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Whole Sample (whole + sample)
Selected AbstractsAlcohol, suppressed anger and violenceADDICTION, Issue 9 2010Thor Norström ABSTRACT Aims Is alcohol related causally to violence, and if so, is the effect of drinking contingent on suppressed anger such that it is strongest among individuals who are highly inclined to withhold angry feelings? We addressed these questions by analysing panel data using a method that diminishes the effects of confounding factors. Design We analysed data on heavy episodic drinking and violent behaviour from the second (1994) and third (1999) waves of the Young in Norway Longitudinal Study (n = 2697; response rate: 67%). The first difference method was applied to estimate the association between these behaviours, implying that changes in the frequency of violence were regressed on changes in the frequency of drinking. Hence, the effects of time-invariant confounders were eliminated. Analyses were conducted for the whole sample, and for groups scoring low, medium and high on a short version of the STAXI anger suppression scale. Findings Changes in drinking were related positively and significantly to changes in violent behaviour, but the alcohol effect varied with the level of suppressed anger: it was strongest in the high-anger group (elasticity estimate = 0.053, P = 0.011) and weakest (and insignificant) in the low-anger group (elasticity estimate = 0.004, P = 0.806). Conclusions Alcohol use may be related causally to violence, but the effect of drinking is confined to individuals who are inclined to suppress their angry feelings. [source] Predictors of hangover during a week of heavy drinking on holidayADDICTION, Issue 3 2010Morten Hesse ABSTRACT Aims To investigate predictors of hangover during a week of heavy drinking in young adults. Design Observational prospective study. Methods A total of 112 young Danish tourists were interviewed on three occasions during their holiday. They completed the Acute Hangover Scale and answered questions about their alcohol consumption and rest duration. The incidence of hangover was analysed as the proportion of heavy drinkers (i.e. those reporting drinking more than 12 standard units of alcohol during the night before) scoring above the 90th percentile of light drinkers (i.e. those who had consumed fewer than seven standard units the night before). We estimated the course and predictors of hangover using random effects regression. Results The incidence of hangover was 68% after drinking more than 12 standard units in the whole sample. The severity of hangover increased significantly during a week of heavy drinking and there was a time × number of drinks interaction, indicating that the impact of alcohol consumed on hangover became more pronounced later in the week. Levels of drinking before the holiday did not predict hangover. Conclusions Hangovers after heavy drinking during holidays appear to be related both to amount drunk and time into the holiday. [source] The Effects of Screening and Monitoring on Credit Rationing of SMEsECONOMIC NOTES, Issue 2 2008Mariarosaria Agostino In this paper, we seek to empirically assess which determinants of the capability and incentives of banks to screen and monitor firms are significant in explaining credit rationing to Italian SMEs. After testing for the presence of non-random selection bias and the potential endogeneity of some determinants of interest, the probit model results we obtain suggest that the average banking size and the multiple banking relationship phenomenon are statistically significant factors affecting credit rationing, presumably through their impact on the aforementioned banks' capability and incentives. Other potential determinants of banks' incentives to monitor and screen, such as local banking competition and firm' capacity to collateralize, are never significant. However, when we split the sample according to the level of competition in credit markets, we find that the estimated marginal effects of all significant determinants of interest are larger in absolute value than those obtained when using the whole sample. [source] The impact of physical and sexual abuse on body image in eating disordersEUROPEAN EATING DISORDERS REVIEW, Issue 2 2005Tamás Treuer Abstract Objective The role of childhood sexual abuse as a risk factor for the development of eating disorders has gained considerable attention in the literature in the last few years, especially its role in bulimia nervosa. Although physical abuse was also frequently explored in the history of patients with eating disorders, its role was unclear in the aetiopathogenesis of these disorders. The goal of our study was to test the hypothesis, based on our clinical experience, that physical abuse is more frequent in eating disorders than thought previously and that the patient's distortion in body image is more severe in these cases. Method A standardized interview method was used to elicit details of physical and sexual abuse in a group of 63 patients with eating disorders. The frequency of laxative use and the severity of body image distortion was also examined with the Body Attitude Test. These clinical data were analysed on the whole sample and also on the subgroups of eating disorders. Results We found significantly more severe body image distortions in those patients who had been physically abused (p,<,0.05) and there were significantly more severe body image distortions in those patients who had a history of laxative abuse (p,<,0.001). Sexual abuse occured in 29%, physical abuse in 57% and laxative abuse in 46% within the whole sample of examined eating disorder patients. Physical abuse and laxative abuse were the most frequent in the binge eating/purging type of anorexia nervosa (92% and 69%). Also, these patients had the worse rates on sexual abuse and body image distortion items. According to our results, the presence of sexual abuse was not associated with more severe body image distortion in eating disorder patients. Conclusions Childhood physical abuse seems to be a more important factor in the development of body image distortion than had been thought before; its importance in this aspect may be greater than sexual abuse. Physical abuse, laxative abuse and the binge,purge subtype in anorexia nervosa are a considerable risk factor for the severity of the distortion in body image and their presence makes the prognosis of the eating disorder worse. Further studies of the nature of these relationships are warranted. Copyright © 2005 John Wiley & Sons, Ltd and Eating Disorders Association. [source] The impact of a motivational assessment interview on initial response to treatment in adolescent anorexia nervosaEUROPEAN EATING DISORDERS REVIEW, Issue 2 2004S. G. Gowers Abstract This study was a pilot for a larger study to evaluate a time-limited outpatient programme for adolescent anorexia nervosa, to explore the ability of an assessment interview to change self-reported motivation and ascertain the extent to which this predicted engagement with treatment and early behavioural change. Forty-two adolescents with anorexia nervosa rated their motivation for change before and after attending a new-style assessment interview. Initial (6 week) effectiveness of the programme was evaluated by measuring engagement with treatment, weight change, clinician (HoNOSCA) and self-rated (EDI, MFQ, HoNOSCA-SR) outcome measures, overall and in relation to motivational status. The assessment interview significantly improved motivation. Motivational category after interview was unrelated to physical status, cognition or general functioning but predicted engagement with treatment. Whilst for the whole sample, treatment produced physical, cognitive and general improvements at 6 weeks, motivational status was a powerful predictor of weight gain. A client-centred assessment interview engaged 80% in an outpatient programme based on CBT. Motivational enhancement may improve engagement and specifically result in behavioural change and early weight gain. Copyright © 2004 John Wiley & Sons, Ltd and Eating Disorders Association. [source] Global Techniques for Characterizing Phase Transformations , A Tutorial ReviewADVANCED ENGINEERING MATERIALS, Issue 6 2010Michel Perez To characterize phase transformations, it is necessary to get both local and global information. No experimental technique alone is capable of providing these two types of information. Local techniques are very useful to get information on morphology and chemistry but fail to deal with global information like phase fraction and size distribution since the analyzed volume is very limited. This is why, it is important to use, in parallel, global experimental techniques, that investigate the response of the whole sample to a stimulus (electrical, thermal, mechanical,). The aim of this paper is not to give an exhaustive list of all global experimental techniques, but to focus on a few examples of recent studies dealing with the characterization of phase transformations, namely (i) the measurement of the solubility limit of copper in iron, (ii) the tempering of martensite, (iii) the control of the crystallinity degree of a ultra high molecular weight polyethylene and (iii) a precipitation sequence in aluminum alloys. Along these examples, it will be emphasized that any global technique requires a calibration stage and some modeling to connect the measured signal with the investigated information. [source] Haplotype association analysis for late onset diseases using nuclear family dataGENETIC EPIDEMIOLOGY, Issue 3 2006Chun Li Abstract In haplotype-based association studies for late onset diseases, one attractive design is to use available unaffected spouses as controls (Valle et al. [1998] Diab. Care 21:949,958). Given cases and spouses only, the standard expectation-maximization (EM) algorithm (Dempster et al. [1977] J. R. Stat. Soc. B 39:1,38) for case-control data can be used to estimate haplotype frequencies. But often we will have offspring for at least some of the spouse pairs, and offspring genotypes provide additional information about the haplotypes of the parents. Existing methods may either ignore the offspring information, or reconstruct haplotypes for the subjects using offspring information and discard data from those whose haplotypes cannot be reconstructed with high confidence. Neither of these approaches is efficient, and the latter approach may also be biased. For case-control data with some subjects forming spouse pairs and offspring genotypes available for some spouse pairs or individuals, we propose a unified, likelihood-based method of haplotype inference. The method makes use of available offspring genotype information to apportion ambiguous haplotypes for the subjects. For subjects without offspring genotype information, haplotypes are apportioned as in the standard EM algorithm for case-control data. Our method enables efficient haplotype frequency estimation using an EM algorithm and supports probabilistic haplotype reconstruction with the probability calculated based on the whole sample. We describe likelihood ratio and permutation tests to test for disease-haplotype association, and describe three test statistics that are potentially useful for detecting such an association. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc. [source] Designing sexual health services for young people: a methodology for capturing the user voiceHEALTH & SOCIAL CARE IN THE COMMUNITY, Issue 4 2009Sally Jerome MSc Abstract The aim of the study was to assess the suitability of the Thurstone paired comparison method for capturing the user voice, through a survey of young people's views on the most salient priorities for a sexual health service. A convenience sample of 161 12,24 year olds was used. A psychometrically robust questionnaire was developed from a review of the relevant literature and from the information provided by three focus groups. The data derived from both stages were distilled into seven themes, and adapted to a Thurstone paired comparison format, in which each theme was paired with every other theme, with an 8-point scale between each pairing (21 pairings in total). Respondents were required to indicate their preference for one theme over the other in each pairing. The questionnaire was completed by 161 young people between April and July 2007, and the results were analysed using the Kendall coefficient of concordance to establish the degree of within-group agreement. The results suggested that there was significant agreement as to the essential desirable features of a sexual health service, both within the whole sample as well as within sub-samples (i.e. gender, age group and previous sexual health service use). The priorities were privacy, and a dedicated service close to home, with a drop-in facility and male and female staff being next most important, and an informal service and young staff being lowest priorities. The feedback from the pilot study, the 40% return and absence of spoiled questionnaires together indicated that the respondents found the method acceptable, while the actual findings corroborated those from other studies. Taken together, these results suggest that the Thurstone method offers a quick and simple method of capturing the user voice, with the results having sufficient validity to inform the planning of a local sexual health service. [source] Community mental healthcare in England: associations between service organisation and quality of lifeHEALTH & SOCIAL CARE IN THE COMMUNITY, Issue 6 2002Justine Schneider Abstract The present authors set out to explore the relationship between different forms of service organisation and quality of life (QoL) for service users. Four mental health trusts and their corresponding social services departments were recruited to exemplify: (1) high and low levels of integration between health and social services; and (2) high and low levels of targeting at users with severe mental health problems. The authors used the Lancashire Quality of Life