbred lines and their corresponding testcrosses with a highly susceptible tester line were grown in a field in four different environments (location-year combinations) with artificial inoculation. Plots were separated by a nonhost to promote autoinfections and minimize interplot interference. Leaf-rust severity was rated on three leaf insertions at three dates. The testcrosses showed a considerably higher disease severity than the lines. High correlations (r , 0.9, P = 0.01) existed among the leaf insertions and the rating dates. Large genotypic variation for resistance was found in both the inbred and testcross populations. Genotype-environment interaction and error variances were of minor importance, thus high entry-mean heritabilities were achieved. A tight correlation between the inbreds and their corresponding testcrosses was found (r = 0.88, P = 0.01). Heterosis for resistance was significant (P = 0.05), but not very important. In a seedling test with 20,30 single-pustule isolates, 34 out of 44 inbreds reacted race-specifically. From the remaining inbred lines, three were medium and seven highly susceptible. In a further greenhouse test with 16 inbreds, seven were susceptible and five were resistant in both seedling and adult-plant stages. The remaining four lines had adult-plant resistance. In conclusion, race-specific leaf-rust resistance can be selected among inbred lines per se. Lines should also be tested in the adult-plant stage. [source]


    European Mathematical Genetics Meeting, Heidelberg, Germany, 12th,13th April 2007

    ANNALS OF HUMAN GENETICS, Issue 4 2007
    Article 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]


    A probabilistic approach for earthquake potential evaluation based on the load/unload response ratio method

    CONCURRENCY AND COMPUTATION: PRACTICE & EXPERIENCE, Issue 12 2010
    Huai-Zhong Yu
    Abstract Previous studies indicate that the occurrence of a large earthquake might be predicted by anomalous temporal increase of the load/unload response ratio (LURR), which was often defined as the ratio of Benioff strain of small earthquakes released during loading and unloading time periods, corresponding to earth tide-induced Coulomb failure stress change on optimally oriented faults. The conventional LURR anomalous evaluation usually sets a critical LURR value, above which an earthquake may occur. In this paper a probabilistic approach for the evaluation of earthquake potential based on the LURR method is developed. In the approach, the occurrence probability of a future earthquake is quantitatively evaluated by assessing the confidence level of LURR anomaly associated with its stochastic distribution. As retrospective studies, we apply the approach to investigate the time series of LURR prior to the 50M>6.3 earthquakes that occurred in the Chinese mainland and the 21M>6.0 earthquakes in southern California over the past 30 years, and find high correlation between the confidence level of the LURR anomalies and the occurrence of the large earthquakes. We then depict all the high peaks that appeared in the LURR time series, and evaluate the earthquake occurrence rate as a function of the confidence level. The research results show considerable promise that our probabilistic approach may provide a useful tool to evaluate quantitatively the occurrence possibilities of future earthquakes. Copyright © 2009 John Wiley & Sons, Ltd. [source]


    Development of the neuromuscular system during asexual propagation in an invertebrate chordate

    DEVELOPMENTAL DYNAMICS, Issue 8 2009
    Stefano Tiozzo
    Abstract Botryllus schlosseri is a colonial ascidian, and the closest relative to vertebrates that can completely regenerate its entire body, including all somatic and germline tissues, using an asexual developmental pathway called blastogenesis. This regenerative potential exhibited by Botryllus and other colonial ascidians does not exist in any other chordate and makes B. schlosseri a promising model to investigate the cellular and molecular basis of regeneration. In this report, we describe postembryonic myogenesis and characterized the development of the neural system during blastogenic development. ,-Tubulin immunoreactivity revealed a high correlation with previous studies on the motor nervous system. The pattern of the serotoninergic system in the adult reflects that observed in solitary ascidians, but in early blastogenesis suggests a morphogenic role of this monoamine. In summary, this study provides the morphological framework to dissect the mechanisms underlying the ability to regenerate entire organ systems as an adult in a chordate model. Developmental Dynamics 238:2081,2094, 2009. © 2009 Wiley-Liss, Inc. [source]


    How persistent are phonological difficulties?

