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Initial Findings (initial + finding)
Selected AbstractsLearning and Organization in the Knowledge-Based Information Economy: Initial Findings from a Participatory Action Research Case StudyBRITISH JOURNAL OF MANAGEMENT, Issue 2 2000Richard T. Harrison This paper reports on an ongoing, multiphase, project-based action learning and research project. In particular, it summarizes some aspects of the learning climate and outcomes for a case-study company in the software industry. Using a participatory action research approach, the learning company framework developed by Pedler et al. (1997) is used to initiate critical reflection in the company at three levels: managing director, senior management team and technical and professional staff. As such, this is one of the first systematic attempts to apply this framework to the entire organization and to a company in the knowledge-based learning economy. Two sets of issues are of general concern to the company: internal issues surrounding the company's reward and recognition policies and practices and the provision of accounting and control information in a business-relevant way to all levels of staff; and external issues concerning the extent to which the company and its members actively learn from other companies and effectively capture, disseminate and use information accessed by staff in boundary-spanning roles. The paper concludes with some illustrations of changes being introduced by the company as a result of the feedback on and discussion of these issues. [source] Analyses of second-generation ,legal highs' in the UK: Initial findingsDRUG TESTING AND ANALYSIS, Issue 8 2010Simon D. Brandt Abstract In the UK, mephedrone and other so-called ,legal high' derivatives have recently been classified as Class B, Schedule I under the Misuse of Drugs Act 1971. Since then, alternative products have been advertised on a number of websites. In order to obtain an immediate snapshot of the situation, 24 products were purchased online from 18 UK-based websites over a period of 6 weeks following the ban in April 2010. Qualitative analyses were carried out by gas chromatography ion trap mass spectrometry using electron- and chemical ionization modes, nuclear magnetic resonance spectroscopy, and comparison with reference standards. Overall, the purchased products consisted of single cathinones or cathinone mixtures including mephedrone, butylone, 4-methyl- N -ethylcathinone, flephedrone (4-fluoromethcathinone) and MDPV (3,4-methylenedioxypyrovalerone), respectively. Benzocaine, caffeine, lidocaine, and procaine were also detected. The emphasis was placed on ,Energy 1' (NRG-1), a product advertised as a legal replacement for mephedrone-type derivatives usually claiming to contain naphyrone (naphthylpyrovalerone, O-2482). It was found that 70% of NRG-1 and NRG-2 products appeared to contain a mixture of cathinones banned in April 2010 and rebranded as ,new' legal highs, rather than legal chemicals such as naphyrone as claimed by the retailers. Only one out of 13 NRG-1 samples appeared to show analytical data consistent with naphyrone. These findings also suggest that both consumers and online sellers (unlike manufacturers and wholesalers) are, most likely unknowingly, confronted with the risk of criminalization and potential harm. Copyright © 2010 John Wiley & Sons, Ltd. [source] Relationships in nurse prescribing in district nursing practice in England: A preliminary investigationINTERNATIONAL JOURNAL OF NURSING PRACTICE, Issue 3 2005Rick Fisher RGN DNT BA(Hons) MScArticle first published online: 25 APR 200 Nurse prescribing is a significant change in the working lives of district nurses in the United Kingdom. It has been achieved as the result of a 13-year sociopolitical struggle, eventually culminating in an Act of Parliament, which enabled selected nurses to prescribe from a limited formulary. This research attempts to discover the nature of its impact on the relationships between prescribers, nurses, doctors, pharmacists, patients and carers. Using a qualitative approach, guided interviews were carried out with nurses, doctors, pharmacists, patients and carers. Initial findings indicate that far from producing an independent prescribing workforce, some prescribers are reverting to their preprescribing behaviour. For these prescribers, there is a suggestion that old hierarchies are being reinforced, which might be detrimental to nurse prescribing. [source] Rights, sexuality and relationships in Ireland: ,It'd be nice to be kind of trusted'BRITISH JOURNAL OF LEARNING DISABILITIES, Issue 4 2009Grace Kelly Accessible summary ,,This paper talks about what a group of people with intellectual disabilities in Ireland had to say about their