Profile, and chose their sample size to be able to detect a difference of 0.5 in subjective satisfaction scales. Analysis of covariance was used to investigate the simultaneous impact of variables representing user characteristics, objective and subjective QoL, and service organisation. Two hundred and sixty users selected at random from the active caseloads of mental health services in the four districts were interviewed at time 1 and 232 people were interviewed 6 months later (time 2). No bias was detected in the non-respondents at time 2. The authors found few differences between districts. As in other similar studies, QoL seemed to be stable for the whole sample over time. In 6 months, general satisfaction with leisure increased and the number of people who had been in hospital fell. Negative affect score was the only variable found to be associated with subjective QoL, and no predictors of objective QoL were identified. There was some evidence of better objective outcomes for people in receipt of integrated mental health services. They socialised more, and seemed to have less difficulty accessing police and legal services. The results also suggest that interventions targeted at negative affect could have benefits for subjective QoL. [source] Using faecal elastase-1 to screen for chronic pancreatitis in patients admitted with acute pancreatitisHPB, Issue 3 2006R.C. Turner Abstract Background: Patients presenting with acute pancreatitis may have co-existing chronic pancreatitis, the accurate diagnosis of which would potentially guide appropriate management. Gold standard tests are often invasive, costly or time-consuming, but the faecal elastase-1 assay has been shown to be comparatively accurate for moderate and severe exocrine deficiency. This study aimed to evaluate fecal elastase-1 concentration [FE-1] against clinical criteria for chronicity in an acute setting. Patients and methods: [FE-1] was performed on patients admitted with acute onset of epigastric pain and a serum lipase at least three times the upper limit of normal. Clinical diagnosis of chronic pancreatitis was defined by the presence of specific clinical, pathological or radiological criteria. A [FE-1] value of <200 µg/g was similarly considered indicative of chronic exocrine insufficiency. Thus a 2×2 table comparing [FE-1] and clinical diagnosis was constructed. Results: After exclusion of liquid stool specimens, 105 stool specimens from 87 patients were suitable for [FE-1] determination. [FE-1] was evaluated against the clinical diagnosis of chronic pancreatitis, initially for the whole sample, and then after exclusion of cases of moderate and severe acute pancreatitis (Ranson score >2). The latter analysis, based on an exocrine insufficiency threshold of 200 µg/g, yielded a sensitivity of 79.5%, specificity of 98.0%, positive predictive value of 96.9% and negative predictive value of 86.0%. Conclusion: [FE-1] is an accurate screening tool for underlying chronic exocrine insufficiency when taken in the course of a hospital admission for mild acute pancreatitis. [source] Cognitive function, P3a/P3b brain potentials, and cortical thickness in agingHUMAN BRAIN MAPPING, Issue 11 2007Anders M. Fjell Abstract The purpose of the study was to assess the relationship between the P3a/P3b brain potentials, cortical thickness, and cognitive function in aging. Thirty-five younger and 37 older healthy participants completed a visual three-stimuli oddball ERP (event-related potential)-paradigm, a battery of neuropsychological tests, and MRI scans. Groups with short vs. long latency, and low vs. high amplitude, were compared on a point by point basis across the entire cortical mantle. In the young, thickness was only weakly related to P3. In the elderly, P3a amplitude effects were found in parietal areas, the temporoparietal junction, and parts of the posterior cingulate cortex. P3b latency was especially related to cortical thickness in large frontal regions. Path models with the whole sample pooled together were constructed, demonstrating that cortical thickness in the temporoparietal cortex predicted P3a amplitude, which in turn predicted executive function, and that thickness in orbitofrontal cortex predicted P3b latency, which in turn predicted fluid function. When age was included in the model, the relationship between P3 and cognitive function vanished, while the relationship between regional cortical thickness and P3 remained. It is concluded that thickness in specific cortical areas correlates with scalp recorded P3a/P3b in elderly, and that these relationships differentially mediate higher cognitive function. Hum Brain Mapp 2007. © 2007 Wiley-Liss, Inc. [source] Correcting wind-induced bias in solid precipitation measurements in case of limited and uncertain dataHYDROLOGICAL PROCESSES, Issue 17 2008Vincent Fortin Abstract Automatic precipitation gauges tend to underestimate solid precipitation in the presence of wind. Loss as a function of wind speed is typically evaluated by comparing the gauge with a more accurate measurement made using a double-fence intercomparison reference gauge (DFIR). For small precipitation events, small errors in the observations can induce large errors in the ,catch' ratio, i.e. the ratio of the automatic gauge measurement to the DFIR observation. For this reason, precipitation events of less than 3 mm are typically discarded before performing the regression analysis. This can mean discarding more than 90% of the observations. This paper shows how the method of weighted least squares can be used to perform a regression analysis that can take into account the whole sample to provide a more accurate estimation of the relationship between the catch ratio and the wind speed. This methodology is then used to obtain an adjustment curve for a shielded Geonor T-200B precipitation gauge in Northern Québec. Copyright © 2008 John Wiley & Sons, Ltd and Her Majesty the Queen in right of Canada. [source] Families, Not Parents, Differ: Development of Communication in Finnish InfantsINFANCY, Issue 2 2009Maija Haapakoski This longitudinal study on Finnish families was conducted to identify developmental differences in family-level communication among mothers, fathers, and their infants during the second half of the infant's first year, and associations with infants' later language and communicative skills. We examined coregulated communication of parent-infant dyads during 5-min laboratory play sessions at 7 and 11 months. Few differences in mutually regulated communicative exchanges emerged between maternal and paternal dyads, and few developmental changes were found across the whole sample. Families with different communication profiles were identified, and changes rather than stability characterized communicative development at the family level. The family-level differences at 7 months predicted variation in children's language and communicative skills at 14 months. [source] Factors associated with suicidal behaviors in a large French sample of inpatients with eating disordersINTERNATIONAL JOURNAL OF EATING DISORDERS, Issue 7 2007Valérie J. Fedorowicz MDCM Abstract Objective: The objective of the present study was to identify factors associated with suicidal behaviors among patients with eating disorders. Method: A large database including sociodemographic and clinical characteristics of 1,009 consecutive patients hospitalized for an eating disorder in Paris, France, was examined. Data gathered upon admission to hospital were analyzed to identify factors associated with a history of suicide attempt or current suicidal ideation, among the whole sample as well as among each subtype of eating disorder. Results: Among the whole sample, the factor most strongly associated with suicide attempt or suicidal ideation was the diagnostic category, with the highest odds ratio for bulimia nervosa followed by anorexia nervosa of the binging/purging subtype. Among diagnostic subgroups, the strongest factors were drug use, alcohol use, and tobacco use. Conclusion: Suicide risk should be monitored carefully among patients with eating disorders, paying particular attention to combinations of risk factors. © 2007 by Wiley Periodicals, Inc. Int J Eat Disord 2007 [source] The Association Between Heel Ultrasound and Hormone Replacement Therapy Is Modulated by a Two-Locus Vitamin D and Estrogen Receptor GenotypeJOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2000Yves Gigučre Abstract Evidence supports the role of estrogen deprivation in the process of bone remodeling and increased risk of fracture in postmenopausal women but little is known about the genetic basis of individual differences in response to therapy. In a cross-sectional study, 425 ambulatory postmenopausal French-Canadian women from Quebec (age range, 42,85 years old) were genotyped for a common Bsm I polymorphism at the vitamin D receptor (VDR) gene as well as a Pvu II polymorphism in the estrogen receptor (ESR1) gene. Heel ultrasound was determined by right calcaneal quantitative ultrasound (QUS) and results were expressed as an age- and-weight-adjusted stiffness index (heel SI z score). Our aim was to investigate the interaction between hormone-replacement therapy (HRT) and receptor genotypes in an effect on heel SI. Notably, a two-locus genotype (VDR-bb/ESR-PP) present in 9.5% of women was responsible for over 30% of the total HRT-related heel SI difference in the whole sample. Women bearing this combined VDR/ESR1 genotype who received HRT for more than 5 years had a 21% (1.25 SD) greater heel SI (p = 0.002) than those bearing the same genotype but who received HRT for <5 years. This may translate into a 2- to 3-fold difference in the risk of fracture. Although follow-up studies are needed, our findings suggest that QUS of the heel in postmenopausal women taking HRT is affected by variation in VDR and ESR1 loci, jointly. [source] Cultural and practical barriers to seeking mental health treatment for Chinese AmericansJOURNAL OF COMMUNITY PSYCHOLOGY, Issue 1 2004Winnie W. KungArticle first published online: 11 DEC 200 Based on a sample of 1747 from the Chinese American Psychiatric Epidemiological Study, this report examined perceived barriers to mental health treatment. Two factors emerged, namely practical barriers, which included cost of treatment, time, knowledge of access, and language, and cultural barriers consisting of credibility of treatment, recognition of need, and fear of loss of face. Average ratings of all practical barrier items were higher than cultural barrier items, demonstrating the importance of pragmatic considerations for this population. In a novel attempt, this study examined the empirical link between these perceived barriers and actual mental health service use. The practical barrier factor showed significance in predicting service use for both the whole sample and a subsample of individuals with at least one lifetime mental disorder. Cultural barriers, however, did not attain significance. Practice and research implications of the findings are discussed. © 2004 Wiley Periodicals, Inc. J Comm Psychol 32: 27,43, 2004. [source] First experiments on diffraction-enhanced imaging at LNLSJOURNAL OF SYNCHROTRON RADIATION, Issue 6 2003C. Giles Diffraction-enhanced images have been obtained using two silicon crystals in a non-dispersive set-up at the XRD2 beamline at the Brazilian Synchrotron Light Laboratory (LNLS). A first asymmetrically cut silicon crystal using the (333) reflection vertically expanded the monochromated beam from 1,mm to 20,mm allowing the imaging of the whole sample without movements. A symmetrically cut Si(333) second crystal was used as a Bragg analyzer. Images of biological samples including human tissue were recorded using a direct-conversion CCD detector resulting in enhancement of the contrast compared with absorption-contrast images. [source] Psychometric Properties of the Brazilian Version of the Drug Use Screening InventoryALCOHOLISM, Issue 10 2002Denise De Micheli Background Adolescent involvement with alcohol and other drugs is rising in Brazil, and there is an increasing need for psychometrically sound assessment tools to detect early drug involvement. Methods The psychometric properties of the Brazilian version of the Drug Use Screening Inventory (DUSI) were examined in a sample composed of 71 non,drug-dependent adolescents and 142 adolescents who met DSM-III-R criteria for drug dependence. Results With a cutoff score of 13% or lower for the absolute density index of the substance use area, DUSI correctly classified 80% of the drug-dependent adolescents and 90% of the non,drug-dependent adolescents, thus correctly classifying 83.6% of the sample. Factor analysis applied to each of the 10 DUSI areas indicated their unidimensionality, with substantial percentages of variance on the first factor. The Brazilian version of DUSI presented strong internal consistency reliability for the whole sample (drug-dependents and non,drug-dependent adolescents) with an average across all 10 scales for Cronbach's , reliability coefficient of 0.96 (standard deviation = 0.02) and for the split-half reliability coefficient of 0.88 (standard deviation = 0.08). Conclusions These results suggest that the Brazilian version of DUSI preserves its original psychometric properties and is a sensitive and useful screening instrument for drug use. [source] The distant activity of Short Period Comets,, II.MONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 1 2008E. Mazzotta Epifani ABSTRACT The activity of the Short Period Comets (SPCs) at large heliocentric distance (Rh > 3 au) occurs in a region of the Solar system where the water sublimation rate is low and so the sublimation of other volatiles, for example CO or CO2, could drive the presence of a coma. The detection of distant activity in a SPC can therefore give important hints on its composition. Moreover, a complete characterization of the distant SPCs degree of activity is crucial in order to give correct estimates of the nucleus size and to obtain more reliable size-distribution