Strategies for genetic model specification in the screening of genome-wide meta-analysis signals for further replication

Background Meta-analysis is increasingly being employed as a screening procedure in large-scale association studies to select promising variants for follow-up studies. However, standard methods for meta-analysis require the assumption of an underlying genetic model, which is typically unknown a priori. This drawback can introduce model misspecifications, causing power to be suboptimal, or the evaluation of multiple genetic models, which augments the number of false-positive associations, ultimately leading to waste of resources with fruitless replication studies. We used simulated meta-analyses of large genetic association studies to investigate naive strategies of genetic model specification to optimize screenings of genome-wide meta-analysis signals for further replication. Methods Different methods, meta-analytical models and strategies were compared in terms of power and type-I error. Simulations were carried out for a binary trait in a wide range of true genetic models, genome-wide thresholds, minor allele frequencies (MAFs), odds ratios and between-study heterogeneity (tau(2)). Results Among the investigated strategies, a simple Bonferroni-corrected approach that fits both multiplicative and recessive models was found to be optimal in most examined scenarios, reducing the likelihood of false discoveries and enhancing power in scenarios with small MAFs either in the presence or in absence of heterogeneity. Nonetheless, this strategy is sensitive to tau(2) whenever the susceptibility allele is common (MAF epsilon 30%), resulting in an increased number of false-positive associations compared with an analysis that considers only the multiplicative model. Conclusion Invoking a simple Bonferroni adjustment and testing for both multiplicative and recessive models is fast and an optimal strategy in large meta-analysis-based screenings. However, care must be taken when examined variants are common, where specification of a multiplicative model alone may be preferable.

The impact of functional connectivity changes on support vector machines mapping of fMRI data

Functional magnetic resonance imaging (fMRI) is currently one of the most widely used methods for studying human brain function in vivo. Although many different approaches to fMRI analysis are available, the most widely used methods employ so called ""mass-univariate"" modeling of responses in a voxel-by-voxel fashion to construct activation maps. However, it is well known that many brain processes involve networks of interacting regions and for this reason multivariate analyses might seem to be attractive alternatives to univariate approaches. The current paper focuses on one multivariate application of statistical learning theory: the statistical discrimination maps (SDM) based on support vector machine, and seeks to establish some possible interpretations when the results differ from univariate `approaches. In fact, when there are changes not only on the activation level of two conditions but also on functional connectivity, SDM seems more informative. We addressed this question using both simulations and applications to real data. We have shown that the combined use of univariate approaches and SDM yields significant new insights into brain activations not available using univariate methods alone. In the application to a visual working memory fMRI data, we demonstrated that the interaction among brain regions play a role in SDM`s power to detect discriminative voxels. (C) 2008 Elsevier B.V. All rights reserved.

Rationale and design of a randomized placebo-controlled trial assessing the effects of etiologic treatment in Chagas` cardiomyopathy: The BENznidazole Evaluation For Interrupting Trypanosomiasis (BENEFIT)

Background Benznidazole is effective for treating acute and chronic (recently acquired) Tryponosoma cruzi infection (Chagas` disease). Recent data indicate that parasite persistence plays a pivotal role in the pathogenesis of chronic Chagas` cardiomyopathy. However, the efficacy of trypanocidal therapy in preventing clinical complications in patients with preexisting cardiac disease is unknown. Study Design BENEFIT is a multicenter, randomized, double-blind, placebo-controlled clinical trial of 3,000 patients with Chagas` cardiomyopathy in Latin America. Patients are randomized to receive benznidazole (5 mg/kg per day) or matched placebo, for 60 days. The primary outcome is the composite of death; resuscitated cardiac arrest; sustained ventricular tachycardia; insertion of pacemaker or cardiac defibrillator; cardiac transplantation; and development of new heart failure, stroke, or systemic or pulmonary thromboembolic events. The average follow-up time will be 5 years, and the trial has a 90% power to detect a 25% relative risk reduction. The BENEFIT program also comprises a substudy evaluating the effects of benznidazole on parasite clearance and an echo substudy exploring the impact of etiologic treatment on left ventricular function. Recruitment started in November 2004, and >1,000 patients have been enrolled in 35 centers from Argentina, Brazil, and Colombia to date. Conclusion This is the largest trial yet conducted in Chagas` disease. BENEFIT will clarify the role of trypanocidal therapy in preventing cardiac disease progression and death.