experiences of relationships and sexuality, and the type of support they might like in this area of their lives. ,,Many people did not get enough information about sexuality. There were lots of things they did not understand properly and they wanted more information. ,,Many people wanted to have boyfriend and girlfriend relationships, but relationships were not allowed in their service. Some people had to have relationships in secret. ,,In Ireland it is against the law to have a sexual relationship with a person who cannot live without support, or protect themselves from abuse, unless you are married. ,,The law needs to be changed because some people with intellectual disabilities who need support in their lives are still capable of having sexual relationships and protecting themselves from abuse. ,,People with intellectual disabilities need better sexual information and need support to have their voices heard by government. Summary How to translate the right of people with intellectual disabilities to a full sexual and intimate life into proactive support remains a challenge for disabilities services in Ireland. Little formal research has been undertaken in this country into what people with intellectual disabilities think about these issues and what they would like to see happen in this area of their lives. This paper presents a preliminary analysis of the first author's PhD research into the views and experiences of a small group of Irish people with intellectual disabilities in the area of sexuality and relationships. Initial findings suggest that people with intellectual disabilities are getting insufficient sex education and that changes are needed at a disabilities service level to ensure that people with intellectual disabilities can express their sexuality in an open and supportive climate. At a government level, changes will need to be made to Irish legislation concerning the sexuality of vulnerable adults so that this country is meeting its obligations under the UN Convention on the Rights of Persons with Disabilities (2006). The authors argue that people with intellectual disabilities' views must come first in all debates concerning their sexuality. [source] HMGA2 Is Confirmed To Be Associated with Human Adult HeightANNALS OF HUMAN GENETICS, Issue 1 2010Tie-Lin Yang Summary Recent genome-wide association studies have identified a novel polymorphism, rs1042725, in the HMGA2 gene for human adult height, a highly heritable complex trait. Replications in independent populations are needed to evaluate a positive finding and determine its generality. Thus, we performed a replication study to examine the associations between polymorphisms in HMGA2 and adult height in two US Caucasian populations (an unrelated sample of 998 subjects and a family-based sample of 8385 subjects) and a Chinese population (1638 unrelated Han subjects). We confirmed the association between rs1042725 in HMGA2 and adult height both in the unrelated and family-based Caucasian populations (overall P= 4.25 × 10,9). Another two SNPs (rs7968902 and rs7968682), which were in high linkage disequilibrium with rs1042725, also achieved the significance level in both Caucasian populations (overall P= 6.34 × 10,7, and 2.72 × 10,9, respectively). Our results provide strong support to the initial finding. Moreover, SNP rs1042725 was firstly found to be associated with adult height (P= 0.008) in the Chinese population, and the effect is in the same direction as in the Caucasian populations, suggesting that it is a common variant across different populations. Our study further highlights the importance of the HMGA2 gene's involvement in normal growth. [source] PAEDIATRIC MOTORBIKE INJURIES: DO CHILDREN RIDING MOTORBIKES GET THE SAME INJURIES AS THOSE RIDING BICYCLES?ANZ JOURNAL OF SURGERY, Issue 7 2008Jonathon Robertson Background: Health workers have the impression that injuries sustained by children on motorcycles are more severe and debilitating than those of children on bicycles. This was not reflected by data collected for a statewide trauma registry: the two groups looked very similar at first glance. Methods: A retrospective chart review audit was carried out to further collect clinical data that might be deemed to be consequential to patients, their families and the health system, to see if this initial finding was reproduced. Results: Registry outcomes such as length of stay and mortality were no different, but number of procedures required, number of injuries and functional injuries were very different. Conclusions: Showing that children are more severely injured when riding motorcycles rather than bicycles is needed to promote cultural and legislative change. [source] Customized mandibular orthotics in the prevention of concussion/mild traumatic