Deriving percentage study weights in multi-parameter meta-analysis models: with application to meta-regression, network meta-analysis and one-stage individual participant data models.

Many meta-analysis models contain multiple parameters, for example due to multiple outcomes, multiple treatments or multiple regression coefficients. In particular, meta-regression models may contain multiple study-level covariates, and one-stage individual participant data meta-analysis models may contain multiple patient-level covariates and interactions. Here, we propose how to derive percentage study weights for such situations, in order to reveal the (otherwise hidden) contribution of each study toward the parameter estimates of interest. We assume that studies are independent, and utilise a decomposition of Fisher's information matrix to decompose the total variance matrix of parameter estimates into study-specific contributions, from which percentage weights are derived. This approach generalises how percentage weights are calculated in a traditional, single parameter meta-analysis model. Application is made to one- and two-stage individual participant data meta-analyses, meta-regression and network (multivariate) meta-analysis of multiple treatments. These reveal percentage study weights toward clinically important estimates, such as summary treatment effects and treatment-covariate interactions, and are especially useful when some studies are potential outliers or at high risk of bias. We also derive percentage study weights toward methodologically interesting measures, such as the magnitude of ecological bias (difference between within-study and across-study associations) and the amount of inconsistency (difference between direct and indirect evidence in a network meta-analysis)

Mechanisms for Decreased Function of B Cells in Aged Mice and Humans

Abstract The immune system has been known for some time to be compromised in aged individuals, e.g., both mice and humans, and in both humoral and cellular responses. Our studies have begun to elucidate intrinsic B lymphocyte defects in Ig class switch recombination, activation-induced cytidine deaminase, and E47 transcription factor expression. These defects occur in both mice and humans. Our studies have also shown that tristetraprolin is one of the key players in regulating the decreased E47 mRNA stability in aged B lymphocytes. These and current studies should lead to improvements in B lymphocyte function in aged populations

Early social environment influences the behaviour of a family-living lizard

Financial support for this research was provided by the Australian Research Council (DP130102998; grant to M.J.W. and R.B.W.), Natural Sciences and Engineering Research Council of Canada (scholarship to J.L.R.), the Australasian Society for the Study of Animal Behaviour, and Macquarie University. D.W.A.N. was supported by an ARC Discovery Early Career Research Award (DE150101774) and UNSW Vice Chancellors Fellowship.Early social environment can play a significant role in shaping behavioural development. For instance, in many social mammals and birds, isolation rearing results in individuals that are less exploratory, shyer, less social and more aggressive than individuals raised in groups. Moreover, dynamic aspects of social environments, such as the nature of relationships between individuals, can also impact the trajectory of development. We tested if being raised alone or socially affects behavioural development in the family-living tree skink, Egernia striolata. Juveniles were raised in two treatments: alone or in a pair. We assayed exploration, boldness, sociability and aggression repeatedly throughout each juvenile's first year of life, and also assessed social interactions between pairs to determine if juveniles formed dominant–subordinate relationships. We found that male and/or the larger skinks within social pairs were dominant. Developing within this social environment reduced skink growth, and subordinate skinks were more prone to tail loss. Thus, living with a conspecific was costly for E. striolata. The predicted negative effects of isolation failed to materialize. Nevertheless, there were significant differences in behavioural traits depending on the social environment (isolated, dominant or subordinate member of a pair). Isolated skinks were more social than subordinate skinks. Subordinate skinks also became more aggressive over time, whereas isolated and dominant skinks showed invariable aggression. Dominant skinks became bolder over time, whereas isolated and subordinate skinks were relatively stable in their boldness. In summary, our study is evidence that isolation rearing does not consistently affect behaviour across all social taxa. Our study also demonstrates that the social environment plays an important role in behavioural development of a family-living lizard.Publisher PDFPeer reviewe

The Effects of Stimulant Medication on the Online Story Narrations of Children with ADHD