curves of cometary nuclei. The aim of this paper is to present the last results of a program of CCD imaging of distant SPCs, started in 2004 December and concluded with observing runs at the 3.5-m Telescopio Nazionale Galileo at La Palma, in 2005 April, and at the 2.2-m Centro Astronómico Hispano Alemán (CAHA) telescope in Spain, in 2005 May. During the Spring 2005 campaign, 12 SPCs have been targeted in the R band (eight numbered SPCs and four still unnumbered SPCs): 61P/Schajn,Schaldach, 71P/Clark, 98P/Takamizawa, 103P/Hartley 2, 117P/Helin,Roman,Alu 1, 118P/Shoemaker,Levy 4, 121P/Shoemaker,Holt 2, 136P/Mueller 3, P/2002 T5 (LINEAR), P/2003 S1 (NEAT), P/2003 S2 (NEAT), P/2004 DO29 (Spacewatch,LINEAR). The heliocentric distance of the targets was 3.05 ,Rh, 5.30 au. Several levels of activity were detected in the sample, from stellar appearance to well-developed coma and tail. In some cases, the occurrence of cometary activity could be enhanced only with deep visible imaging (e.g. with very long exposure time). For comets with stellar appearance, it was possible to derive a value or a range for the nucleus radius rnucleus (assuming a ,classical' albedo value of 0.04): 98P (rnucleus= 0.43 ± 0.10 km), 136P (rnucleus= 1.2 ± 0.2 km), P/2003 S2 (rnucleus= 0.81 to 1.55 km). For the active comets, we measured dust production levels in terms of Af, quantity, which was 9.9 , Af,, 671 cm. Ensemble properties of the whole sample of the long-term program (a total of 17 SPCs) have been analysed in terms of the relationship among distant activity and dynamical evolution of the targets (in particular, an inward ,jump' of the perihelion distance): we can conclude that, even if there is some theoretical indication that this could occur, the hypothesis of distant activity triggered by a rise in perihelion temperature cannot be univocally invoked for these comets. [source] Radio imaging of the Subaru/XMM,Newton Deep Field , II.MONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 2 2008The 37 brightest radio sources ABSTRACT We study the 37 brightest radio sources in the Subaru/XMM,Newton Deep Field. We have spectroscopic redshifts for 24 of 37 objects and photometric redshifts for the remainder, yielding a median redshift zmed for the whole sample of zmed, 1.1 and a median radio luminosity close to the ,Fanaroff,Riley type I/type II (FR I/FR II)' luminosity divide. Using mid-infrared (mid-IR) (Spitzer MIPS 24 ,m) data we expect to trace nuclear accretion activity, even if it is obscured at optical wavelengths, unless the obscuring column is extreme. Our results suggest that above the FR I/FR II radio luminosity break most of the radio sources are associated with objects that have excess mid-IR emission, only some of which are broad-line objects, although there is one clear low-accretion-rate object with an FR I radio structure. For extended steep-spectrum radio sources, the fraction of objects with mid-IR excess drops dramatically below the FR I/FR II luminosity break, although there exists at least one high-accretion-rate ,radio-quiet' QSO. We have therefore shown that the strong link between radio luminosity (or radio structure) and accretion properties, well known at z, 0.1, persists to z, 1. Investigation of mid-IR and blue excesses shows that they are correlated as predicted by a model in which, when significant accretion exists, a torus of dust absorbs ,30 per cent of the light, and the dust above and below the torus scatters ,1 per cent of the light. [source] Self-rated health status in spinocerebellar ataxia,Results from a European multicenter study,MOVEMENT DISORDERS, Issue 5 2010Tanja Schmitz-Hübsch MD Abstract Patient-based measures of subjective health status are increasingly used as outcome measures in interventional trials. We aimed to determine the variability and predictors of subjective health ratings in a possible target group for future interventions: the spinocerebellar ataxias (SCAs). A consecutive sample of 526 patients with otherwise unexplained progressive ataxia and genetic diagnoses of SCA1 (117), SCA2 (163), SCA3 (139), and SCA6 (107) were enrolled at 18 European referral centers. Subjective health status was assessed with a generic measure of health related quality of life, the EQ-5D (Euroqol) questionnaire. In addition, we performed a neurological examination and a screening questionnaire for affective disorders (patient health questionnaire). Patient-reported health status was compromised in patients of all genotypes (EQ-5D visual analogue scale (EQ-VAS) mean 61.45 ± 20.8). Specifically, problems were reported in the dimensions of mobility (86.9% of patients), usual activities (68%), pain/discomfort (49.4%), depression/anxiety (46.4%), and self care (38.2%). Multivariate analysis revealed three independent predictors of subjective health status: ataxia severity, extent of noncerebellar involvement, and the presence of depressive syndrome. This model explained 30.5% of EQ-VAS variance in the whole sample and might be extrapolated to other SCA genotypes. © 2010 Movement Disorder Society [source] Association between maternal seafood consumption before pregnancy and fetal growth: evidence for an association in overweight women.PAEDIATRIC & PERINATAL EPIDEMIOLOGY, Issue 1 2009The EDEN mother-child cohort Summary Studies in countries with high seafood consumption have shown a benefit on fetal growth and child development. The objective of our study was to determine the association between seafood consumption in French pregnant women and fetal growth. Pregnant women included in the EDEN mother-child cohort study completed two food frequency questionnaires on their usual diet in the year before and during the last 3 months of pregnancy (n = 1805). Fetal circumferences were measured by ultrasound and anthropometry at birth. Variables were compared across tertiles of the mother's seafood consumption using multiple linear regression to adjust for confounding variables. Analyses were stratified by maternal overweight status because of an interaction between maternal seafood consumption and her body mass index (P < 0.01). There was no association between seafood intake and fetal growth in the whole sample of women. For overweight women (n = 464), higher consumption of seafood before pregnancy was associated with higher fetal biparietal and abdominal circumferences and anthropometric measures. From the lowest to the highest tertiles, mean birthweight was 167 g higher (P = 0.002). No significant association was found with consumption at the end of pregnancy. In conclusion, high seafood consumption before pregnancy is positively associated with fetal growth in overweight women. [source] Is dosage of physiotherapy a critical factor in deciding patterns of recovery from stroke: a pragmatic randomized controlled trialPHYSIOTHERAPY RESEARCH INTERNATIONAL, Issue 4 2000Dr Cecily Partridge Abstract Background and Purpose The best treatment and management of stroke patients has been shown to be in stroke units by multidisciplinary rehabilitation teams. Since the composition of stroke units differs it is important to know the extent to which the different components contribute to this result. Physiotherapy is one component of most rehabilitation teams and recent systematic reviews have shown that patients with stroke receiving more physiotherapy achieve more recovery from disability. However, information about the actual amounts of physiotherapy needed to achieve this result is not known. Method A pragmatic, randomized, single-blind, controlled trial comparing recovery from disability in subjects receiving the current standard amount of 30 minutes' physiotherapy with those receiving double that amount (60 minutes). The study included measures of physical performance and function, psychological aspects of anxiety and depression, and perceived control over recovery. Results Some 114 subjects were recruited to the study; full six-week data are available for 104 subjects and six-month data for 93 subjects. Comparison of initial to six-week difference scores in the control and intervention groups of the whole sample did not show a significant difference. Scrutiny of the recovery curves of the whole sample showed that, in half the sample, three distinct patterns of recovery were demonstrated. Conclusion These results suggest that doubling the physiotherapy time available for patients in a stroke unit will not provide a measurable benefit for all patients. The subgroup analysis of patterns of recovery must be regarded as speculative, but provides the basis for hypotheses about those likely to respond well to more intensive therapy. Copyright © 2000 Whurr Publishers Ltd. [source] Effect of water treatment on analyte and matrix ion yields in matrix-assisted time-of-flight secondary ion mass spectrometry: the case of insulin in and on hydroxycinnamic acidRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 21 2002Wilfried Szymczak A systematic study was performed to identify the origin of surprisingly high analyte-to-matrix yield ratios recently observed in time-of-flight secondary ion mass spectrometry (TOF-SIMS) analysis of oligo- and polypeptides mixed in matrices of ,-cyano-4-hydroxycinnamic acid (4HCCA). Several sets of samples of porcine insulin in 4HCCA (1:3100 molar) were prepared from liquid solutions by a nebuliser technique, with more than one order of magnitude variation in sprayed material (substrate silicon). Following different periods of storage in air and/or vacuum as well as exposure to high-purity water, TOF-SIMS analysis was performed under oblique impact of 22 keV SF5+. Treatment with water involved either deposition of a droplet covering the whole sample for times between 1 and 20,min or spraying with water in droplet equivalent quantities. The analyte and matrix molecules were detected as protonated molecules (insulin also in doubly protonated form). Even the as-prepared samples usually showed insulin-to-4HCCA yield ratios exceeding the molar ratio of the mixed material. Upon ageing in vacuum the matrix ion yields remained constant but the analyte yields decreased, partly due to break-up of intrachain disulfide bonds. Water treatment resulted in a pronounced decrease in the 4HCCA yield, typically by a factor of five, in parallel with an increase of the insulin yield, by up to a factor of four. Evidence is provided that these changes occur concurrently with a partial dissolution of 4HCCA at the sample surface. The enhanced insulin yield was not correlated with the Na+ yield. The typically 20-fold increase in the insulin-to-4HCCA yield ratio, generated by water exposure of the samples, provides the explanation for the high yield ratios observed previously with water-treated samples. Spraying with water or repeated exposure to water droplets caused a pronounced degradation of the insulin parent yields in combination with an increasing appearance of signals due to the B- and A-chains of insulin. To clarify the issue of surface segregation, a few samples were prepared by spraying acetone-diluted solutions of insulin on previously deposited layers of 4HCCA. Whereas the insulin yields from as-prepared samples were rather low, the yields observed after water treatment were comparable with those observed with samples of insulin in 4HCCA. The results suggest that a large amount of insulin is present at the surface of samples prepared from liquid mixtures of insulin in 4HCCA. With both methods of sample preparation, however, high secondary ion yields of insulin were only obtained after exposure of the samples to water. The chemical changes responsible for this beneficial effect still need to be identified. Copyright © 2002 John Wiley & Sons, Ltd. [source] Toll-like receptor 4 genetic diversity among pig populationsANIMAL GENETICS, Issue 3 2009S. Palermo Summary The transmembrane glycoprotein encoded by the Toll-like receptor 4 gene (TLR4) acts as the transducing subunit of the lipopolysaccharide receptor complex of mammals, which is a major sensor of infections by Gram-negative bacteria. As variation in TLR4 may alter host immune response to lipopolysaccharide, the association between TLR4 polymorphisms and immune traits of the respiratory and gut systems has important implications for livestock. Here, a sequence dataset from 259 animals belonging to commercial and traditional European pig populations, consisting of 4305 bp of TLR4, including the full transcribed region, a portion of intron 2 and the putative promoter region, was used to explore genetic variation segregating at the TLR4 locus. We identified 34 single nucleotide polymorphisms, 17 in the coding sequence and 17 in the non-coding region. Five non-synonymous mutations clustered within, or in close proximity to, the hypervariable domain of exon 3. In agreement with studies in other mammals, a major exon 3 haplotype segregated at high frequency in the whole sample of 259 pigs, while variants carrying non-synonymous substitutions showed frequencies ranging between 0.6% and 8.7%. Although results on exon 3 provided suggestive evidence for purifying selection occurring at the porcine TLR4 gene, the analysis of both coding and non-coding regions highlighted the fact that demographic factors strongly influence the tests of departure from neutrality. The phylogenetic analysis of TLR4 identified three clusters of variation (ancestral, Asian, European), supporting the evidence of Asian introgression in European main breeds and the well documented history of pig breed domestication previously identified by mtDNA analysis. [source] European Mathematical Genetics Meeting, Heidelberg, Germany, 12th,13th April 2007ANNALS OF HUMAN GENETICS, Issue 4 2007Article first published online: 28 MAY 200 Saurabh Ghosh 11 Indian Statistical Institute, Kolkata, India High correlations between two quantitative traits may be either due to common genetic factors or common environmental factors or a combination of both. In this study, we develop statistical methods to extract the contribution of a common QTL to the total correlation between the components of a bivariate