A comprehensive meta-analysis of common genetic variants in autism spectrum conditions

Background Autism spectrum conditions (ASC) are a group of neurodevelopmental conditions characterized by difficulties in social interaction and communication alongside repetitive and stereotyped behaviours. ASC are heritable, and common genetic variants contribute substantial phenotypic variability. More than 600 genes have been implicated in ASC to date. However, a comprehensive investigation of candidate gene association studies in ASC is lacking. Methods In this study, we systematically reviewed the literature for association studies for 552 genes associated with ASC. We identified 58 common genetic variants in 27 genes that have been investigated in three or more independent cohorts and conducted a meta-analysis for 55 of these variants. We investigated publication bias and sensitivity and performed stratified analyses for a subset of these variants. Results We identified 15 variants nominally significant for the mean effect size, 8 of which had P values below a threshold of significance of 0.01. Of these 15 variants, 11 were re-investigated for effect sizes and significance in the larger Psychiatric Genomics Consortium dataset, and none of them were significant. Effect direction for 8 of the 11 variants were concordant between both the datasets, although the correlation between the effect sizes from the two datasets was poor and non-significant. Conclusions This is the first study to comprehensively examine common variants in candidate genes for ASC through meta-analysis. While for majority of the variants, the total sample size was above 500 cases and 500 controls, the total sample size was not large enough to accurately identify common variants that contribute to the aetiology of ASC.

Meta-analysis to integrate effect sizes within a paper: Possible misuse and Type-1 error inflation

In recent years an increasing number of papers have employed meta-analysis to integrate effect sizes of researchers’ own series of studies within a single paper (“internal meta-analysis”). Although this approach has the obvious advantage of obtaining narrower confidence intervals, we show that it could inadvertently inflate false-positive rates if researchers are motivated to use internal meta-analysis in order to obtain a significant overall effect. Specifically, if one decides whether to stop or continue a further replication experiment depending on the significance of the results in an internal meta-analysis, false-positive rates would increase beyond the nominal level. We conducted a set of Monte-Carlo simulations to demonstrate our argument, and provided a literature review to gauge awareness and prevalence of this issue. Furthermore, we made several recommendations when using internal meta-analysis to make a judgment on statistical significance.

Are visual threats prioritized without awareness? A critical review and meta analysis involving 3 behavioral paradigms and 2696 observers

Given capacity limits, only a subset of stimuli 1 give rise to a conscious percept. Neurocognitive models suggest that humans have evolved mechanisms that operate without awareness and prioritize threatening stimuli over neutral stimuli in subsequent perception. In this meta analysis, we review evidence for this ‘standard hypothesis’ emanating from three widely used, but rather different experimental paradigms that have been used to manipulate awareness. We found a small pooled threat-bias effect in the masked visual probe paradigm, a medium effect in the binocular rivalry paradigm and highly inconsistent effects in the breaking continuous flash suppression paradigm. Substantial heterogeneity was explained by the stimulus type: the only threat stimuli that were robustly prioritized across all three paradigms were fearful faces. Meta regression revealed that anxiety may modulate threat biases, but only under specific presentation conditions. We also found that insufficiently rigorous awareness measures, inadequate control of response biases and low level confounds may undermine claims of genuine unconscious threat processing. Considering the data together, we suggest that uncritical acceptance of the standard hypothesis is premature: current behavioral evidence for threat-sensitive visual processing that operates without awareness is weak.

Sexually Dimorphic Effect of the Val66Met Polymorphism of BDNF on Susceptibility to Alzheimer`s Disease: New Data and Meta-Analysis

Conflicting results have been reported as to whether genetic variations (Val66Met and C270T) of the brain-derived neurotrophic factor gene (RDNF) confer susceptibility to Alzheimer`s disease (AD). We genotyped these polymorphisms in a Japanese sample of 657 patients with AD and 525 controls, and obtained weak evidence of association for Val66Met (P = 0.063), but not for C270T. After stratification by sex, we found a significant allelic association between Val66Met and AD in women (P = 0.017), but not in men. To confirm these observations, we collected genotyping data for each sex from 16 research centers worldwide (4,711 patients and 4,537 controls in total). The meta-analysis revealed that there was a clear sex difference in the allelic association; the Met66 allele confers susceptibility to AD in women (odds ratio = 1.14, 95% CI 1.05-1.24, P = 0.002), but not in men. Our results provide evidence that the Met66 allele of BDNF has a sexually dimorphic effect on susceptibility to AD. (C) 2009 Wiley-Liss, Inc.