brain injury in football players: a preliminary studyDENTAL TRAUMATOLOGY, Issue 5 2009G. Dave Singh However, previous investigations have primarily studied non-customized mouthguards without dental/temporo-mandibular joint examinations of the subjects. Therefore, the aim of this study is to determine whether the use of a customized mandibular orthotic after temporo-mandibular joint assessment reduces the incidence of concussion/mild traumatic brain injuries in high-school football players. Materials and methods:, Using a longitudinal, retrospective design, data were collected from a cohort of football players (n = 28) over three seasons using a questionnaire. The mean age of the sample prior to the use of the customized mandibular orthotic was 17.3 years ± 1.9. Prior to deployment, dental records and temporo-mandibular joint evaluations were undertaken, as well as neurocognitive assessment, including history of concussion/mild traumatic brain injuries. After establishing optimal jaw position, a customized mandibular orthotic was fabricated to the new spatial relations. Results:, The mean age of the sample after three seasons was 19.7 years ± 2.0. Prior to the use of the customized mandibular orthotic, the mean self-reported incidence of concussion/mild traumatic brain injuries was 2.1 ± 1.4 concussive events. After the deployment of the customized mandibular orthotic the number of concussive events fell to 0.11 ± 0.3 with an odds ratio of 38.33 (95% CI 8.2,178.6), P < 0.05. Conclusion:, The preliminary results of this study suggest that a customized mandibular orthotic may decrease the incidence of concussion/mild traumatic brain injuries in high- school football athletes, but a comprehensive study is required to confirm these initial findings. Furthermore, additional research is necessary to indicate the possible mode(s) of action of a customized mandibular orthotic in the prevention of concussion/mild traumatic brain injuries. [source] The gluten connection: the association between schizophrenia and celiac diseaseACTA PSYCHIATRICA SCANDINAVICA, Issue 2 2006A. E. Kalaydjian Objective:, Schizophrenia affects roughly 1% of the population and is considered one of the top 10 causes of disability worldwide. Given the immense cost to society, successful treatment options are imperative. Based on initial findings, gluten withdrawal may serve as a safe and economical alternative for the reduction of symptoms in a subset of patients. Method:, A review of the literature relevant to the association between schizophrenia and celiac disease (gluten intolerance) was conducted. Results:, A drastic reduction, if not full remission, of schizophrenic symptoms after initiation of gluten withdrawal has been noted in a variety of studies. However, this occurs only in a subset of schizophrenic patients. Conclusion:, Large-scale epidemiological studies and clinical trials are needed to confirm the association between gluten and schizophrenia, and address the underlying mechanisms by which this association occurs. [source] SECOND LOOK COLONOSCOPY: INDICATION AND REQUIREMENTSDIGESTIVE ENDOSCOPY, Issue 2009Jean-Francois Rey Background:, There are circumstances when a colonoscopy should be repeated after a short interval following the first endoscopic procedure which has not completely fulfilled its objective. Review of the literature:, A second look colonoscopy is proposed when there remains a doubt about missed neoplastic lesions, either because the intestinal preparation was poor or because the video-endoscope did not achieved a complete course in the colon. The second look colonoscopy is also proposed at a short interval when it is suspected that the endoscopic removal of a single or of multiple neoplastic lesions was incomplete and that a complement of treatment is required. When the initial endoscopic procedure has completely fulfilled its objective, a second look colonoscopy can be proposed at longer intervals in surveillance programs. The intervals in surveillance after polypectomy are now adapted to the initial findings according to established guidelines. This also applies to the surveillance of incident focal cancer in patients suffering from a chronic inflammatory bowel disease. Conclusion:, Finally, in most developed countries, a priority is attributed to screening of colorectal cancer and focus is given on quality assurance of colonoscopy which is considered as the gold standard procedure in the secondary prevention of colorectal cancer. [source] MICROVASCULAR PATTERNS OF ESOPHAGEAL MICRO SQUAMOUS CELL CARCINOMA ON MAGNIFYING ENDOSCOPYDIGESTIVE ENDOSCOPY, Issue 1 2008Hideaki Arima Background:, Recently, esophageal microcancers have been frequently diagnosed and are receiving increasing attention as initial findings of