phenotype. Using data on bivariate phenotypes and marker genotypes for sib-pairs, we propose a test for linkage between a common QTL and a marker locus based on the conditional cross-sib trait correlations (trait 1 of sib 1 , trait 2 of sib 2 and conversely) given the identity-by-descent sharing at the marker locus. The null hypothesis cannot be rejected unless there exists a common QTL. We use Monte-Carlo simulations to evaluate the performance of the proposed test under different trait parameters and quantitative trait distributions. An application of the method is illustrated using data on two alcohol-related phenotypes from the Collaborative Study On The Genetics Of Alcoholism project. Rémi Kazma 1 , Catherine Bonaďti-Pellié 1 , Emmanuelle Génin 12 INSERM UMR-S535 and Université Paris Sud, Villejuif, 94817, France Keywords: Gene-environment interaction, sibling recurrence risk, exposure correlation Gene-environment interactions may play important roles in complex disease susceptibility but their detection is often difficult. Here we show how gene-environment interactions can be detected by investigating the degree of familial aggregation according to the exposure of the probands. In case of gene-environment interaction, the distribution of genotypes of affected individuals, and consequently the risk in relatives, depends on their exposure. We developed a test comparing the risks in sibs according to the proband exposure. To evaluate the properties of this new test, we derived the formulas for calculating the expected risks in sibs according to the exposure of probands for various values of exposure frequency, relative risk due to exposure alone, frequencies of latent susceptibility genotypes, genetic relative risks and interaction coefficients. We find that the ratio of risks when the proband is exposed and not exposed is a good indicator of the interaction effect. We evaluate the power of the test for various sample sizes of affected individuals. We conclude that this test is valuable for diseases with moderate familial aggregation, only when the role of the exposure has been clearly evidenced. Since a correlation for exposure among sibs might lead to a difference in risks among sibs in the different proband exposure strata, we also add an exposure correlation coefficient in the model. Interestingly, we find that when this correlation is correctly accounted for, the power of the test is not decreased and might even be significantly increased. Andrea Callegaro 1 , Hans J.C. Van Houwelingen 1 , Jeanine Houwing-Duistermaat 13 Dept. of Medical Statistics and Bioinformatics, Leiden University Medical Center, The Netherlands Keywords: Survival analysis, age at onset, score test, linkage analysis Non parametric linkage (NPL) analysis compares the identical by descent (IBD) sharing in sibling pairs to the expected IBD sharing under the hypothesis of no linkage. Often information is available on the marginal cumulative hazards (for example breast cancer incidence curves). Our aim is to extend the NPL methods by taking into account the age at onset of selected sibling pairs using these known marginal hazards. Li and Zhong (2002) proposed a (retrospective) likelihood ratio test based on an additive frailty model for genetic linkage analysis. From their model we derive a score statistic for selected samples which turns out to be a weighed NPL method. The weights depend on the marginal cumulative hazards and on the frailty parameter. A second approach is based on a simple gamma shared frailty model. Here, we simply test whether the score function of the frailty parameter depends on the excess IBD. We compare the performance of these methods using simulated data. Céline Bellenguez 1 , Carole Ober 2 , Catherine Bourgain 14 INSERM U535 and University Paris Sud, Villejuif, France 5 Department of Human Genetics, The University of Chicago, USA Keywords: Linkage analysis, linkage disequilibrium, high density SNP data Compared with microsatellite markers, high density SNP maps should be more informative for linkage analyses. However, because they are much closer, SNPs present important linkage disequilibrium (LD), which biases classical nonparametric multipoint analyses. This problem is even stronger in population isolates where LD extends over larger regions with a more stochastic pattern. We investigate the issue of linkage analysis with a 500K SNP map in a large and inbred 1840-member Hutterite pedigree, phenotyped for asthma. Using an efficient pedigree breaking strategy, we first identified linked regions with a 5cM microsatellite map, on which we focused to evaluate the SNP map. The only method that models LD in the NPL analysis is limited in both the pedigree size and the number of markers (Abecasis and Wigginton, 2005) and therefore could not be used. Instead, we studied methods that identify sets of SNPs with maximum linkage information content in our pedigree and no LD-driven bias. Both algorithms that directly remove pairs of SNPs in high LD and clustering methods were evaluated. Null simulations were performed to control that Zlr calculated with the SNP sets were not falsely inflated. Preliminary results suggest that although LD is strong in such populations, linkage information content slightly better than that of microsatellite maps can be extracted from dense SNP maps, provided that a careful marker selection is conducted. In particular, we show that the specific LD pattern requires considering LD between a wide range of marker pairs rather than only in predefined blocks. Peter Van Loo 1,2,3 , Stein Aerts 1,2 , Diether Lambrechts 4,5 , Bernard Thienpont 2 , Sunit Maity 4,5 , Bert Coessens 3 , Frederik De Smet 4,5 , Leon-Charles Tranchevent 3 , Bart De Moor 2 , Koen Devriendt 3 , Peter Marynen 1,2 , Bassem Hassan 1,2 , Peter Carmeliet 4,5 , Yves Moreau 36 Department of Molecular and Developmental Genetics, VIB, Belgium 7 Department of Human Genetics, University of Leuven, Belgium 8 Bioinformatics group, Department of Electrical Engineering, University of Leuven, Belgium 9 Department of Transgene Technology and Gene Therapy, VIB, Belgium 10 Center for Transgene Technology and Gene Therapy, University of Leuven, Belgium Keywords: Bioinformatics, gene prioritization, data fusion The identification of genes involved in health and disease remains a formidable challenge. Here, we describe a novel bioinformatics method to prioritize candidate genes underlying pathways or diseases, based on their similarity to genes known to be involved in these processes. It is freely accessible as an interactive software tool, ENDEAVOUR, at http://www.esat.kuleuven.be/endeavour. Unlike previous methods, ENDEAVOUR generates distinct prioritizations from multiple heterogeneous data sources, which are then integrated, or fused, into one global ranking using order statistics. ENDEAVOUR prioritizes candidate genes in a three-step process. First, information about a disease or pathway is gathered from a set of known "training" genes by consulting multiple data sources. Next, the candidate genes are ranked based on similarity with the training properties obtained in the first step, resulting in one prioritized list for each data source. Finally, ENDEAVOUR fuses each of these rankings into a single global ranking, providing an overall prioritization of the candidate genes. Validation of ENDEAVOUR revealed it was able to efficiently prioritize 627 genes in disease data sets and 76 genes in biological pathway sets, identify candidates of 16 mono- or polygenic diseases, and discover regulatory genes of myeloid differentiation. Furthermore, the approach identified YPEL1 as a novel gene involved in craniofacial development from a 2-Mb chromosomal region, deleted in some patients with DiGeorge-like birth defects. Finally, we are currently evaluating a pipeline combining array-CGH, ENDEAVOUR and in vivo validation in zebrafish to identify novel genes involved in congenital heart defects. Mark Broom 1 , Graeme Ruxton 2 , Rebecca Kilner 311 Mathematics Dept., University of Sussex, UK 12 Division of Environmental and Evolutionary Biology, University of Glasgow, UK 13 Department of Zoology, University of Cambridge, UK Keywords: Evolutionarily stable strategy, parasitism, asymmetric game Brood parasites chicks vary in the harm that they do to their companions in the nest. In this presentation we use game-theoretic methods to model this variation. Our model considers hosts which potentially abandon single nestlings and instead choose to re-allocate their reproductive effort to future breeding, irrespective of whether the abandoned chick is the host's young or a brood parasite's. The parasite chick must decide whether or not to kill host young by balancing the benefits from reduced competition in the nest against the risk of desertion by host parents. The model predicts that three different types of evolutionarily stable strategies can exist. (1) Hosts routinely rear depleted broods, the brood parasite always kills host young and the host never then abandons the nest. (2) When adult survival after deserting single offspring is very high, hosts always abandon broods of a single nestling and the parasite never kills host offspring, effectively holding them as hostages to prevent nest desertion. (3) Intermediate strategies, in which parasites sometimes kill their nest-mates and host parents sometimes desert nests that contain only a single chick, can also be evolutionarily stable. We provide quantitative descriptions of how the values given to ecological and behavioral parameters of the host-parasite system influence the likelihood of each strategy and compare our results with real host-brood parasite associations in nature. Martin Harrison 114 Mathematics Dept, University of Sussex, UK Keywords: Brood parasitism, games, host, parasite The interaction between hosts and parasites in bird populations has been studied extensively. Game theoretical methods have been used to model this interaction previously, but this has not been studied extensively taking into account the sequential nature of this game. We consider a model allowing the host and parasite to make a number of decisions, which depend on a number of natural factors. The host lays an egg, a parasite bird will arrive at the nest with a certain probability and then chooses to destroy a number of the host eggs and lay one of it's own. With some destruction occurring, either natural or through the actions of the parasite, the host chooses to continue, eject an egg (hoping to eject the parasite) or abandon the nest. Once the eggs have hatched the game then falls to the parasite chick versus the host. The chick chooses to destroy or eject a number of eggs. The final decision is made by the host, choosing whether to raise or abandon the chicks that are in the nest. We consider various natural parameters and probabilities which influence these decisions. We then use this model to look at real-world situations of the interactions of the Reed Warbler and two different parasites, the Common Cuckoo and the Brown-Headed Cowbird. These two parasites have different methods in the way that they parasitize the nests of their hosts. The hosts in turn have a different reaction to these parasites. Arne Jochens 1 , Amke Caliebe 2 , Uwe Roesler 1 , Michael Krawczak 215 Mathematical Seminar, University of Kiel, Germany 16 Institute of Medical Informatics and Statistics, University of Kiel, Germany Keywords: Stepwise mutation model, microsatellite, recursion equation, temporal behaviour We consider the stepwise mutation model which occurs, e.g., in microsatellite loci. Let X(t,i) denote the allelic state of individual i at time t. We compute expectation, variance and covariance of X(t,i), i=1,,,N, and provide a recursion equation for P(X(t,i)=z). Because the variance of X(t,i) goes to infinity as t grows, for the description of the temporal behaviour, we regard the scaled process X(t,i)-X(t,1). The results furnish a better understanding of the behaviour of the stepwise mutation model and may in future be used to derive tests for neutrality under this model. Paul O'Reilly 1 , Ewan Birney 2 , David Balding 117 Statistical Genetics, Department of Epidemiology and Public Health, Imperial, College London, UK 18 European Bioinformatics Institute, EMBL, Cambridge, UK Keywords: Positive selection, Recombination rate, LD, Genome-wide, Natural Selection In recent years efforts to develop population genetics methods that estimate rates of recombination and levels of natural selection in the human genome have intensified. However, since the two processes have an intimately related impact on genetic variation their inference is vulnerable to confounding. Genomic regions subject to recent selection are likely to have a relatively recent common ancestor and consequently less opportunity for historical recombinations that are detectable in contemporary populations. Here we show that selection can reduce the population-based recombination rate estimate substantially. In genome-wide studies for detecting selection we observe a tendency to highlight loci that are subject to low levels of recombination. We find that the outlier approach commonly adopted in such studies may have low power unless variable recombination is accounted for. We introduce a new genome-wide method for detecting selection that exploits the sensitivity to recent selection of methods for estimating recombination rates, while accounting for variable recombination using pedigree data. Through simulations we demonstrate the high power of the Ped/Pop approach to discriminate between neutral and adaptive evolution, particularly in the context of choosing outliers from a genome-wide distribution. Although methods have been developed showing good power to detect selection ,in action', the corresponding window of opportunity is small. In contrast, the power of the Ped/Pop method is maintained for many generations after the fixation of an advantageous variant Sarah Griffiths 1 , Frank Dudbridge 120 MRC Biostatistics Unit, Cambridge, UK Keywords: Genetic