The current study investigated the inclusion of goal-based story events in the online story narrations of children with ADHD, as compared with their peers, and explored the effect of stimulant medication on the narrations in children with ADHD. Children completed a narration task on two separate occasions. Children with ADHD (n = 17) completed one narration on medication and the other one on placebo. Results indicated that narrations of comparison children (n= 25) were significantly more likely than narrations of children with ADHD to include the story’s positive outcome, completion of the story’s overall goal, and specific attempts linked to the goal. Children with ADHD included a larger total number of clauses in their narrations when on stimulant medication than when on placebo, but medication showed no significant effects for any other variables. Results indicate that stimulant medication may not be effective at reducing goal-based story comprehension deficits in children with ADHD

Sperm storage in a family-living lizard, the Tree Skink (Egernia striolata)

This work was supported by the Australian Research Council (ARC DP130102998 grant to MJW and RWB), Natural Sciences and Engineering Research Council of Canada (scholarship to JLR), the Australasian Society for the Study of Animal Behavior, the Australian Museum, and Macquarie University (scholarship to JLR).The ability to produce viable offspring without recently mating, either through sperm storage or parthenogenesis, can provide fitness advantages under a suite of challenging ecological scenarios. Using genetic analysis, we demonstrate that three wild-caught female Tree Skinks (Egernia striolata) reproduced in captivity with no access to males for over a year, and that this is best explained by sperm storage. To the best of our knowledge, this is the first time female sperm storage has been documented in any monogamous family-living reptile, including social Australian egerniine skinks (from the subfamily Egerniinae). Furthermore, by using paternal reconstruction of genotypes we show that captive-born offspring produced by the same females in the preceding year, presumably without sperm storage, were sired by different males. We qualitatively compared aspects of these females' mates and offspring between years. The parents of each litter were unrelated, but paternal and offspring genotypes from litters resulting from stored sperm were more heterozygous than those inferred to be from recent matings. Family-living egerniine skinks generally have low rates of multiple paternity, yet our study suggests that female sperm storage, potentially from outside social partners, offers the real possibility of benefits. Possible benefits include increasing genetic compatibility of mates and avoiding inbreeding depression via cryptic female choice. Sperm storage in Tree Skinks, a family-living lizard with a monogamous mating system, suggests that females may bet-hedge through extra-pair copulation with more heterozygous males, reinforcing the idea that females could have more control on reproductive outcomes than previously thought.PostprintPeer reviewe

Genomic divergence of Escherichia coli strains: evidence for horizontal transfer and variation in mutation rates

This report describes the sequencing in the Escherichia coli B genome of 36 randomly chosen regions that are present in most or all of the fully sequenced E. coli genomes. The phylogenetic relationships among E. coli strains were examined, and evidence for the horizontal gene transfer and variation in mutation rates was determined. The overall phylogenetic tree indicated that E. coli B and K-12 are the most closely related strains, with E. coli O157:H7 being more distantly related, Shigella flexneri 2a even more, and E. coli CFT073 the most distant strain. Within the B, K-12, and O157:H7 clusters, several regions supported alternative topologies. While horizontal transfer may explain these phylogenetic incongruities, faster evolution at synonymous sites along the O157:H7 lineage was also identified. Further interpretation of these results is confounded by an association among genes showing more rapid evolution and results supporting horizontal transfer. Using genes supporting the B and K-12 clusters, an estimate of the genomic mutation rate from a long-term experiment with E. coli B, and an estimate of 200 generations per year, it was estimated that B and K-12 diverged several hundred thousand years ago, while O157:H7 split off from their common ancestor about 1.5–2 million years ago [Int Microbiol 2005 8(4):271-278

Alcohol Use and Strenuous Physical Activity in College Students: A Longitudinal Test of 2 Explanatory Models of Health Behavior

Objective: To help clarify the effect of gender on the bidirectional relationship between alcohol use and strenuous physical activity in college students. Participants: Five hundred twenty-four (52% female) college students recruited in August 2008 and 2009 and followed up in April 2009 and April 2011, respectively. Methods: Participants reported their alcohol use and strenuous physical activity on 2 occasions (baseline and follow-up) spaced approximately 1 or 2 years apart. Results: For females, alcohol use quantity at baseline was associated with increased strenuous physical activity at 1- and 2-year follow-ups, and alcohol use frequency at baseline was associated with decreased strenuous physical activity at 2-year follow-up. For males, alcohol use frequency at baseline predicted decreased strenuous physical activity at 1-year follow-up. Conclusions: Gender differences may be explained from an eating disorders perspective such that women use physical activity as a compensatory strategy to combat potential weight gain from calories consumed during alcohol use