cancer. We examined whether the clinicopathological features and microvascular patterns of esophageal microcancers on magnifying endoscopy are useful for diagnosis. Methods:, Magnifying endoscopy was performed to examine the histopathological features of 55 esophageal cancers measuring ,10 mm in diameter (34 small cancers, 16 microcancers, and five supermicrocancers). Results:, Although some lesions were detected only on iodine staining, most were detected on conventional endoscopic examination. Most small cancers and microcancers were m1 or m2; some were m3 or sm2. Supermicrocancers were dysplasia or m1 cancer. As for the microvascular pattern, most m1 and m2 cancers showed type 3 vessels, while most submucosal cancers showed type 4 vessels. Conclusions:, Microvascular patterns on magnifying endoscopy are useful for the differential diagnosis of benign and malignant esophageal cancers and for estimating the depth of tumor invasion. The shape of small lesions is often altered considerably by biopsy. Residual tumor may persist unless the basal layer of the lesion is included in biopsy specimens, even in microcancers. Consequently, endoscopic mucosal resection, without biopsy, is being performed in increasing numbers of patients with lesions suspected to be cancer on the basis of their microvascular patterns. [source] The successful management of organisational change in tourism SMEs: initial findings in UK visitor attractionsINTERNATIONAL JOURNAL OF TOURISM RESEARCH, Issue 4 2008Rune Todnem By Abstract Organisational change management theory for small and medium-sized enterprises (SMEs) within the tourism industry is an under-researched field. Changing political, economic, social and technological factors can leave unprepared SMEs exposed to external as well as internal pressures, which can lead to underperformance, or in worst case scenario, business failure. This paper, reporting on the findings of exploratory research of nine UK-based visitor attractions, all qualifying as SMEs, suggests that the successful management of change is crucial for SMEs' survival and success. The findings argue that the current approach taken to organisational change management within the industry is bumpy incremental, bumpy continuous and planned. Hence, the paper provides a framework for managing organisational change based on eight critical success factors identified by the study: adaptability and flexibility, commitment and support, communication and co-operation, continuous learning and improvement, formal strategies, motivation and reward, pragmatism, and the right people. Copyright © 2008 John Wiley & Sons, Ltd. [source] Promoting creative thinking through the use of ICTJOURNAL OF COMPUTER ASSISTED LEARNING, Issue 3 2002S. Wheeler Abstract A great deal has been written about the use of web-based technologies such as the Internet in promoting learning in education. In schools, research has focused primarily on social interaction and group work, student achievement levels and curriculum development. Very little study seems to have been brought to bear upon the promotion of creative thinking by the use of online technologies, and this paper attempts to contribute to this field of study. This paper reports on a pilot study which has investigated the creative impact of information and communication technology (ICT) in a rural primary school in South-west England. The school is unique because it provides a personal networked computer for each of its 41 Year 6 students (aged 10,11 years). A small group of students were interviewed about the learning activities they engaged in over the year, and this paper reports on initial findings with a special emphasis on creative working and thinking (n = 6). A model of creativity is presented with three discrete but related modes of activity , problem solving, creative cognition, and social interaction. The paper provides new findings about the nature of creativity in the context of computer based learning environments. [source] Eminent Domain and the Psychology of Property Rights: Proposed Use, Subjective Attachment, and Taker IdentityJOURNAL OF EMPIRICAL LEGAL STUDIES, Issue 4 2008Janice Nadler The U.S. Supreme Court's decision in Kelo v. City of New London, allowing governments to force the sale of private property to promote economic development, provoked bipartisan and widespread public outrage. Given that the decision in Kelo was rendered virtually inevitable by the Court's earlier public use decisions, what accounts for the dread and dismay that the decision provoked among ordinary citizens? We conducted two experiments that represent an early effort at addressing a few of the many possible causes underlying the Kelo backlash. Together, these studies suggest that the constitutional focus on public