association, multimarker tag, haplotype, likelihood analysis In association studies it is generally too expensive to genotype all variants in all subjects. We can exploit linkage disequilibrium between SNPs to select a subset that captures the variation in a training data set obtained either through direct resequencing or a public resource such as the HapMap. These ,tag SNPs' are then genotyped in the whole sample. Multimarker tagging is a more aggressive adaptation of pairwise tagging that allows for combinations of two or more tag SNPs to predict an untyped SNP. Here we describe a new method for directly testing the association of an untyped SNP using a multimarker tag. Previously, other investigators have suggested testing a specific tag haplotype, or performing a weighted analysis using weights derived from the training data. However these approaches do not properly account for the imperfect correlation between the tag haplotype and the untyped SNP. Here we describe a straightforward approach to testing untyped SNPs using a missing-data likelihood analysis, including the tag markers as nuisance parameters. The training data is stacked on top of the main body of genotype data so there is information on how the tag markers predict the genotype of the untyped SNP. The uncertainty in this prediction is automatically taken into account in the likelihood analysis. This approach yields more power and also a more accurate prediction of the odds ratio of the untyped SNP. Anke Schulz 1 , Christine Fischer 2 , Jenny Chang-Claude 1 , Lars Beckmann 121 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany 22 Institute of Human Genetics, University of Heidelberg, Germany Keywords: Haplotype, haplotype sharing, entropy, Mantel statistics, marker selection We previously introduced a new method to map genes involved in complex diseases, using haplotype sharing-based Mantel statistics to correlate genetic and phenotypic similarity. Although the Mantel statistic is powerful in narrowing down candidate regions, the precise localization of a gene is hampered in genomic regions where linkage disequilibrium is so high that neighboring markers are found to be significant at similar magnitude and we are not able to discriminate between them. Here, we present a new approach to localize susceptibility genes by combining haplotype sharing-based Mantel statistics with an iterative entropy-based marker selection algorithm. For each marker at which the Mantel statistic is evaluated, the algorithm selects a subset of surrounding markers. The subset is chosen to maximize multilocus linkage disequilibrium, which is measured by the normalized entropy difference introduced by Nothnagel et al. (2002). We evaluated the algorithm with respect to type I error and power. Its ability to localize the disease variant was compared to the localization (i) without marker selection and (ii) considering haplotype block structure. Case-control samples were simulated from a set of 18 haplotypes, consisting of 15 SNPs in two haplotype blocks. The new algorithm gave correct type I error and yielded similar power to detect the disease locus compared to the alternative approaches. The neighboring markers were clearly less often significant than the causal locus, and also less often significant compared to the alternative approaches. Thus the new algorithm improved the precision of the localization of susceptibility genes. Mark M. Iles 123 Section of Epidemiology and Biostatistics, LIMM, University of Leeds, UK Keywords: tSNP, tagging, association, HapMap Tagging SNPs (tSNPs) are commonly used to capture genetic diversity cost-effectively. However, it is important that the efficacy of tSNPs is correctly estimated, otherwise coverage may be insufficient. If the pilot sample from which tSNPs are chosen is too small or the initial marker map too sparse, tSNP efficacy may be overestimated. An existing estimation method based on bootstrapping goes some way to correct for insufficient sample size and overfitting, but does not completely solve the problem. We describe a novel method, based on exclusion of haplotypes, that improves on the bootstrap approach. Using simulated data, the extent of the sample size problem is investigated and the performance of the bootstrap and the novel method are compared. We incorporate an existing method adjusting for marker density by ,SNP-dropping'. We find that insufficient sample size can cause large overestimates in tSNP efficacy, even with as many as 100 individuals, and the problem worsens as the region studied increases in size. Both the bootstrap and novel method correct much of this overestimate, with our novel method consistently outperforming the bootstrap method. We conclude that a combination of insufficient sample size and overfitting may lead to overestimation of tSNP efficacy and underpowering of studies based on tSNPs. Our novel approach corrects for much of this bias and is superior to the previous method. Sample sizes larger than previously suggested may still be required for accurate estimation of tSNP efficacy. This has obvious ramifications for the selection of tSNPs from HapMap data. Claudio Verzilli 1 , Juliet Chapman 1 , Aroon Hingorani 2 , Juan Pablo-Casas 1 , Tina Shah 2 , Liam Smeeth 1 , John Whittaker 124 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, UK 25 Division of Medicine, University College London, UK Keywords: Meta-analysis, Genetic association studies We present a Bayesian hierarchical model for the meta-analysis of candidate gene studies with a continuous outcome. Such studies often report results from association tests for different, possibly study-specific and non-overlapping markers (typically SNPs) in the same genetic region. Meta analyses of the results at each marker in isolation are seldom appropriate as they ignore the correlation that may exist between markers due to linkage disequlibrium (LD) and cannot assess the relative importance of variants at each marker. Also such marker-wise meta analyses are restricted to only those studies that have typed the marker in question, with a potential loss of power. A better strategy is one which incorporates information about the LD between markers so that any combined estimate of the effect of each variant is corrected for the effect of other variants, as in multiple regression. Here we develop a Bayesian hierarchical linear regression that models the observed genotype group means and uses pairwise LD measurements between markers as prior information to make posterior inference on adjusted effects. The approach is applied to the meta analysis of 24 studies assessing the effect of 7 variants in the C-reactive protein (CRP) gene region on plasma CRP levels, an inflammatory biomarker shown in observational studies to be positively associated with cardiovascular disease. Cathryn M. Lewis 1 , Christopher G. Mathew 1 , Theresa M. Marteau 226 Dept. of Medical and Molecular Genetics, King's College London, UK 27 Department of Psychology, King's College London, UK Keywords: Risk, genetics, CARD15, smoking, model Recently progress has been made in identifying mutations that confer susceptibility to complex diseases, with the potential to use these mutations in determining disease risk. We developed methods to estimate disease risk based on genotype relative risks (for a gene G), exposure to an environmental factor (E), and family history (with recurrence risk ,R for a relative of type R). ,R must be partitioned into the risk due to G (which is modelled independently) and the residual risk. The risk model was then applied to Crohn's disease (CD), a severe gastrointestinal disease for which smoking increases disease risk approximately 2-fold, and mutations in CARD15 confer increased risks of 2.25 (for carriers of a single mutation) and 9.3 (for carriers of two mutations). CARD15 accounts for only a small proportion of the genetic component of CD, with a gene-specific ,S, CARD15 of 1.16, from a total sibling relative risk of ,S= 27. CD risks were estimated for high-risk individuals who are siblings of a CD case, and who also smoke. The CD risk to such individuals who carry two CARD15 mutations is approximately 0.34, and for those carrying a single CARD15 mutation the risk is 0.08, compared to a population prevalence of approximately 0.001. These results imply that complex disease genes may be valuable in estimating with greater precision than has hitherto been possible disease risks in specific, easily identified subgroups of the population with a view to prevention. Yurii Aulchenko 128 Department of Epidemiology & Biostatistics, Erasmus Medical Centre Rotterdam, The Netherlands Keywords: Compression, information, bzip2, genome-wide SNP data, statistical genetics With advances in molecular technology, studies accessing millions of genetic polymorphisms in thousands of study subjects will soon become common. Such studies generate large amounts of data, whose effective storage and management is a challenge to the modern statistical genetics. Standard file compression utilities, such as Zip, Gzip and Bzip2, may be helpful to minimise the storage requirements. Less obvious is the fact that the data compression techniques may be also used in the analysis of genetic data. It is known that the efficiency of a particular compression algorithm depends on the probability structure of the data. In this work, we compared different standard and customised tools using the data from human HapMap project. Secondly, we investigate the potential uses of data compression techniques for the analysis of linkage, association and linkage disequilibrium Suzanne Leal 1 , Bingshan Li 129 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA Keywords: Consanguineous pedigrees, missing genotype data Missing genotype data can increase false-positive evidence for linkage when either parametric or nonparametric analysis is carried out ignoring intermarker linkage disequilibrium (LD). Previously it was demonstrated by Huang et al (2005) that no bias occurs in this situation for affected sib-pairs with unrelated parents when either both parents are genotyped or genotype data is available for two additional unaffected siblings when parental genotypes are missing. However, this is not the case for consanguineous pedigrees, where missing genotype data for any pedigree member within a consanguinity loop can increase false-positive evidence of linkage. The false-positive evidence for linkage is further increased when cryptic consanguinity is present. The amount of false-positive evidence for linkage is highly dependent on which family members are genotyped. When parental genotype data is available, the false-positive evidence for linkage is usually not as strong as when parental genotype data is unavailable. Which family members will aid in the reduction of false-positive evidence of linkage is highly dependent on which other family members are genotyped. For a pedigree with an affected proband whose first-cousin parents have been genotyped, further reduction in the false-positive evidence of linkage can be obtained by including genotype data from additional affected siblings of the proband or genotype data from the proband's sibling-grandparents. When parental genotypes are not available, false-positive evidence for linkage can be reduced by including in the analysis genotype data from either unaffected siblings of the proband or the proband's married-in-grandparents. Najaf Amin 1 , Yurii Aulchenko 130 Department of Epidemiology & Biostatistics, Erasmus Medical Centre Rotterdam, The Netherlands Keywords: Genomic Control, pedigree structure, quantitative traits The Genomic Control (GC) method was originally developed to control for population stratification and cryptic relatedness in association studies. This method assumes that the effect of population substructure on the test statistics is essentially constant across the genome, and therefore unassociated markers can be used to estimate the effect of confounding onto the test statistic. The properties of GC method were extensively investigated for different stratification scenarios, and compared to alternative methods, such as the transmission-disequilibrium test. The potential of this method to correct not for occasional cryptic relations, but for regular pedigree structure, however, was not investigated before. In this work we investigate the potential of the GC method for pedigree-based association analysis of quantitative traits. The power and type one error of the method was compared to standard methods, such as the measured genotype (MG) approach and quantitative trait transmission-disequilibrium test. In human pedigrees, with trait heritability varying from 30 to 80%, the power of MG and GC approach was always higher than that of TDT. GC had correct type 1 error and its power was close to that of MG under moderate heritability (30%), but decreased with higher heritability. William Astle 1 , Chris Holmes 2 , David Balding 131 Department of Epidemiology and Public Health, Imperial College London, UK 32 Department of Statistics, University of Oxford, UK Keywords: Population structure, association studies, genetic epidemiology, statistical genetics In the analysis of population association studies, Genomic Control (Devlin & Roeder, 1999) (GC) adjusts the Armitage test statistic to correct the type I error for the effects of population substructure, but its power is often sub-optimal. Turbo Genomic Control (TGC) generalises GC to incorporate co-variation of relatedness and phenotype, retaining control over type I error while improving power. TGC is similar to the method of Yu et al. (2006), but we extend it to binary (case-control) in addition to quantitative phenotypes, we implement improved estimation of relatedness coefficients, and we derive an explicit statistic that generalizes the Armitage test statistic and is fast to compute. TGC also has similarities to EIGENSTRAT (Price et al., 2006) which is a new method based on principle components analysis. The problems of population structure(Clayton et al., 2005) and