Gender, marital status, farm size and other factors influencing the extent of cash cropping in Kenya: A case study

This article examines the effects of commercialisation of agriculture on land use and work patterns by means of a case study in the Nyeri district in Kenya. The study uses cross sectional data collected from small-scale farmers in this district. We find that good quality land is allocated to non-food cash crops, which may lead to a reduction in non-cash food crops and expose some households to greater risks of possible famine. Also the proportion of land allocated to food crops declines as the farm size increases while the proportion of land allocated to non-food cash crops rises as the size of farm increases. Cash crops are also not bringing in as much revenue commensurate with the amount of land allocated to them. With growing commercialisation, women still work more hours than men. They not only work on non-cash food crops but also on cash crops including non-food cash crops. Evidence indicates that women living with husbands work longer hours than those married but living alone, and also longer than the unmarried women. Married women seem to lose their decision-making ability with growth of commercialisation, as husbands make most decisions to do with cash crops. Furthermore husbands appropriate family cash income. Husbands are less likely to use such income for the welfare of the family compared to wives due to different expenditure patterns. Married women in Kenya also have little or no power to change the way land is allocated between food and non-food cash crops. Due to deteriorating terms of trade for non-food cash crops, men have started cultivation of food cash crops with the potential of crowding out women. It is found that both the area of non-cash crops tends to rise with farm size but also the proportion of the farm area cash cropped rises in Central Kenya.

Marital status, farm size and other influences on the extent of cash cropping in Kenya: A household case study

This article examines the effects of marital status, farm size and other factors on the extent of cash cropping (and allocation of land use) by means of a case study in the Nyeri district in Kenya. It was found that married women are involved in the production of a relatively greater amount of output of cash crops than unmarried women since husbands prefer to have more land under cash crops than food crops. Farmers with better quality land allocate a high proportion of it to non-food cash crops, which may expose some households to greater risks of possible famine. The proportion of land allocated to food crops declines as the farm size increases while the proportion of land allocated to non-food cash crops rises as the size of farm increases. Age is also inversely associated with subsistence. Education, though inversely associated with subsistence farming does not appear to be statistically very significant as an influence on the composition of land use and composition of farm output. With growing commercialisation, married women work more hours than unmarried ones, working not only on non-cash food crops but also on non-food cash crops. Married women seem to lose their decision-making ability with growth of agricultural commercialisation, as husbands make most decisions to do with cash crops. Married women in Kenya also have little or no power to change the way land is allocated between food and non-food cash crops.

Detecting environmental impacts on metapopulations of mound spring invertebrates - Assessing an incidence function model

We use a stochastic patch occupancy model of invertebrates in the Mound Springs ecosystem of South Australia to assess the ability of incidence function models to detect environmental impacts on metapopulations. We assume that the probability of colonisation decreases with increasing isolation and the probability of extinction is constant across spring vents. We run the models to quasi-equilibrium, and then impose an impact by increasing the local extinction probability. We sample the output at various times pre- and postimpact, and examine the probability of detecting a significant change in population parameters. The incidence function model approach turns out to have little power to detect environmental impacts on metapopulations with small numbers of patches. (C) 2001 Elsevier Science Ltd. All rights reserved.

Model-based procedure for scale-up of wet, overflow ball mills - Part III: Validation and discussion

A new ball mill scale-up procedure is developed. This procedure has been validated using seven sets of Ml-scale ball mil data. The largest ball mills in these data have diameters (inside liners) of 6.58m. The procedure can predict the 80% passing size of the circuit product to within +/-6% of the measured value, with a precision of +/-11% (one standard deviation); the re-circulating load to within +/-33% of the mass-balanced value (this error margin is within the uncertainty associated with the determination of the re-circulating load); and the mill power to within +/-5% of the measured value. This procedure is applicable for the design of ball mills which are preceded by autogenous (AG) mills, semi-autogenous (SAG) mills, crushers and flotation circuits. The new procedure is more precise and more accurate than Bond's method for ball mill scale-up. This procedure contains no efficiency correction which relates to the mill diameter. This suggests that, within the range of mill diameter studied, milling efficiency does not vary with mill diameter. This is in contrast with Bond's equation-Bond claimed that milling efficiency increases with mill diameter. (C) 2001 Elsevier Science Ltd. All rights reserved.