purpose in Kelo does not fully, or even principally, explain the public outrage that followed it. Our experiments suggest that subjective attachment to property looms far larger in determining the perceived justice of a taking. We have only begun to map the contours of this response, but these initial findings show promise in helping to build a more democratic model for the law and policies dealing with takings. [source] Palliation in cancer of the oesophagus , what passes down an oesophageal stent?JOURNAL OF HUMAN NUTRITION & DIETETICS, Issue 5 2003A. Holdoway Introduction: Self-expanding metal stents are becoming an increasingly popular method of palliation of dysphagia in advanced oesophageal carcinoma. Approximately 10% require intervention post-placement because of blockage (Angorn, 1981). This could be prevented by effective dietary advice. We set out to write evidence-based dietary guidelines for patients undergoing oesophageal stent insertion. A comprehensive literature search failed to identify evidence to support the present guidelines used by manufacturers and dietitians on foods allowed or to avoid and the use of fizzy drinks to ,clean' the stent. Only reference on the ability to consume a semi-solid or solid diet was made (Nedin, 2002). We therefore tested the ability of 50 foods to pass through a stent and the efficacy of fizzy water in unblocking an occluded stent. Method: Normal mouthfuls of raw and cooked, peeled/unpeeled fruit and vegetables, casseroles, griddle or grilled plain meat, poultry or fish, eggs, nuts, dried fruit and bread in various forms were tested. An adult female chewed a ,normal' mouthful of each test food and at the point of swallowing the bolus of food was passed into an expanded Ultraflex metal covered stent (internal diameter 18 mm). If occlusion occurred, water was dribbled through the stent, simulating swallowing fluid, in an attempt to unblock the stent. If the occlusion remained, the stent was agitated to mimic advice given about moving around to unblock a stent in a patient. If it remained occluded, a smaller amount of food, approximately half a mouthful, was chewed for twice as long and re-tested. To test the efficacy of fizzy water to clear an occlusion, we compared the ability of water, warm water and fizzy water to unblock a stent artificially occluded with a bolus of bread. Results: Foods that occluded the stent but passed through if eaten in half mouthfuls and chewed for twice normal chewing time included sandwiches, dry toast, apple, tinned pineapple, fresh orange segments with pith removed, up to six sultanas, chopped dried apricot, boiled egg, muesli, meat and poultry. Dry meat, fruit with pith, skins of capsicum peppers and tomatoes, more than seven sultanas and dried apricots caused occlusion. Nuts and vegetables such as lettuce, which are cited in many diet sheets as items to avoid (Nedin, 2002), passed through the stent when chewed to a normal level. The volumes of fluid required to unblock a stent occluded with bread were 5 l of fizzy water, 3.5 l of cold water or 1 l of warm water. Conclusion: If a patient has good dentition and can chew well and take small mouthfuls and prepare and cook food appropriately, it is likely that they can enjoy a wide variety of solid foods. The use of fizzy drinks to maintain the patency of the stent in patients prone to reflux is questionable, warm fluids may be more efficacious. Based on these initial findings we are updating our dietary guidelines for patients undergoing oesophageal stent insertion and hope to audit stent occlusion following implementation. [source] Empirical-based recovery and maintenance of input error-correction featuresJOURNAL OF SOFTWARE MAINTENANCE AND EVOLUTION: RESEARCH AND PRACTICE, Issue 6 2007Minh Ngoc Ngo Abstract Most information systems deal with inputs submitted from their external environments. In such systems, input validation is often incorporated to reject erroneous inputs. Unfortunately, many input errors cannot be detected automatically and therefore result in errors in the effects raised by the system. Therefore, the provision of input error-correction features (IECFs) to correct these erroneous effects is critical. However, recovery and maintenance of these features are complicated, tedious and error prone because there are many possible input errors during user interaction with the system; each input error, in turn, might result in several erroneous effects. Through empirical study, we have discovered some interesting control flow graph patterns with regard to the implementation of IECFs in information systems. Motivated by these initial findings, in this paper, we propose an approach to the automated recovery of IECFs by realizing these patterns from the source code. On the basis