cryptic relatedness (Voight & Pritchard, 2005) are essentially the same: if patterns of shared ancestry differ between cases and controls, whether distant (coancestry) or recent (cryptic relatedness), false positives can arise and power can be diminished. With large numbers of widely-spaced genetic markers, coancestry can now be measured accurately for each pair of individuals via patterns of allele-sharing. Instead of modelling subpopulations, we work instead with a coancestry coefficient for each pair of individuals in the study. We explain the relationships between TGC, GC and EIGENSTRAT. We present simulation studies and real data analyses to illustrate the power advantage of TGC in a range of scenarios incorporating both substructure and cryptic relatedness. References Clayton, D. G.et al. (2005) Population structure, differential bias and genomic control in a large-scale case-control association study. Nature Genetics37(11) November 2005. Devlin, B. & Roeder, K. (1999) Genomic control for association studies. Biometics55(4) December 1999. Price, A. L.et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics38(8) (August 2006). Voight, B. J. & Pritchard, J. K. (2005) Confounding from cryptic relatedness in case-control association studies. Public Library of Science Genetics1(3) September 2005. Yu, J.et al. (2006) A unified mixed-model method for association mapping that accounts for multiple levels of relatedness. Nature Genetics38(2) February 2006. Hervé Perdry 1 , Marie-Claude Babron 1 , Françoise Clerget-Darpoux 133 INSERM U535 and Univ. Paris Sud, UMR-S 535, Villejuif, France Keywords: Modifier genes, case-parents trios, ordered transmission disequilibrium test A modifying locus is a polymorphic locus, distinct from the disease locus, which leads to differences in the disease phenotype, either by modifying the penetrance of the disease allele, or by modifying the expression of the disease. The effect of such a locus is a clinical heterogeneity that can be reflected by the values of an appropriate covariate, such as the age of onset, or the severity of the disease. We designed the Ordered Transmission Disequilibrium Test (OTDT) to test for a relation between the clinical heterogeneity, expressed by the covariate, and marker genotypes of a candidate gene. The method applies to trio families with one affected child and his parents. Each family member is genotyped at a bi-allelic marker M of a candidate gene. To each of the families is associated a covariate value; the families are ordered on the values of this covariate. As the TDT (Spielman et al. 1993), the OTDT is based on the observation of the transmission rate T of a given allele at M. The OTDT aims to find a critical value of the covariate which separates the sample of families in two subsamples in which the transmission rates are significantly different. We investigate the power of the method by simulations under various genetic models and covariate distributions. Acknowledgments H Perdry is funded by ARSEP. Pascal Croiseau 1 , Heather Cordell 2 , Emmanuelle Génin 134 INSERM U535 and University Paris Sud, UMR-S535, Villejuif, France 35 Institute of Human Genetics, Newcastle University, UK Keywords: Association, missing data, conditionnal logistic regression Missing data is an important problem in association studies. Several methods used to test for association need that individuals be genotyped at the full set of markers. Individuals with missing data need to be excluded from the analysis. This could involve an important decrease in sample size and a loss of information. If the disease susceptibility locus (DSL) is poorly typed, it is also possible that a marker in linkage disequilibrium gives a stronger association signal than the DSL. One may then falsely conclude that the marker is more likely to be the DSL. We recently developed a Multiple Imputation method to infer missing data on case-parent trios Starting from the observed data, a few number of complete data sets are generated by Markov-Chain Monte Carlo approach. These complete datasets are analysed using standard statistical package and the results are combined as described in Little & Rubin (2002). Here we report the results of simulations performed to examine, for different patterns of missing data, how often the true DSL gives the highest association score among different loci in LD. We found that multiple imputation usually correctly detect the DSL site even if the percentage of missing data is high. This is not the case for the naďve approach that consists in discarding trios with missing data. In conclusion, Multiple imputation presents the advantage of being easy to use and flexible and is therefore a promising tool in the search for DSL involved in complex diseases. Salma Kotti 1 , Heike Bickeböller 2 , Françoise Clerget-Darpoux 136 University Paris Sud, UMR-S535, Villejuif, France 37 Department of Genetic Epidemiology, Medical School, University of Göttingen, Germany Keywords: Genotype relative risk, internal controls, Family based analyses Family based analyses using internal controls are very popular both for detecting the effect of a genetic factor and for estimating the relative disease risk on the corresponding genotypes. Two different procedures are often applied to reconstitute internal controls. The first one considers one pseudocontrol genotype formed by the parental non-transmitted alleles called also 1:1 matching of alleles, while the second corresponds to three pseudocontrols corresponding to all genotypes formed by the parental alleles except the one of the case (1:3 matching). Many studies have compared between the two procedures in terms of the power and have concluded that the difference depends on the underlying genetic model and the allele frequencies. However, the estimation of the Genotype Relative Risk (GRR) under the two procedures has not been studied. Based on the fact that on the 1:1 matching, the control group is composed of the alleles untransmitted to the affected child and on the 1:3 matching, the control group is composed amongst alleles already transmitted to the affected child, we expect a difference on the GRR estimation. In fact, we suspect that the second procedure leads to biased estimation of the GRRs. We will analytically derive the GRR estimators for the 1:1 and 1:3 matching and will present the results at the meeting. Family based analyses using internal controls are very popular both for detecting the effect of a genetic factor and for estimating the relative disease risk on the corresponding genotypes. Two different procedures are often applied to reconstitute internal controls. The first one considers one pseudocontrol genotype formed by the parental non-transmitted alleles called also 1:1 matching of alleles, while the second corresponds to three pseudocontrols corresponding to all genotypes formed by the parental alleles except the one of the case (1:3 matching). Many studies have compared between the two procedures in terms of the power and have concluded that the difference depends on the underlying genetic model and the allele frequencies. However, the estimation of the Genotype Relative Risk (GRR) under the two procedures has not been studied. Based on the fact that on the 1:1 matching, the control group is composed of the alleles untransmitted to the affected child and on the 1:3 matching, the control group is composed amongst alleles already transmitted to the affected child, we expect a difference on the GRR estimation. In fact, we suspect that the second procedure leads to biased estimation of the GRR. We will analytically derive the GRR estimator for the 1:1 and 1:3 matching and will present the results at the meeting. Luigi Palla 1 , David Siegmund 239 Department of Mathematics,Free University Amsterdam, The Netherlands 40 Department of Statistics, Stanford University, California, USA Keywords: TDT, assortative mating, inbreeding, statistical power A substantial amount of Assortative Mating (AM) is often recorded on physical and psychological, dichotomous as well as quantitative traits that are supposed to have a multifactorial genetic component. In particular AM has the effect of increasing the genetic variance, even more than inbreeding because it acts across loci beside within loci, when the trait has a multifactorial origin. Under the assumption of a polygenic model for AM dating back to Wright (1921) and refined by Crow and Felsenstein (1968,1982), the effect of assortative mating on the power to detect genetic association in the Transmission Disequilibrium Test (TDT) is explored as parameters, such as the effective number of genes and the allelic frequency vary. The power is reflected by the non centrality parameter of the TDT and is expressed as a function of the number of trios, the relative risk of the heterozygous genotype and the allele frequency (Siegmund and Yakir, 2007). The noncentrality parameter of the relevant score statistic is updated considering the effect of AM which is expressed in terms of an ,effective' inbreeding coefficient. In particular, for dichotomous traits it is apparent that the higher the number of genes involved in the trait, the lower the loss in power due to AM. Finally an attempt is made to extend this relation to the Q-TDT (Rabinowitz, 1997), which involves considering the effect of AM also on the phenotypic variance of the trait of interest, under the assumption that AM affects only its additive genetic component. References Crow, & Felsenstein, (1968). The effect of assortative mating on the genetic composition of a population. Eugen.Quart.15, 87,97. Rabinowitz,, 1997. A Transmission Disequilibrium Test for Quantitative Trait Loci. Human Heredity47, 342,350. Siegmund, & Yakir, (2007) Statistics of gene mapping, Springer. Wright, (1921). System of mating.III. Assortative mating based on somatic resemblance. Genetics6, 144,161. Jérémie Nsengimana 1 , Ben D Brown 2 , Alistair S Hall 2 , Jenny H Barrett 141 Leeds Institute of Molecular Medicine, University of Leeds, UK 42 Leeds Institute for Genetics, Health and Therapeutics, University of Leeds, UK Keywords: Inflammatory genes, haplotype, coronary artery disease Genetic Risk of Acute Coronary Events (GRACE) is an initiative to collect cases of coronary artery disease (CAD) and their unaffected siblings in the UK and to use them to map genetic variants increasing disease risk. The aim of the present study was to test the association between CAD and 51 single nucleotide polymorphisms (SNPs) and their haplotypes from 35 inflammatory genes. Genotype data were available for 1154 persons affected before age 66 (including 48% before age 50) and their 1545 unaffected siblings (891 discordant families). Each SNP was tested for association to CAD, and haplotypes within genes or gene clusters were tested using FBAT (Rabinowitz & Laird, 2000). For the most significant results, genetic effect size was estimated using conditional logistic regression (CLR) within STATA adjusting for other risk factors. Haplotypes were assigned using HAPLORE (Zhang et al., 2005), which considers all parental mating types consistent with offspring genotypes and assigns them a probability of occurence. This probability was used in CLR to weight the haplotypes. In the single SNP analysis, several SNPs showed some evidence for association, including one SNP in the interleukin-1A gene. Analysing haplotypes in the interleukin-1 gene cluster, a common 3-SNP haplotype was found to increase the risk of CAD (P = 0.009). In an additive genetic model adjusting for covariates the odds ratio (OR) for this haplotype is 1.56 (95% CI: 1.16-2.10, p = 0.004) for early-onset CAD (before age 50). This study illustrates the utility of haplotype analysis in family-based association studies to investigate candidate genes. References Rabinowitz, D. & Laird, N. M. (2000) Hum Hered50, 211,223. Zhang, K., Sun, F. & Zhao, H. (2005) Bioinformatics21, 90,103. Andrea Foulkes 1 , Recai Yucel 1 , Xiaohong Li 143 Division of Biostatistics, University of Massachusetts, USA Keywords: Haploytpe, high-dimensional, mixed modeling The explosion of molecular level information coupled with large epidemiological studies presents an exciting opportunity to uncover the genetic underpinnings of complex diseases; however, several analytical challenges remain to be addressed. Characterizing the components to complex diseases inevitably requires consideration of synergies across multiple genetic loci and environmental and demographic factors. In addition, it is critical to capture information on allelic phase, that is whether alleles within a gene are in cis (on the same chromosome) or in trans (on different chromosomes.) In associations studies of unrelated individuals, this alignment of alleles within a chromosomal copy is generally not observed. We address the potential ambiguity in allelic phase in this high dimensional data setting using mixed effects models. Both a semi-parametric and fully likelihood-based approach to estimation are considered to account for missingness in cluster identifiers. In the first case, we apply a multiple imputation procedure coupled with a first stage expectation maximization algorithm for parameter estimation. A bootstrap approach is employed to assess sensitivity to variability induced by parameter estimation. Secondly, a fully likelihood-based approach using an expectation conditional maximization algorithm is described. Notably, these models allow for characterizing high-order gene-gene interactions while providing a flexible statistical framework to account for the confounding or mediating role of person specific covariates. The proposed method is applied to data arising from a cohort of human immunodeficiency virus type-1 (HIV-1) infected individuals at risk for therapy associated dyslipidemia. Simulation studies demonstrate reasonable power and control of family-wise type 1 error rates. Vivien Marquard 1 , Lars Beckmann 1 , Jenny Chang-Claude 144 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany Keywords: Genotyping errors, type I error, haplotype-based