Genetics of brain function and cognition

There is overwhelming evidence for the existence of substantial genetic influences on individual differences in general and specific cognitive abilities, especially in adults. The actual localization and identification of genes underlying variation in cognitive abilities and intelligence has only just started, however. Successes are currently limited to neurological mutations with rather severe cognitive effects. The current approaches to trace genes responsible for variation in the normal ranges of cognitive ability consist of large scale linkage and association studies. These are hampered by the usual problems of low statistical power to detect quantitative trait loci (QTLs) of small effect. One strategy to boost the power of genomic searches is to employ endophenotypes of cognition derived from the booming field of cognitive neuroscience This special issue of Behavior Genetics reports on one of the first genome-wide association studies for general IQ. A second paper summarizes candidate genes for cognition, based on animal studies. A series of papers then introduces two additional levels of analysis in the ldquoblack boxrdquo between genes and cognitive ability: (1) behavioral measures of information-processing speed (inspection time, reaction time, rapid naming) and working memory capacity (performance on on single or dual tasks of verbal and spatio-visual working memory), and (2) electrophyiosological derived measures of brain function (e.g., event-related potentials). The obvious way to assess the reliability and validity of these endophenotypes and their usefulness in the search for cognitive ability genes is through the examination of their genetic architecture in twin family studies. Papers in this special issue show that much of the association between intelligence and speed-of-information processing/brain function is due to a common gene or set of genes, and thereby demonstrate the usefulness of considering these measures in gene-hunting studies for IQ.

Prediction of outcomes in hypertensive patients with suspected coronary disease

Stress echocardiography has been shown to improve the diagnosis of coronary artery disease in the presence of hypertension, but its value in prognostic evaluation is unclear. We sought to determine whether stress echocardiography could be used to predict mortality in 2363 patients with hypertension, who were followed for up to 10 years (mean 4.0+/-1.8) for death and revascularization. Stress echocardiograms were normal in 1483 patients (63%), 16% had resting left ventricular (LV) dysfunction alone, and 21% had ischemia. Abnormalities were confined to one territory in 489 patients (21%) and to multiple territories in 365 patients (15%). Cardiac death was less frequent among the patients able to exercise than among those undergoing dobutamine echocardiography (4% versus 7%, P<0.001). The risk of death in patients with a negative stress echocardiogram was <1% per year. Ischemia identified by stress echocardiography was an independent predictor of mortality in those able to exercise (hazard ratio 2.21, 95% confidence intervals 1.10 to 4.43, P=0.0001) as well as those undergoing dobutamine echo (hazard ratio 2.39, 95% confidence intervals 1.53 to 3.75, P=0.0001); other predictors were age, heart failure, resting LV dysfunction, and the Duke treadmill score. In stepwise models replicating the sequence of clinical evaluation, the results of stress echocardiography added prognostic power to models based on clinical and stress-testing variables. Thus, the results of stress echocardiography are an independent predictor of cardiac death in hypertensive patients with known or suspected coronary artery disease, incremental to clinical risks and exercise results.

Protection of mice from group A streptococcal infection by intranasal immunisation with a peptide vaccine that contains a conserved M protein B cell epitope and lacks a T cell autoepitope

Infection with group A streptococci (GAS) can lead to rheumatic fever (RF) and rheumatic heart disease (RHD) which are a major health concern particularly in indigenous populations worldwide, and especially in Australian Aboriginals. A primary route of GAS infection is via the upper respiratory tract, and therefore, a major goal of research is the development of a mucosal-based GAS vaccine, The majority of the research to date has focused on the GAS M protein since immunity to GAS is mediated by M protein type-specific opsonic antibodies. There are two major impediments to the development of a vaccine-the variability in M proteins and the potential for the induction of an autoimmune response. To develop a safe and broad-based vaccine, we have therefore focused on the GAS M protein conserved C-region, and have identified peptides, J8 and the closely related J8 peptide (J14), which may be important in protective immunity to GAS infection. Using a mucosal animal model system, our data have shown a high degree of throat GAS colonisation in B10.BR mice 24 h following intranasal immunisation with the mucosal adjuvant, cholera toxin B subunit (CTB), and/or diptheria toxoid (dT) carrier, or PBS alone, and challenge with the M1 GAS strain. However, GAS colonisation of the throat was significantly reduced following intranasal immunisation of mice with the vaccine candidate J8 conjugated to dT or J14-dT when administered with CTB. Moreover, J8-dT/CTB and J14-dT/CTB-immunised mice had a significantly higher survival when compared to CTB and PBS-immunised control mice. These data indicate that immunity to GAS infection can be evoked by intranasal immunisation with a GAS M protein C-region peptide vaccine that contains a protective B cell epitope and lacks a T cell autoepitope. (C) 2002 Published by Elsevier Science Ltd.