of the recovered information, we further propose a decomposition-slicing technique to aid the maintenance of these features without interfering with other parts of the system. A case study has been conducted to show the usefulness of the proposed approach. Copyright © 2007 John Wiley & Sons, Ltd. [source] MINISTERIAL ADVISERS, POLITICIZATION AND THE RETREAT FROM WESTMINSTER: THE CASE OF NEW ZEALANDPUBLIC ADMINISTRATION, Issue 3 2007CHRIS EICHBAUM Political advisers are an established third element in a number of Westminster-styled jurisdictions, as they are in New Zealand's institution of executive government. In this paper we report the initial findings of a research project focusing on the role and accountabilities of ministerial advisers in New Zealand. We locate these findings in the context of a growing body of international and comparative research on the role and accountabilities of non civil- or public-service advisers within political executives and comment on the extent to which the findings affirm or refute the view that the ,third element' constitutes a threat to the continued application of Westminster principles and practices in New Zealand's system of government , once described as more Westminster than Westminster. In doing so, we highlight deficiencies in standard conceptions of politicization and argue that there is a need to more clearly differentiate between its procedural and substantive dimensions. [source] Prognostic factors in rapidly progressive interstitial pneumoniaRESPIROLOGY, Issue 2 2010Yasuhiro KONDOH ABSTRACT Background and objective: The aim of the present study was to examine clinical and other features that might allow prognostic distinctions between histological patterns in presentations with rapidly progressive interstitial pneumonia (RPIP), and to assess prognostic factors for survival. Methods: Patients with RPIP among 425 consecutive patients with diffuse lung disease, who underwent surgical lung biopsy, were studied retrospectively. The discriminatory value of clinical and investigative features for identifying disease with a better outcome was evaluated. An a priori comparison was made between diffuse alveolar damage (DAD)/usual interstitial pneumonia with DAD pattern (Group A), and organizing pneumonia/non-specific interstitial pneumonia pattern (Group B). Results: Twenty-eight patients (6.6%) fulfilled the criteria for RPIP. The diagnosis was Group A disease in 15 (DAD in 10, usual interstitial pneumonia with DAD in 5), and Group B disease in 13 (organizing pneumonia in 8, non-specific interstitial pneumonia in 5). There were no significant differences in initial findings between the groups. Prognosis was significantly better for Group B patients than for Group A patients (P = 0.021). Neither BAL nor parenchymal high-resolution CT score was indicative of therapeutic responsiveness or outcome. Distinction between Group A and Group B on the basis of disease pattern was the only significant determinant of prognosis. Conclusions: RPIP included varied histological patterns with different outcomes, and in many cases these could not be predicted using baseline clinical data. Histology was the only significant predictor of ultimate prognosis. [source] Linkage Validation of RP25 Using the 10K GeneChip Array and Further Refinement of the Locus by New Linked FamiliesANNALS OF HUMAN GENETICS, Issue 4 2008I. Barragán Summary Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of retinal dystrophies, characterised by rod photoreceptor cell degeneration with autosomal recessive RP (arRP) as the commonest form worldwide. To date, a total of 26 loci have been reported for arRP, each having a prevalence of 1,5%, except for the RP25 locus which was identified as the genetic cause of 14% of arRP cases in Spain. In order to validate the original linkage of RP25, we undertook a total genome scan using the 10K GeneChip mapping array on three of the previously linked families. The data obtained supported the initial findings of linkage. Additionally, linkage analysis in 18 newly ascertained arRP families was performed using microsatellite markers spanning the chromosome 6p12.1-q15 interval. Five out of the 18 families showed suggestive evidence of linkage to RP25, hence supporting the high prevalence of this locus in the Spanish population. Furthermore, the finding of a crossover in one of these families is likely to have refined the disease interval from the original 16 cM to only a 2.67 cM region between D6S257 and D6S1557. [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] 2222: Hydrogen sulphide: a new CNS mediatorACTA OPHTHALMOLOGICA, Issue 2010N OSBORNE The recent discovery that hydrogen sulphide (H2S) is an endogenously produced gaseous secondary messenger capable of modulating many