association methods It has been shown in several simulation studies that genotyping errors may have a great impact on the type I error of statistical methods used in genetic association analysis of complex diseases. Our aim was to investigate type I error rates in a case-control study, when differential and non-differential genotyping errors were introduced in realistic scenarios. We simulated case-control data sets, where individual genotypes were drawn from a haplotype distribution of 18 haplotypes with 15 markers in the APM1 gene. Genotyping errors were introduced following the unrestricted and symmetric with 0 edges error models described by Heid et al. (2006). In six scenarios, errors resulted from changes of one allele to another with predefined probabilities of 1%, 2.5% or 10%, respectively. A multiple number of errors per haplotype was possible and could vary between 0 and 15, the number of markers investigated. We examined three association methods: Mantel statistics using haplotype-sharing; a haplotype-specific score test; and Armitage trend test for single markers. The type I error rates were not influenced for any of all the three methods for a genotyping error rate of less than 1%. For higher error rates and differential errors, the type I error of the Mantel statistic was only slightly and of the Armitage trend test moderately increased. The type I error rates of the score test were highly increased. The type I error rates were correct for all three methods for non-differential errors. Further investigations will be carried out with different frequencies of differential error rates and focus on power. Arne Neumann 1 , Dörthe Malzahn 1 , Martina Müller 2 , Heike Bickeböller 145 Department of Genetic Epidemiology, Medical School, University of Göttingen, Germany 46 GSF-National Research Center for Environment and Health, Neuherberg & IBE-Institute of Epidemiology, Ludwig-Maximilians University München, Germany Keywords: Interaction, longitudinal, nonparametric Longitudinal data show the time dependent course of phenotypic traits. In this contribution, we consider longitudinal cohort studies and investigate the association between two candidate genes and a dependent quantitative longitudinal phenotype. The set-up defines a factorial design which allows us to test simultaneously for the overall gene effect of the loci as well as for possible gene-gene and gene time interaction. The latter would induce genetically based time-profile differences in the longitudinal phenotype. We adopt a non-parametric statistical test to genetic epidemiological cohort studies and investigate its performance by simulation studies. The statistical test was originally developed for longitudinal clinical studies (Brunner, Munzel, Puri, 1999 J Multivariate Anal 70:286-317). It is non-parametric in the sense that no assumptions are made about the underlying distribution of the quantitative phenotype. Longitudinal observations belonging to the same individual can be arbitrarily dependent on one another for the different time points whereas trait observations of different individuals are independent. The two loci are assumed to be statistically independent. Our simulations show that the nonparametric test is comparable with ANOVA in terms of power of detecting gene-gene and gene-time interaction in an ANOVA favourable setting. Rebecca Hein 1 , Lars Beckmann 1 , Jenny Chang-Claude 147 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany Keywords: Indirect association studies, interaction effects, linkage disequilibrium, marker allele frequency Association studies accounting for gene-environment interactions (GxE) may be useful for detecting genetic effects and identifying important environmental effect modifiers. Current technology facilitates very dense marker spacing in genetic association studies; however, the true disease variant(s) may not be genotyped. In this situation, an association between a gene and a phenotype may still be detectable, using genetic markers associated with the true disease variant(s) (indirect association). Zondervan and Cardon [2004] showed that the odds ratios (OR) of markers which are associated with the disease variant depend highly on the linkage disequilibrium (LD) between the variant and the markers, and whether the allele frequencies match and thereby influence the sample size needed to detect genetic association. We examined the influence of LD and allele frequencies on the sample size needed to detect GxE in indirect association studies, and provide tables for sample size estimation. For discordant allele frequencies and incomplete LD, sample sizes can be unfeasibly large. The influence of both factors is stronger for disease loci with small rather than moderate to high disease allele frequencies. A decline in D' of e.g. 5% has less impact on sample size than increasing the difference in allele frequencies by the same percentage. Assuming 80% power, large interaction effects can be detected using smaller sample sizes than those needed for the detection of main effects. The detection of interaction effects involving rare alleles may not be possible. Focussing only on marker density can be a limited strategy in indirect association studies for GxE. Cyril Dalmasso 1 , Emmanuelle Génin 2 , Catherine Bourgain 2 , Philippe Broët 148 JE 2492 , Univ. Paris-Sud, France 49 INSERM UMR-S 535 and University Paris Sud, Villejuif, France Keywords: Linkage analysis, Multiple testing, False Discovery Rate, Mixture model In the context of genome-wide linkage analyses, where a large number of statistical tests are simultaneously performed, the False Discovery Rate (FDR) that is defined as the expected proportion of false discoveries among all discoveries is nowadays widely used for taking into account the multiple testing problem. Other related criteria have been considered such as the local False Discovery Rate (lFDR) that is a variant of the FDR giving to each test its own measure of significance. The lFDR is defined as the posterior probability that a null hypothesis is true. Most of the proposed methods for estimating the lFDR or the FDR rely on distributional assumption under the null hypothesis. However, in observational studies, the empirical null distribution may be very different from the theoretical one. In this work, we propose a mixture model based approach that provides estimates of the lFDR and the FDR in the context of large-scale variance component linkage analyses. In particular, this approach allows estimating the empirical null distribution, this latter being a key quantity for any simultaneous inference procedure. The proposed method is applied on a real dataset. Arief Gusnanto 1 , Frank Dudbridge 150 MRC Biostatistics Unit, Cambridge UK Keywords: Significance, genome-wide, association, permutation, multiplicity Genome-wide association scans have introduced statistical challenges, mainly in the multiplicity of thousands of tests. The question of what constitutes a significant finding remains somewhat unresolved. Permutation testing is very time-consuming, whereas Bayesian arguments struggle to distinguish direct from indirect association. It seems attractive to summarise the multiplicity in a simple form that allows users to avoid time-consuming permutations. A standard significance level would facilitate reporting of results and reduce the need for permutation tests. This is potentially important because current scans do not have full coverage of the whole genome, and yet, the implicit multiplicity is genome-wide. We discuss some proposed summaries, with reference to the empirical null distribution of the multiple tests, approximated through a large number of random permutations. Using genome-wide data from the Wellcome Trust Case-Control Consortium, we use a sub-sampling approach with increasing density to estimate the nominal p-value to obtain family-wise significance of 5%. The results indicate that the significance level is converging to about 1e-7 as the marker spacing becomes infinitely dense. We considered the concept of an effective number of independent tests, and showed that when used in a Bonferroni correction, the number varies with the overall significance level, but is roughly constant in the region of interest. We compared several estimators of the effective number of tests, and showed that in the region of significance of interest, Patterson's eigenvalue based estimator gives approximately the right family-wise error rate. Michael Nothnagel 1 , Amke Caliebe 1 , Michael Krawczak 151 Institute of Medical Informatics and Statistics, University Clinic Schleswig-Holstein, University of Kiel, Germany Keywords: Association scans, Bayesian framework, posterior odds, genetic risk, multiplicative model Whole-genome association scans have been suggested to be a cost-efficient way to survey genetic variation and to map genetic disease factors. We used a Bayesian framework to investigate the posterior odds of a genuine association under multiplicative disease models. We demonstrate that the p value alone is not a sufficient means to evaluate the findings in association studies. We suggest that likelihood ratios should accompany p values in association reports. We argue, that, given the reported results of whole-genome scans, more associations should have been successfully replicated if the consistently made assumptions about considerable genetic risks were correct. We conclude that it is very likely that the vast majority of relative genetic risks are only of the order of 1.2 or lower. Clive Hoggart 1 , Maria De Iorio 1 , John Whittakker 2 , David Balding 152 Department of Epidemiology and Public Health, Imperial College London, UK 53 Department of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, UK Keywords: Genome-wide association analyses, shrinkage priors, Lasso Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants of small effect, which is a plausible scenario for many complex diseases. Moreover, many simulation studies assume a single causal variant and so more complex realities are ignored. Analysing large numbers of variants simultaneously is now becoming feasible, thanks to developments in Bayesian stochastic search methods. We pose the problem of SNP selection as variable selection in a regression model. In contrast to single SNP tests this approach simultaneously models the effect of all SNPs. SNPs are selected by a Bayesian interpretation of the lasso (Tibshirani, 1996); the maximum a posterior (MAP) estimate of the regression coefficients, which have been given independent, double exponential prior distributions. The double exponential distribution is an example of a shrinkage prior, MAP estimates with shrinkage priors can be zero, thus all SNPs with non zero regression coefficients are selected. In addition to the commonly-used double exponential (Laplace) prior, we also implement the normal exponential gamma prior distribution. We show that use of the Laplace prior improves SNP selection in comparison with single -SNP tests, and that the normal exponential gamma prior leads to a further improvement. Our method is fast and can handle very large numbers of SNPs: we demonstrate its performance using both simulated and real genome-wide data sets with 500 K SNPs, which can be analysed in 2 hours on a desktop workstation. Mickael Guedj 1,2 , Jerome Wojcik 2 , Gregory Nuel 154 Laboratoire Statistique et Génome, Université d'Evry, Evry France 55 Serono Pharmaceutical Research Institute, Plan-les-Ouates, Switzerland Keywords: Local Replication, Local Score, Association In gene-mapping, replication of initial findings has been put forwards as the approach of choice for filtering false-positives from true signals for underlying loci. In practice, such replications are however too poorly observed. Besides the statistical and technical-related factors (lack of power, multiple-testing, stratification, quality control,) inconsistent conclusions obtained from independent populations might result from real biological differences. In particular, the high degree of variation in the strength of LD among populations of different origins is a major challenge to the discovery of genes. Seeking for Local Replications (defined as the presence of a signal of association in a same genomic region among populations) instead of strict replications (same locus, same risk allele) may lead to more reliable results. Recently, a multi-markers approach based on the Local Score statistic has been proposed as a simple and efficient way to select candidate genomic regions at the first stage of genome-wide association studies. Here we propose an extension of this approach adapted to replicated association studies. Based on simulations, this method appears promising. In particular it outperforms classical simple-marker strategies to detect modest-effect genes. Additionally it constitutes, to our knowledge, a first framework dedicated to the detection of such Local Replications. Juliet Chapman 1 , Claudio Verzilli 1 , John Whittaker 156 Department of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, UK Keywords: FDR, Association studies, Bayesian model selection As genomewide association studies become commonplace there is debate as to how such studies might be analysed and what we might hope to gain from the data. It is clear that standard single locus approaches are limited in that they do not adjust for the effects of other loci and problematic since it is not obvious how to adjust for multiple comparisons. False discovery rates have been suggested, but it is unclear how well these will cope with highly correlated genetic data. We consider the validity of standard false discovery rates in large scale association studies. We also show that a Bayesian procedure has advantages in detecting causal loci amongst a large number of dependant SNPs and investigate properties of a Bayesian FDR. Peter Kraft 157 Harvard School of Public Health, Boston USA Keywords: Gene-environment interaction, genome-wide association scans Appropriately analyzed two-stage designs,where a subset of