    DYSLEXIA, Issue 1 2006
    A longitudinal study of reading retarded children
    Abstract The present study examined the persistency of phonological deficiencies over time. The participants were 40 pupils in grade 2 with documented reading and writing difficulties and a comparison group of 30 pupils. The participants were followed over a 10-year period by word- and non-word-reading tests and tests of cognitive ability. The persistence of phonological deficits was indicated by a high correlation between non-word-reading tests in grades 3 and 12 in the reading-disabled group. A dyslexia cut-off definition based on phonological ability was the most consistent definition over time compared to a word-decoding definition or multiple cut-off definition based on IQ. Phonological decoding abilities were remarkably stable over time, and non-word-reading was found to be a valid instrument in diagnosing and discerning dyslexia both in children and adults. Copyright © 2005 John Wiley & Sons, Ltd. [source]


    Diastolic Blood Pressure-Estimated Left Ventricular dp/dt

    ECHOCARDIOGRAPHY, Issue 2 2002
    Hüseyin Y, lmaz M.D.
    Background: Peak dp/dt is one of the best isovolumic phase indexes of the myocardial contractile state requiring invasive procedures or presence of mitral regurgitation severe enough to measure in clinical practice by Doppler echocardiography. In this study, we sought the correlation between two noninvasive methods of measurements for left ventricular dp/dt-diastolic blood pressure- (DBP) estimated and continuous-wave Doppler-derived dp/dt-min electrocardiographic/echocardiographic study to emphasize the clinical feasibility of the DBP-estimated method. Method: Thirty-six randomized patients (27 male, 9 female; 58 ± 8 years) with mild mitral regurgitation were enrolled in this study. DBP-estimated dp/dt was calculated from DBP minus the left ventricular end-diastolic pressure (LVEDP) over the isovolumetric contraction time (IVCT). LVEDP was assumed to be 10 mmHg for all patients. Doppler-determined left ventricular dp/dt was derived from the continuous-wave Doppler spectrum of mitral regurgitation jet by dividing the magnitude of the left ventricular atrial pressure gradient rise between 1 mm/sec,3 mm/sec of mitral regurgitant velocity signal by the time taken for this change. Results: Left ventricular dp/dt by Doppler was 1122 ± 303 mmHg/sec and blood pressure-estimated dp/dt was 1063 ± 294 mmHg/sec. There was a high correlation (r = 0.97, P < 0.001) of dp/dt between the two techniques. Conclusions: DBP and IVCT can generate left ventricular dp/dt without invasive procedures, even in the absence of mitral regurgitation in clinical practice. [source]


    Comparative population genetic structures of the fruit fly Urophora cardui and its primary parasitoid Eurytoma robusta

    ENTOMOLOGIA EXPERIMENTALIS ET APPLICATA, Issue 3 2003
    Jes Johannesen
    Abstract The interaction between two species may depend on geographic scale and this in turn can affect co-evolution among them. The present study comparatively examines population genetic structures of the tephritid gall fly Urophora cardui and its primary ectoparasitoid Eurytoma robusta for inference of relative dispersal patterns and host-parasitoid specificity. Genetic differentiation patterns indicated two levels of hierarchical structure in both species: locally similar distance-dependencies but globally differences. Locally, both species showed isolation by distance and a high correlation between host and parasitoid FST for the same population-pairs was found. At the local level, E. robusta populations were most structured. These findings suggest that locally E. robusta is tracking behind its host, U. cardui, and that colonisation of new patches by both species underlie a stepping-stone dispersal process. The investigation as a whole showed that U. cardui populations were hierarchically structured across a genetic-geographical cline. There was no sign of a comparable cline in E. robusta where populations globally became independent of one another and of the host. The different degree of hierarchical genetic structure of the two species suggests that dispersal processes or interactions differ relative to geographical scale and population history. [source]