physiological processes, much like nitric oxide, prompted us to investigate the potential role of H2S as a retinal neuroprotective agent. In the current study we use dithiolethiones (kindly provided by Dr. Piero Del Soldato, Milan, Italy) as H2S donors and show that such substances attenuate the effect of retinal ischemia as well as oxidative and light-induced injury to a transformed line of cells (RGC-5 cells) in culture. Ischemia was delivered to rats by elevation of the intraocular pressure above the systolic blood pressure. Partial damage to the retina after seven days was determined by a combination of procedures which included analysis of electroretinograms, immunohistochemistry and changes in the retinal content of proteins and mRNAs known to be associated with ganglion cell function and apoptosis. Most of the changes caused by ischemia were significantly attenuated by intravitreal injection of a H2S donor directly after ischemia. Both light (400-700nm, intensity 1000 lux) and hydrogen peroxide caused death to RGC-5 cells in culture over a period of 24-48 hours in a time and dose-dependent manner, respectively. Light and hydrogen peroxide-induced RGC-5 cell death is by different forms of apoptosis but they are both attenuated by the H2S donor, ACS1. These initial findings demonstrate that donors of H2S may be value in the treatment of various retinal dysfunctions where oxidative stress, light or ischemia is implicated as causative fact [source] Serum albumin level predicts initial intravenous immunoglobulin treatment failure in Kawasaki diseaseACTA PAEDIATRICA, Issue 10 2010Ho-Chang Kuo Abstract Objectives:, Kawasaki disease (KD) is a systemic vasculitis primarily affecting children who are <5 years old. Intravenous immunoglobulin (IVIG) is the standard therapy for KD. However, many patients with KD still show poor response to initial IVIG treatment. This study was conducted to investigate the risk factors for initial IVIG treatment failure in KD. Methods:, Children who met KD diagnosis criteria and were admitted for IVIG treatment were retrospectively enrolled for analysis. Patients were divided into IVIG-responsive and IVIG-resistant groups. Initial laboratory data before IVIG treatment were collected for analysis. Results:, A total of 131 patients were enrolled during the study period. At 48 h after completion of initial IVIG treatment, 20 patients (15.3%) had an elevated body temperature. Univariate analysis showed that patients who had initial findings of high neutrophil count, abnormal liver function, low serum albumin level (,2.9 g/dL) and pericardial effusion were at risk for IVIG treatment failure. Multivariate analysis with a logistic regression procedure showed that serum albumin level was considered the independent predicting factor of IVIG resistance in patients with KD (p = 0.006, OR = 40, 95% CI: 52.8,562). There was no significant correlation between age, gender, fever duration before IVIG treatment, haemoglobin level, total leucocyte and platelet counts, C-reactive protein level, or sterile pyuria and initial IVIG treatment failure. The specificity and sensitivity for prediction of IVIG treatment failure in this study were 96% and 34%, respectively. Conclusion:, Pre-IVIG treatment serum albumin levels are a useful predictor of IVIG resistance in patients with KD. [source] From Dioxin to Drug Lead,The Development of 2,3,7,8-TetrachlorophenothiazineCHEMMEDCHEM, Issue 6 2007Kristian Abstract Polychlorinated dibenzo-p-dioxins are persistent environmental pollutants. The most potent congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), causes a wasting syndrome and is a potent carcinogen and immunosuppressant in the rat at high doses. However, low doses cause opposite effects to some of those observed at higher doses, resulting in chemoprevention, stimulation of the immune system, and longevity in experimental animals. The new TCDD analogue, 2,3,7,8-tetrachlorophenothiazine (TCPT), was developed to take advantage of the low-dose effects of dioxins that have potential application as therapeutics. Its development marked a deviation from the traditional scope of phenothiazine drug design by deriving biological effects from aryl substituents. TCPT was synthesized in three steps. The key ring-closing step was performed utilizing a Buchwald-Hartwig amination to provide TCPT in 37,% yield. Its potency to induce CYP1A1 activity over 24,h was 370 times lower than that of TCDD in,vitro. The elimination half-life of the parent compound in serum was 5.4,h in the rat and 2.7,h in the guinea pig, compared to 11 and 30 days, respectively, for TCDD. These initial findings clearly differentiate TCPT from TCDD and provide the basis for further studies of its potential as a drug lead. [source] | ||||||||||||||||