available subjects are genotyped on a genome-wide panel of markers at the first stage and then a much smaller subset of the most promising markers are genotyped on the remaining subjects,can have nearly as much power as a single-stage study where all subjects are genotyped on the genome-wide panel yet can be much less expensive. Typically, the "most promising" markers are selected based on evidence for a marginal association between genotypes and disease. Subsequently, the few markers found to be associated with disease at the end of the second stage are interrogated for evidence of gene-environment interaction, mainly to understand their impact on disease etiology and public health impact. However, this approach may miss variants which have a sizeable effect restricted to one exposure stratum and therefore only a modest marginal effect. We have proposed to use information on the joint effects of genes and a discrete list of environmental exposures at the initial screening stage to select promising markers for the second stage [Kraft et al Hum Hered 2007]. This approach optimizes power to detect variants that have a sizeable marginal effect and variants that have a small marginal effect but a sizeable effect in a stratum defined by an environmental exposure. As an example, I discuss a proposed genome-wide association scan for Type II diabetes susceptibility variants based in several large nested case-control studies. Beate Glaser 1 , Peter Holmans 158 Biostatistics and Bioinformatics Unit, Cardiff University, School of Medicine, Heath Park, Cardiff, UK Keywords: Combined case-control and trios analysis, Power, False-positive rate, Simulation, Association studies The statistical power of genetic association studies can be enhanced by combining the analysis of case-control with parent-offspring trio samples. Various combined analysis techniques have been recently developed; as yet, there have been no comparisons of their power. This work was performed with the aim of identifying the most powerful method among available combined techniques including test statistics developed by Kazeem and Farrall (2005), Nagelkerke and colleagues (2004) and Dudbridge (2006), as well as a simple combination of ,2-statistics from single samples. Simulation studies were performed to investigate their power under different additive, multiplicative, dominant and recessive disease models. False-positive rates were determined by studying the type I error rates under null models including models with unequal allele frequencies between the single case-control and trios samples. We identified three techniques with equivalent power and false-positive rates, which included modifications of the three main approaches: 1) the unmodified combined Odds ratio estimate by Kazeem & Farrall (2005), 2) a modified approach of the combined risk ratio estimate by Nagelkerke & colleagues (2004) and 3) a modified technique for a combined risk ratio estimate by Dudbridge (2006). Our work highlights the importance of studies investigating test performance criteria of novel methods, as they will help users to select the optimal approach within a range of available analysis techniques. David Almorza 1 , M.V. Kandus 2 , Juan Carlos Salerno 2 , Rafael Boggio 359 Facultad de Ciencias del Trabajo, University of Cádiz, Spain 60 Instituto de Genética IGEAF, Buenos Aires, Argentina 61 Universidad Nacional de La Plata, Buenos Aires, Argentina Keywords: Principal component analysis, maize, ear weight, inbred lines The objective of this work was to evaluate the relationship among different traits of the ear of maize inbred lines and to group genotypes according to its performance. Ten inbred lines developed at IGEAF (INTA Castelar) and five public inbred lines as checks were used. A field trial was carried out in Castelar, Buenos Aires (34° 36' S , 58° 39' W) using a complete randomize design with three replications. At harvest, individual weight (P.E.), diameter (D.E.), row number (N.H.) and length (L.E.) of the ear were assessed. A principal component analysis, PCA, (Infostat 2005) was used, and the variability of the data was depicted with a biplot. Principal components 1 and 2 (CP1 and CP2) explained 90% of the data variability. CP1 was correlated with P.E., L.E. and D.E., meanwhile CP2 was correlated with N.H. We found that individual weight (P.E.) was more correlated with diameter of the ear (D.E.) than with length (L.E). Five groups of inbred lines were distinguished: with high P.E. and mean N.H. (04-70, 04-73, 04-101 and MO17), with high P.E. but less N.H. (04-61 and B14), with mean P.E. and N.H. (B73, 04-123 and 04-96), with high N.H. but less P.E. (LP109, 04-8, 04-91 and 04-76) and with low P.E. and low N.H. (LP521 and 04-104). The use of PCA showed which variables had more incidence in ear weight and how is the correlation among them. Moreover, the different groups found with this analysis allow the evaluation of inbred lines by several traits simultaneously. Sven Knüppel 1 , Anja Bauerfeind 1 , Klaus Rohde 162 Department of Bioinformatics, MDC Berlin, Germany Keywords: Haplotypes, association studies, case-control, nuclear families The area of gene chip technology provides a plethora of phase-unknown SNP genotypes in order to find significant association to some genetic trait. To circumvent possibly low information content of a single SNP one groups successive SNPs and estimates haplotypes. Haplotype estimation, however, may reveal ambiguous haplotype pairs and bias the application of statistical methods. Zaykin et al. (Hum Hered, 53:79-91, 2002) proposed the construction of a design matrix to take this ambiguity into account. Here we present a set of functions written for the Statistical package R, which carries out haplotype estimation on the basis of the EM-algorithm for individuals (case-control) or nuclear families. The construction of a design matrix on basis of estimated haplotypes or haplotype pairs allows application of standard methods for association studies (linear, logistic regression), as well as statistical methods as haplotype sharing statistics and TDT-Test. Applications of these methods to genome-wide association screens will be demonstrated. Manuela Zucknick 1 , Chris Holmes 2 , Sylvia Richardson 163 Department of Epidemiology and Public Health, Imperial College London, UK 64 Department of Statistics, Oxford Center for Gene Function, University of Oxford, UK Keywords: Bayesian, variable selection, MCMC, large p, small n, structured dependence In large-scale genomic applications vast numbers of markers or genes are scanned to find a few candidates which are linked to a particular phenotype. Statistically, this is a variable selection problem in the "large p, small n" situation where many more variables than samples are available. An additional feature is the complex dependence structure which is often observed among the markers/genes due to linkage disequilibrium or their joint involvement in biological processes. Bayesian variable selection methods using indicator variables are well suited to the problem. Binary phenotypes like disease status are common and both Bayesian probit and logistic regression can be applied in this context. We argue that logistic regression models are both easier to tune and to interpret than probit models and implement the approach by Holmes & Held (2006). Because the model space is vast, MCMC methods are used as stochastic search algorithms with the aim to quickly find regions of high posterior probability. In a trade-off between fast-updating but slow-moving single-gene Metropolis-Hastings samplers and computationally expensive full Gibbs sampling, we propose to employ the dependence structure among the genes/markers to help decide which variables to update together. Also, parallel tempering methods are used to aid bold moves and help avoid getting trapped in local optima. Mixing and convergence of the resulting Markov chains are evaluated and compared to standard samplers in both a simulation study and in an application to a gene expression data set. Reference Holmes, C. C. & Held, L. (2006) Bayesian auxiliary variable models for binary and multinomial regression. Bayesian Analysis1, 145,168. Dawn Teare 165 MMGE, University of Sheffield, UK Keywords: CNP, family-based analysis, MCMC Evidence is accumulating that segmental copy number polymorphisms (CNPs) may represent a significant portion of human genetic variation. These highly polymorphic systems require handling as phenotypes rather than co-dominant markers, placing new demands on family-based analyses. We present an integrated approach to meet these challenges in the form of a graphical model, where the underlying discrete CNP phenotype is inferred from the (single or replicate) quantitative measure within the analysis, whilst assuming an allele based system segregating through the pedigree. [source] The K - z diagram of FIRST radio sources identified in the Boötes and Cetus fieldsASTRONOMISCHE NACHRICHTEN, Issue 8 2009K. El Bouchefry Abstract This paper presents the Hubble diagram (K - z relation) for FIRST (Faint Images of the Radio Sky at 20 cm) radio sources identified in the Boötes and Cetus fields. The correlation between the K magnitude of the FIRST-NDWFS sample and the photometric redshifts found to be linear. The dispersion about the best fit line is given by 1.53 for the whole sample and 0.75 at z > 1. The paper also presents a composite K - z diagram of FIRST radio sources and low-frequency selected radio samples with progressively fainter flux-density limits (3CRR, 6C, 7CRS and the EIS-NVSS sample). The majority of FIRST radio sources lie fainter than the no evolution curve (3 L* galaxies) probably highlighting the fact that the galaxy luminosity is correlated with the radio power (© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Laptop computers and children with disabilities: Factors influencing successAUSTRALIAN OCCUPATIONAL THERAPY JOURNAL, Issue 1 2001Naomi Priest The purpose of this study was to determine factors perceived to influence the successful use of laptop computers by clients of the Crippled Children's Association of South Australia. The study was conducted in two phases: (i) a consultation phase involving key stakeholders; and (ii) a survey phase in which a questionnaire was distributed. Five key themes were identified by the consultation phase which grouped together similar factors perceived to influence the successful use of laptop computers. These themes were factors related to: (i) the laptop user; (ii) the laptop user's parents/family; (iii) attributes of the laptop; (iv) the laptop user's school; and (v) support and assistance which the laptop user may receive. A questionnaire was developed around these themes. Participants rated the importance of factors within these themes in relation to successful laptop computer use by children with disabilities. Results identified the most important factors across the whole sample were portability and teachers ability to adapt learning tasks to suit laptop use. However, each stakeholder group rated different factors as most important. Recommendations for a collaborative approach to laptop computer prescription, ongoing follow up and quality assurance, and the provision of training and development opportunities are suggested. [source] Maximum Likelihood Estimation in Dynamical Models of HIVBIOMETRICS, Issue 4 2007J. Guedj Summary The study of dynamical models of HIV infection, based on a system of nonlinear ordinary differential equations (ODE), has considerably improved the knowledge of its pathogenesis. While the first models used simplified ODE systems and analyzed each patient separately, recent works dealt with inference in non-simplified models borrowing strength from the whole sample. The complexity of these models leads to great difficulties for inference and only the Bayesian approach has been attempted by now. We propose a full likelihood inference, adapting a Newton-like algorithm for these particular models. We consider a relatively complex ODE model for HIV infection and a model for the observations including the issue of detection limits. We apply this approach to the analysis of a clinical trial of antiretroviral therapy (ALBI ANRS 070) and we show that the whole algorithm works well in a simulation study. [source] The effect of fixed-count subsampling on macroinvertebrate biomonitoring in small streamsFRESHWATER BIOLOGY, Issue 2 2000Craig P. Doberstein Summary 1When rigorous standards of collecting and analysing data are maintained, biological monitoring adds valuable information to water resource assessments. Decisions, from study design and field methods to laboratory procedures and data analysis, affect assessment quality. Subsampling - a laboratory procedure in which researchers count and identify a random subset of field samples - is widespread yet controversial. What are the consequences of subsampling? 2To explore this question, random subsamples were computer generated for subsample sizes ranging from 100 to 1000 individuals as compared with the results of counting whole samples. The study was done on benthic invertebrate samples collected from five Puget Sound lowland streams near Seattle, WA, USA. For each replicate subsample, values for 10 biological attributes (e.g. total number of taxa) and for the 10-metric benthic index of biological integrity (B-IBI) were computed. 3Variance of each metric and B-IBI for each subsample size was compared with variance associated with fully counted samples generated using the bootstrap algorithm. From the measures of variance, we computed the maximum number of distinguishable classes of stream condition as a function of sample size for each metric and for B-IBI. 4Subsampling significantly decreased the maximum number of distinguishable stream classes for B-IBI, from 8.2 for fully counted samples to 2.8 classes for 100-organism subsamples. For subsamples containing 100,300 individuals, discriminatory power was low enough to mislead water resource decision makers. [source] | |||||||||||||||||||||||||