    Regulating the use of genetic resources , between international authorities

    ENVIRONMENTAL POLICY AND GOVERNANCE, Issue 5 2006
    G. Kristin Rosendal
    Abstract This article examines interaction between multilateral agreements and the assessment of implementation efforts. The first aim is to portray how regulations emanating from different international regimes are developed and implemented in an interdependent manner. The second main theme concerns the assessment of implementation measures in a situation of interaction. The focus here is on the high level of interaction between regulations pertaining to genetic resources and technological utilization of these through bioprospecting. Particular attention is given to where authority stems from in this context of multiple and interacting institutions. What is the most legitimate framework for making authoritative decisions on the use of genetic resources? Empirical evidence suggests a dual development. First, norm diffusion through international institutions increasingly plays a legitimizing role in international transactions with genetic resources. At the same time, there is a high correlation between dominating countries and key economic interests in the global economy of life sciences, and these interests wield their authority and power through a different set of institutions. Copyright © 2006 John Wiley & Sons, Ltd and ERP Environment. [source]


    Comparison of hardness- and chloride-regulated acute effects of sodium sulfate on two freshwater crustaceans

    ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 4 2007
    David John Soucek
    Abstract Based on previous observations that hardness (and potentially chloride) influences sodium sulfate toxicity, the objective of the current study was to quantify the influence of both chloride and water hardness on acute toxicity to Hyalella azteca and Ceriodaphnia dubia. In addition, observed toxicity data from the present study were compared to toxicity predictions by the salinity/toxicity relationship (STR) model. Hardness had a strong influence on sulfate toxicity that was similar for both crustaceans, and nearly identical median lethal concentration (LC50)/hardness slopes were observed for the two species over the tested range. Chloride had a strong but variable influence on sulfate acute toxicity, depending on the species tested and the concentration range. At lower chloride concentrations, LC50s for H. azteca strongly were correlated positively with chloride concentration, although chloride did not affect the toxicity of sodium sulfate to C. dubia. The opposite trend was observed over the higher range of chloride concentrations where there was a negative correlation between chloride concentration and sulfate LC50 for both species. The widely ranging values for both species and a high correlation between LC50s in terms of sulfate and conductivity suggested that, whether based on sulfate, conductivity, or total dissolved solids (TDS), attempts at water quality standard development should incorporate the fact that water quality parameters such as hardness and chloride strongly influence the toxicity of high TDS solutions. The STR model predicted toxicity to C. dubia relatively well when chloride was variable and hardness fixed at approximately 100 mg/L; however, the model did not account for the protective effect of hardness on major ion/TDS toxicity. [source]


    Toxicity assessment of mono-substituted benzenes and phenols using a Pseudomonas initial oxygen uptake assay

    ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2005
    Ded-Shih Huang
    Abstract A methodology is presented for assessing the toxicity of chemical substances through their inhibitory action toward the Pseudomonas initial oxygen uptake (PIOU) rate. The current studies reveal that the PIOU assay is rapid, cost-efficient, and easy to perform. The oxygen uptake rate was found to be associated with a putative benzoate transporter and highly dependent on benzoate concentration. The putative benzoate transporter has been shown to follow Michaelis,Menten kinetics. Most phenols were found to be noncompetitive inhibitors of the benzoate transporter. The inhibition constant (Ki) of these noncompetitive inhibitors can be related to the concentration causing 50% oxygen uptake inhibition in Pseudomonas putida. Modeling these data by using the response,surface approach leads to the development of a quantitative structure,activity relationship (QSAR) for the toxicity of phenols ((1/Ki) = ,0.435 (±0.038) lowest-unoccupied-molecular orbital + 0.517 (±0.027)log KOW ,2.340 (±0.068), n = 49, r2 = 0.930, s = 0.107, r2adj = 0.926, F = 303.1). A comparison of QSAR models derived from the Ki data of the PIOU method and the toxicity data of 40-h Tetrahymena pyrifomis growth inhibition assay (Tetratox) indicated that there was a high correlation between the two approaches (r2 = 0.925). [source]


    Dose,response and time course relationships for vitellogenin induction in male western fence lizards (Sceloporus occidentalis) exposed to ethinylestradiol

    ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2002
    Sandra M. Brasfield
    Abstract The long-term goal of this research is to develop and validate an in vivo reptile model for endocrine-mediated toxicity using fence lizards (Sceloporus spp.). One of the best defined estrogenic responses in oviparous vertebrates is induction of the yolk precursor protein, vitellogenin (Vtg). In this study, dose,response and time course relationships for Vtg induction were determined in male western fence lizards (Sceloporus occidentalis) given intraperitoneal injections of 17,-ethinylestradiol (EE2). Plasma Vtg was quantified directly with an antibody-capture enzyme-linked immunosorbent assay (ELISA) and indirectly using plasma alkalinelabile phosphate (ALP) in order to compare these two methods. Both ELISA and ALP predicted similar median effective dose (ED50 [dose causing a 50% maximal response]) values for plasma Vtg induction (0.167 mg/kg for ELISA and 0.095 mg/kg for ALP). In addition, both ELISA and ALP detected significant Vtg induction at a dose of 0.0003 mg/kg of EE2, which was the lowest dose used in our study. A decrease in body weight at the highest dose (10 mg/kg) and an increase in hepatosomatic index at the four highest doses were observed. Serial dilutions of plasma from an EE2 -exposed male revealed a high correlation between plasma Vtg and ALP determinations in this species. In conclusion, our data show that plasma ALP may be a suitable alternative for measuring plasma Vtg compared with developing a Vtg ELISA in fence lizards exposed to estrogenic compounds. [source]


    Prevalence of various radiographic manifestations of osteochondrosis and their correlations between and within joints in Dutch Warmblood horses

    EQUINE VETERINARY JOURNAL, Issue 1 2009
    E. M. Van Grevenhof
    Summary Reasons for performing study: Osteochondrosis (OC) is the most important orthopaedic developmental disorder in horses and may manifest in several different forms. No detailed study on the prevalence and/or interrelation of these forms is available, even though these data are a prerequisite for conclusive genetic studies. Objectives: To assess the prevalence of the various manifestations of OC as detected radiographically and to evaluate possible relationships between their occurrence within the same joint and between different joints. Methods: The FP (femoropatellar), TC (tarsocrural) and MCP/MTP (metacarpophalangeal/metatarsophalangeal) joints of 811 yearlings selected randomly, descending from 32 representative stallions, were radiographed and scored for the presence and grade of osteochondrotic lesions. Results were compared at the sire, animal, joint and predilection site levels. Results: In the FP joint, the percentage of animals showing normal joint contours in all sites was 60.7%. For the TC joint and the combined MCP/MTP joints, these figures were 68.6 and 64.6%, respectively. For all joints combined, the percentage dropped to 30.5%. Sedation improved detection of OC lesions in the FP joint. There was a high correlation between the right and left joints. The correlation between flattened bone contours and fragments was considerably less. Conclusions: Scoring on a detailed scale is necessary to achieve good insight into the prevalence of OC. Observations on the right and left joints can be combined in further analyses, whereas flattened bone contours and fragments should be evaluated as statistically different disorders. Potential relevance: This study provides insight into the prevalences of various manifestations of OC and their relationships, within and between joints. These results form the basis for detailed quantitative and/or molecular genetic studies that should lead to the establishment of breeding indices and/or genetic marker sets for OC. [source]