Heuristics for the one-dimensional cutting stock problem with limited multiple stock lengths

This paper deals with the classical one-dimensional integer cutting stock problem, which consists of cutting a set of available stock lengths in order to produce smaller ordered items. This process is carried out in order to optimize a given objective function (e.g., minimizing waste). Our study deals with a case in which there are several stock lengths available in limited quantities. Moreover, we have focused on problems of low demand. Some heuristic methods are proposed in order to obtain an integer solution and compared with others. The heuristic methods are empirically analyzed by solving a set of randomly generated instances and a set of instances from the literature. Concerning the latter. most of the optimal solutions of these instances are known, therefore it was possible to compare the solutions. The proposed methods presented very small objective function value gaps. (C) 2008 Elsevier Ltd. All rights reserved.

Fast heuristics for the Steiner tree problem with revenues, budget and hop constraints

This article describes and compares three heuristics for a variant of the Steiner tree problem with revenues, which includes budget and hop constraints. First, a greedy method which obtains good approximations in short computational times is proposed. This initial solution is then improved by means of a destroy-and-repair method or a tabu search algorithm. Computational results compare the three methods in terms of accuracy and speed. (C) 2007 Elsevier B.V. All rights reserved.

Structural requirement for PPAR gamma binding revealed by a meta analysis of holo-crystal structures

PPAR gamma is a ligand regulated transcriptional factor that modulates the transcription of several genes involved in fat and sugar metabolism. Due to its easy bacterial expression and crystallization, several crystal structures of holo-PPAR gamma have been reported and deposited in the Protein Data Bank. Here, we investigated the three-dimensional electrostatic properties of 55 PPAR gamma ligands and used this information for clustering them through principal component analysis. We found out that, according to their electrostatic potential, these ligands can be separated in three groups, with different binding features. We also observed that non-selective and selective ligands show different 3D electrostatic properties and are separated in different clusters. The relevance of this analysis for the development of new binders is discussed. (C) 2010 Elsevier Masson SAS. All rights reserved.

Cambios en el uso de la lengua meta en el aula tras la introducción de Lgy 11 : Una revisión sistemática de literatura con el objetivo de investigar si ha cambiado el uso de la lengua meta en la enseñanza de lenguas modernas tras la introducción de Lgy 11

Resumen: La tesina investiga si ha cambiado el uso de la lengua meta en la enseñanza de lenguas modernas en la escuela sueca tras el inicio de Lgy 11. El estudio se realiza a través de una revisión sistemática de literatura. Vemos que en nuestro campo de investigación faltan estudios profundos. Los estudios encontrados indican un aumento del uso de la lengua meta en el aula tras el inicio de Lgy 11. Sin embargo, en pocas situaciones parece cumplirse la norma que indica que todo lo esencial de la enseñanza debe realizarse en la lengua meta. Las unidades de gramática parecen ser el segmento de la enseñanza en el cual los profesores usan el sueco más extensamente. Según los estudios analizados solamente una profesora incorpora la lengua meta cuando enseña la gramática. No obstante, la mayoría de los profesores expresan que la gramática es una parte esencial de la enseñanza de lenguas modernas

La noción de lo esencial en la enseñanza de lenguas modernas según los profesores. : Entrevistas con cinco profesores sobre la norma "Todo lo esencial de la enseñanza debe realizarse en la lengua meta" de Gy11.

La tesina investiga cómo cinco profesores interpretan la norma de Gy11 que indica que todo lo esencial de la enseñanza de lenguas modernas debe realizarse en la lengua meta. Las entrevistas semiestructuradas indican que los profesores interpretan la norma de maneras parecidas, es decir, que los profesores deben usar la lengua meta lo máximo posible en la enseñanza. La mayoría de los profesores están de acuerdo con la norma, sin embargo, tienen varias críticas contra Skolverket y la formulación de la norma. Ninguno de los profesores ha cambiado su uso de la lengua meta en el aula debido a la norma.

Simulation model using meta heuristic algorithms for achieving optimal arrangement of storage bins in a sawmill yard

Bin planning (arrangements) is a key factor in the timber industry. Improper planning of the storage bins may lead to inefficient transportation of resources, which threaten the overall efficiency and thereby limit the profit margins of sawmills. To address this challenge, a simulation model has been developed. However, as numerous alternatives are available for arranging bins, simulating all possibilities will take an enormous amount of time and it is computationally infeasible. A discrete-event simulation model incorporating meta-heuristic algorithms has therefore been investigated in this study. Preliminary investigations indicate that the results achieved by GA based simulation model are promising and better than the other meta-heuristic algorithm. Further, a sensitivity analysis has been done on the GA based optimal arrangement which contributes to gaining insights and knowledge about the real system that ultimately leads to improved and enhanced efficiency in sawmill yards. It is expected that the results achieved in the work will support timber industries in making optimal decisions with respect to arrangement of storage bins in a sawmill yard.