Apocalypse forever? International relations implications of 11 September

This is a contribution to ongoing discussion of the international relations issues raised by the terrorist attacks of 11 September 2001. It acknowledges apparent failings (of analysis or prediction) in the IR literature but then suggests the shortcomings are really the product of divergent traditions of analysis (behaviouralism, structuralism and evolutionism) which isolate different aspects of phenomena for attention. The paper then discusses the contrast between hard power and soft power - to help identify the distinctiveness of the new forms of terrorism (their non-linear objectives and the lack of proportionality involved). It concludes on an encouraging note by urging international cooperation as a solution, even in cases where the protagonists' resentments have tended to militate against conventional channels of dispute resolution.

Desafios da administra????o p??blica brasileira: governan??a, autonomia, neutralidade

O objetivo deste texto ?? iniciar um levantamento da dificuldades impostas ?? reforma administrativa a partir da considera????o do problema da neutralidade da burocracia versus o requisito da autonomia de decis??o, elemento fundamental do Modelo de Administra????o P??blica Gerencial. Tal problema assume especial relev??ncia frente aos objetivos de aumentar a governan??a do Estado e constitui um dos desafios centrais do Plano Diretor da Reforma do Aparelho do Estado, particularmente no que diz respeito ?? forma de administra????o do chamado ???n??cleo estrat??gico??? ??? respons??vel pela defini????o das leis e pol??ticas p??blicas ??? e das ???atividades exclusivas de Estado??? ??? caracterizadas pelo exerc??cio do poder de legislar e tributar, fiscalizando, regulamentando e transferindo recursos. Para isso, a discuss??o est?? organizada em quatro se????es. Na primeira, s??o rapidamente apresentados os conceitos de governabilidade e governan??a, com ??nfase no fato de que a distin????o entre eles representa apenas um recurso anal??tico. Na segunda se????o, a partir das distin????es cl??ssicas de Max Weber entre pol??tica e administra????o, pol??ticos e burocratas, busca-se caracterizar a neutralidade burocr??tica e mostrar que representa, na realidade, apenas um dos elementos de uma constru????o t??pico ideal, cada vez mais distante de qualquer correspond??ncia com o mundo real. Em seguida, comenta-se rapidamente o processo de mudan??a do modelo de administra????o p??blica; e s??o apresentadas algumas das caracter??sticas do chamado Modelo de Administra????o P??blica Gerencial que, em lugar da neutralidade, implicam elevado grau de autonomia por parte dos agentes burocr??ticos. Por fim, s??o tecidas algumas considera????es, procurando mostrar que, da mesma maneira que a neutralidade, a autonomia burocr??tica apresenta dificuldades e que a proposta da ???autonomia imersa??? ou ???autonomia inserida??? exibe implica????es que merecem reflex??o mais demorada.

Descentraliza????o da gest??o ambiental: an??lise do processo de cria????o de organiza????es municipais de meio ambiente no sul catarinense

Esta pesquisa est?? inserida na tem??tica da descentraliza????o da gest??o ambiental no Brasil e trata de analisar os principais motivos que t??m levado os munic??pios a institucionalizarem a ??rea ambiental no ??mbito local. Para tanto, foram selecionados munic??pios da regi??o sul catarinense, tendo em vista o processo recente de cria????o de ??rg??os locais de gest??o ambiental e tamb??m a peculiaridade de a grande maioria desses munic??pios estarem optando pelo estabelecimento de funda????es p??blicas municipais de meio ambiente. Como resultado da investiga????o, se percebeu que um dos fatores principais para a cria????o de organiza????es municipais de gest??o ambiental tem sido a necessidade de maior agilidade nos processos de licenciamento ambiental. Em rela????o ?? op????o pela figura jur??dica das funda????es, o principal argumento dos munic??pios tem sido a maior autonomia e independ??ncia em rela????o ao Executivo municipal para a execu????o de suas a????es.