    Income Insurance in European Agriculture

    EUROCHOICES, Issue 1 2003
    Miranda P. M. Meuwissen
    Summary Income Insurance in EuropeanAgriculture The agricultural risk environment in Europe is changing, for example because of WTO agreements and governments increasingly withdrawing from disaster assistance in case of catastrophic events. In this context, some form of income insurance may be a useful risk management tool for farmers. Insuring farmers' incomes, however, is rather problematical for reasons of asymmetric information and high correlation of the risks amongst the would-be insured, for example risks due to price fluctuations, floods, droughts and livestock epidemics. It is concluded that the most aggregated forms of income insurance that are likely to be feasible include revenue insurance for field crops, especially if there are relevant futures markets and area yield data, and business interruption insurance for livestock commodities. In Europe, only a few such schemes currendy exist; some are purely private, others are subsidised. A somewhat larger involvement of the public sector, for example through public-private partnerships for reinsurance, could extend the availability of income insurance schemes throughout Europe. Governments, however, should tread warily in entering the field of subsidised agricultural insurance, which experience shows is beset with pitfalls. Pilot tests are useful in establishing the attractiveness of income insurance schemes and other income stabilising tools for the various parties involved. Le contexte du risque agncoie est en train de changer en Europe, en raison notamment des accords de 'OMC et d'un retrait croissant des gouvernements de , assistance sinistre en cas de catastrophes. Dans ce contexte, une certaine forme ? assurance sur le revenu peut être un outil utile de gestion des risques pour les agriculteurs. Assurer les revenus des agriculteurs, cependant, est une activitécute; assez délicate pour des raisons ? information asymétrique et de forte corrélation des risques chez les assurés potentiels, avec , exemple des risques dus aux fluctuations de prix, aux inondations, aux sécheresses et aux épidémies animales. On en conclut que les formes ? assurance revenu les plus complètes et les plus plausibles comprennent ľ assurance-revenu pour les récoltes, notamment s'il existe des marchés a terme appropriés et des données sur le rendement par région, et ,,assurance pour cessation ?'activite pour les produits de ,élevage;. En Europe, seuls quelques projets similaires existent; certains sont purement privés, ? autres sont subventionés. Une implication un peu plus importante du secteur public, par exemple par le biais de partenariats public-privé pour la réassurance, permettrait ?élargir la disponibilité des plans ? assurance-revenu dans toute , Europe. Les gouvernements, cependant, doivent aborder avec prudence le domaine de , assurance agricole subventionée qui, , expérience le montre, est semée ? embûches. Des expériences pilotes sont utiles pour définir , intérêt des projets ? assurance-revenu et des autres outils permettant de stabiliser les revenus pour les différentes parties impliquées. In Europa ändern sich zur Zeit die _ Rahmenbedingungen für die Landwirtschaft hinsichtlich des Risikos. Dies liegt zum Beispiel an WTO-Abkommen und Regierungen, die ihre Hilfsleistungen im Schadensfall zunehmend verweigern. In diesem Zusammenhang könnte irgendeine Form von Einkommenversicherung im Bereich des Risikomanagements für Landwirte von Nutzen sein. Eine solche Versicherung wirft jedoch Probleme auf, da asymmetrische Information und eine hohe Risikokorrelation bei den potenziellen Versicherungsnehmem vorliegen, wie beispielsweise Risiken, die auf Preisschwankungen, Flut- und Dürrekatastrophen oder Tierseuchen beruhen. Hieraus wird gefolgert, dass zu den umfassendsten realisierbaren Formen von Einkommenversicherungen die Erlösversicherung im Ackerbau - insbesondere bei Vorliegen von relevanten Warenterminmärkten und Flächenertragsdaten - und die Betriebsausfallversicherung für tieriscbe Erzeugnisse gehören. In Europa sind zur Zeit nur wenige solcher Programme vorhanden; bei einigen handelt es sich um ausschließlich private Versicherungen, andere werden subventioniert. Würde der öffentliche Sektor stärker mit eingebunden, zum Beispiel mit Hilfe von öffendich-privaten Rückversicherungsgesellschaften, könnten in ganz Europa weitere Programme zur Einkommenversicherung zur Verfügung gestellt werden. Für die Regierungen jedoch ist beim Etablieren subventionierter Versicherungen im Bereich der Landwirtschaft größte Vorsicht geboten, da dies erfahrungs-gemäß Schwierigkeiten aufwirft. Zunächst sollten Pilotprojekte durchgeführt werden, mit deren Hilfe die Attraktivität von Programmen zur Einkommen-aversicherung und von weiteren einkommensstabilisierendenMaßnahmen fÜr die verschiedenen beteiligten Parteien sicher gestellt wird. [source]