Multivariate and network meta-analysis of multiple outcomes and multiple treatments: rationale, concepts, and examples

Organisations such as the National Institute for Health and Care Excellence require the synthesis of evidence from existing studies to inform their decisions—for example, about the best available treatments with respect to multiple efficacy and safety outcomes. However, relevant studies may not provide direct evidence about all the treatments or outcomes of interest. Multivariate and network meta-analysis methods provide a framework to address this, using correlated or indirect evidence from such studies alongside any direct evidence. In this article, the authors describe the key concepts and assumptions of these methods, outline how correlated and indirect evidence arises, and illustrate the contribution of such evidence in real clinical examples involving multiple outcomes and multiple treatment

Schizophrenia Gene Networks and Pathways and Their Applications for Novel Candidate Gene Selection

Background Schizophrenia (SZ) is a heritable, complex mental disorder. We have seen limited success in finding causal genes for schizophrenia from numerous conventional studies. Protein interaction network and pathway-based analysis may provide us an alternative and effective approach to investigating the molecular mechanisms of schizophrenia. Methodology/Principal Findings We selected a list of schizophrenia candidate genes (SZGenes) using a multi-dimensional evidence-based approach. The global network properties of proteins encoded by these SZGenes were explored in the context of the human protein interactome while local network properties were investigated by comparing SZ-specific and cancer-specific networks that were extracted from the human interactome. Relative to cancer genes, we observed that SZGenes tend to have an intermediate degree and an intermediate efficiency on a perturbation spreading throughout the human interactome. This suggested that schizophrenia might have different pathological mechanisms from cancer even though both are complex diseases. We conducted pathway analysis using Ingenuity System and constructed the first schizophrenia molecular network (SMN) based on protein interaction networks, pathways and literature survey. We identified 24 pathways overrepresented in SZGenes and examined their interactions and crosstalk. We observed that these pathways were related to neurodevelopment, immune system, and retinoic X receptor (RXR). Our examination of SMN revealed that schizophrenia is a dynamic process caused by dysregulation of the multiple pathways. Finally, we applied the network/pathway approach to identify novel candidate genes, some of which could be verified by experiments. Conclusions/Significance This study provides the first comprehensive review of the network and pathway characteristics of schizophrenia candidate genes. Our preliminary results suggest that this systems biology approach might prove promising for selection of candidate genes for complex diseases. Our findings have important implications for the molecular mechanisms for schizophrenia and, potentially, other psychiatric disorders

Meta-analysis of randomized phase II trials to inform subsequent phase III decisions

BACKGROUND: If multiple Phase II randomized trials exist then meta-analysis is favorable to increase statistical power and summarize the existing evidence about an intervention's effect in order to help inform Phase III decisions. We consider some statistical issues for meta-analysis of Phase II trials for this purpose, as motivated by a real example involving nine Phase II trials of bolus thrombolytic therapy in acute myocardial infarction with binary outcomes. METHODS: We propose that a Bayesian random effects logistic regression model is most suitable as it models the binomial distribution of the data, helps avoid continuity corrections, accounts for between-trial heterogeneity, and incorporates parameter uncertainty when making inferences. The model also allows predictions that inform Phase III decisions, and we show how to derive: (i) the probability that the intervention will be truly beneficial in a new trial, and (ii) the probability that, in a new trial with a given sample size, the 95% credible interval for the odds ratio will be entirely in favor of the intervention. As Phase II trials are potentially optimistic due to bias in design and reporting, we also discuss how skeptical prior distributions can reduce this optimism to make more realistic predictions. RESULTS: In the example, the model identifies heterogeneity in intervention effect missed by an I-squared of 0%. Prediction intervals accounting for this heterogeneity are shown to support subsequent Phase III trials. The probability of success in Phase III trials increases as the sample size increases, up to 0.82 for intracranial hemorrhage and 0.79 for reinfarction outcomes. CONCLUSIONS: The choice of meta-analysis methods can influence the decision about whether a trial should proceed to Phase III and thus need to be clearly documented and investigated whenever a Phase II meta-analysis is performed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1745-6215-15-346) contains supplementary material, which is available to authorized users