Lucidez-Embriaguez, movimento e arrebatamento: homens,(Semi)deuses que perambulam e a educação menor num bairro de uma rede municipal

A tese afirma a vida por meio das biopotências que se manifestam em movimentações invisíveis aos olhos acostumados a permitir o ver, o julgar e o falar. Foca o tempo presente, na comunicação em redes, traz em si a potência de reatar a multidão, com a capacidade de sondar possibilidades mostrando o que antes parecia opaco e impossível. Perambular é ligar nas redes quentes de um bairro com/no/do território ao privilegiar o movimento, o processo, sempre caminhando pelas vias e conexões abertas, aposta estética-ética-política nos paradoxos sem superação e não hierarquizados. Toma como método de pesquisa-intervenção elementos de uma cartografia de movimentos e devires, traçando um perambular rizomático em que são problematizados a constituição do problema de pesquisa, que considera a construção do conhecimento diversificada, descentralizada e horizontalizada. Problematiza as práticas discursivas de si em suas relações com a biopolítica, a governabilidade e a biopolítica das populações. O que está(rá) rolando nesse bairro, no que foi chamado de criança, adolescente, escola, compor para que as coisas apareçam, junto com outros que vivem a loucura em duplas e trios. A tese é a possibilidade da existência de uma educação menor na periferia para as populações marginalizadas, muçulmanizadas. Educação menor, da sala de aula, do bairro, do cotidiano de professores, familiares e alunos. Educação que permite revolucionários, na medida em que alguma revolução ainda faz sentido na educação nesses dias. A educação menor constitui-se, assim, num empreendimento de militância, de professores militantes. Plano das afecções em que não há unidades, apenas intensidade. A tese fala do processo, de como reproduzir, ou não, os modos de subjetividade dominante, não se trata de medidas - "menor" ou "pequeno". Nesse sentido, é preciso considerar os efeitos de produção de subjetividade e a incorporação dos fatos à própria vida. A tese analisa movimentos instituintes buscando reconhecê-los em sua natureza contestatória e transgressora e ter conhecimento de como se organiza na escola e muito além dela. Discutindo a produtividade dessa coreografia do perambular, esboçamos movimentos que denominamos: estradas que levam a nada, além muro

Para uma sócio-história da língua Guarani no Espírito Santo : uma análise sob a perspectiva sociolinguística

Estima-se que restam hoje cerca de 50 mil índios Guarani no Brasil, que se situam, principalmente, na faixa litorânea que vai desde os estados do sul até o território capixaba, o Espírito Santo. Considerando que essa comunidade se mantém bilíngue, o presente trabalho objetiva discutir se, na situação de contato entre o Guarani e o Português, a primeira língua está ou não cedendo lugar à segunda. Para alcançar esse objetivo, foi formado um banco de dados de fala por meio de entrevistas realizadas nas aldeias, que versaram sobre as tradições históricas, a família, a religião, a economia e o meio ambiente – aspectos considerados por eles como as principais armas de resistência desse povo. A análise tomou por base os pressupostos da Sociolinguística/Contato Linguístico, com teóricos como Weinreich (1953), Fishman (1968; 1972), Appel e Muysken (1996), Coulmas (2005) e outros, que discutem temas pertinentes à pesquisa em questão: o contato linguístico e a manutenção/substituição de línguas minoritárias. Acredita-se que, apesar do contato com o português pela venda de artesanatos, pela mídia e pela atuação da escola e sua ação integralizadora, prevista pelo Estatuto do Índio, o Guarani mantém a sua língua materna - ainda que estigmatizada - devido à forte religiosidade que norteia todo o seu modo de vida. Ele entende a palavra como um dom e confere a ela um poder mítico de conexão com o mundo espiritual, o que, ao mesmo tempo, confere extrema importância à língua minoritária e favorece a sua preservação, enquanto marca importante da cultura e identidade desse povo.