    Saliva DHEA and cortisol responses following short-term corticosteroid intake

    EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2010
    L. Jollin
    Eur J Clin Invest 2010; 40 (2): 183,186 Abstract Background, Given the high correlation between the serum and saliva hormone values demonstrated at rest, saliva provides a convenient non-invasive way to determine dehydroepiandrosterone (DHEA) and cortisol concentrations. However, to our knowledge, pituitary adrenal recovery following short-term suppression with corticosteroids has never been investigated in saliva. The aim of this study was therefore to examine how steroid hormone concentrations in saliva are influenced by short-term corticosteroid administration. Materials and methods, We studied saliva DHEA and cortisol concentrations before, during (day 1,day 7) and following (day 8,day 16) the administration of oral therapeutic doses of prednisone (50 mg daily for 1 week) in 11 healthy recreationally trained women. Results, Mean saliva DHEA and cortisol concentrations decreased immediately after the start of prednisone treatment (P < 0·05). Three days after concluding prednisone administration, both saliva DHEA and cortisol had returned to pretreatment levels. Conclusions, These data are consistent with previous studies on blood samples and suggest that non-invasive saliva samples may offer a practical approach to assessing pituitary-adrenal function continuously during and after short-term corticosteroid therapy. [source]


    Upregulation of [3H]methyllycaconitine binding sites following continuous infusion of nicotine, without changes of ,7 or ,6 subunit mRNA: an autoradiography and in situ hybridization study in rat brain

    EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2002
    Manolo Mugnaini
    Abstract It is well established that exposure of experimental animals to nicotine results in upregulation of the ,4,2-subtype of neuronal nicotinic acetylcholine receptors (nAChRs). The aim of this study was to determine the effect of nicotine on the levels of ,7-nAChRs in rat brain, for which only partial information is available. Rats were infused with nicotine (3 mg/kg/day) or saline for 2 weeks and their brains processed for receptor autoradiography with [3H]methyllycaconitine (MLA), a radioligand with nanomolar affinity for ,7-nAChRs. In control rats binding was high in hippocampus, intermediate in cerebral cortex and hypothalamus, and low in striatum, thalamus and cerebellum. There was high correlation between the distribution of [3H]MLA binding sites and ,7 subunit mRNA (r = 0.816). With respect to saline-treated controls, nicotine-treated rats presented higher [3H]nicotine binding in 11 out of 15 brain regions analysed (average increase 46 ± 6%). In contrast, only four regions showed greater [3H]MLA binding, among which the ventral tegmental area (VTA) and cingulate cortex (mean increase 32 ± 3%). No changes in ,7 mRNA levels were observed after nicotine treatment. Similarly, there was no variation of ,6 subunit transcript in the VTA, a region which may contain MLA-sensitive (non-,7)-,6*-nAChRs (Klink et al., 2001). In conclusion, nicotine increased [3H]MLA binding, although to a smaller extent and in a more restricted regional pattern than [3H]nicotine. The enhancement of binding was not paralleled by a significant change of ,7 and ,6 subunit transcription. Finally, the present results provide the first anatomical description of the distribution of [3H]MLA binding sites in rat brain. [source]


    Introduction of a new physiological acoustic electromyogram transmitter

    FISHERIES MANAGEMENT & ECOLOGY, Issue 5-6 2008
    G. LEMBO
    Abstract, Electromyogram (EMG) radio transmitters have proven to be a useful tool to monitor activity levels in free swimming fish. Unfortunately, the availability of the EMG transmitter in only radio mode limited its use to the freshwater environment. Applications in the marine environment are numerous and include monitoring activity levels in both wild and cultured finfish. This study presents preliminary data from trials examining activity levels in free swimming sea bass, Dicentrarchus labrax, L., using an acoustic EMG transmitter. Three adult sea bass were surgically implanted with the newly created prototype EMG transmitters. Signals from the transmitter were calibrated to swimming speed using a Bla,ka-style chamber. Swimming trials showed a high correlation between EMG signal and swimming velocity (r2 = 0.978) and were described using a sigmoid model. No significant differences (P < 0.05) were found among the four swimming trials conducted on the same fish or among the trials of the three different fish, indicating minimum variation from the prototypes tested. [source]


    A field test of imaging properties of rotational invariants of the magnetotelluric impedance tensor

    GEOPHYSICAL PROSPECTING, Issue 3 2005
    László Szarka
    ABSTRACT A part of the Békés Basin (an extensional sub-basin of the Pannonian Basin, where the basement under thick Pannonian sediments is well known from deep boreholes and from seismic measurements, and where many magnetotelluric (MT) soundings have been carried out for frequencies ranging from 1 to 10,3 Hz) was selected as a test area to assess the imaging performances of various apparent-resistivity definitions computed with rotational invariants of either the real part of the complex impedance tensor, or its imaginary part, or both. A comparison (based on earlier 3D numerical studies) has been made between the magnetotelluric images obtained in this way and the depths to the high-resistivity basement, as known from boreholes and seismic investigations. The correlation coefficient between the series of basement depth values at 39 MT sites and the apparent-resistivity values was found to be stronger and high correlation appeared at a shorter period when it was computed with apparent resistivities based on the real tensor rather than with apparent resistivities based on the imaginary tensor. In the light of our studies, ,ReZ and the impedance phase seem to be more informative than any other combination of magnetotelluric interpretation parameters. [source]


    Evaluation of six process-based forest growth models using eddy-covariance measurements of CO2 and H2O fluxes at six forest sites in Europe

    GLOBAL CHANGE BIOLOGY, Issue 3 2002
    K. Kramer
    Abstract Reliable models are required to assess the impacts of climate change on forest ecosystems. Precise and independent data are essential to assess this accuracy. The flux measurements collected by the EUROFLUX project over a wide range of forest types and climatic regions in Europe allow a critical testing of the process-based models which were developed in the LTEEF project. The ECOCRAFT project complements this with a wealth of independent plant physiological measurements. Thus, it was aimed in this study to test six process-based forest growth models against the flux measurements of six European forest types, taking advantage of a large database with plant physiological parameters. The reliability of both the flux data and parameter values itself was not under discussion in this study. The data provided by the researchers of the EUROFLUX sites, possibly with local corrections, were used with a minor gap-filling procedure to avoid the loss of many days with observations. The model performance is discussed based on their accuracy, generality and realism. Accuracy was evaluated based on the goodness-of-fit with observed values of daily net ecosystem exchange, gross primary production and ecosystem respiration (gC m,2 d,1), and transpiration (kg H2O m,2 d,1). Moreover, accuracy was also evaluated based on systematic and unsystematic errors. Generality was characterized by the applicability of the models to different European forest ecosystems. Reality was evaluated by comparing the modelled and observed responses of gross primary production, ecosystem respiration to radiation and temperature. The results indicated that: Accuracy. All models showed similar high correlation with the measured carbon flux data, and also low systematic and unsystematic prediction errors at one or more sites of flux measurements. The results were similar in the case of several models when the water fluxes were considered. Most models fulfilled the criteria of sufficient accuracy for the ability to predict the carbon and water exchange between forests and the atmosphere. Generality. Three models of six could be applied for both deciduous and coniferous forests. Furthermore, four models were applied both for boreal and temperate conditions. However, no severe water-limited conditions were encountered, and no year-to-year variability could be tested. Realism. Most models fulfil the criterion of realism that the relationships between the modelled phenomena (carbon and water exchange) and environment are described causally. Again several of the models were able to reproduce the responses of measurable variables such as gross primary production (GPP), ecosystem respiration and transpiration to environmental driving factors such as radiation and temperature. Stomatal conductance appears to be the most critical process causing differences in predicted fluxes of carbon and water between those models that accurately describe the annual totals of GPP, ecosystem respiration and transpiration. As a conclusion, several process-based models are available that produce accurate estimates of carbon and water fluxes at several forest sites of Europe. This considerable accuracy fulfils one requirement of models to be able to predict the impacts of climate change on the carbon balance of European forests. However, the generality of the models should be further evaluated by expanding the range of testing over both time and space. In addition, differences in behaviour between models at the process level indicate requirement of further model testing, with special emphasis on modelling stomatal conductance realistically. [source]