An Empirical Comparison of Meta- and Mega-Analysis With Data From the ENIGMA Obsessive-Compulsive Disorder Working Group

Objective: Brain imaging communities focusing on different diseases have increasingly started to collaborate and to pool data to perform well-powered meta- and mega-analyses. Some methodologists claim that a one-stage individual-participant data (IPD) mega-analysis can be superior to a two-stage aggregated data meta-analysis, since more detailed computations can be performed in a mega-analysis. Before definitive conclusions regarding the performance of either method can be drawn, it is necessary to critically evaluate the methodology of, and results obtained by, meta- and mega-analyses. Methods: Here, we compare the inverse variance weighted random-effect meta-analysis model with a multiple linear regression mega-analysis model, as well as with a linear mixed-effects random-intercept mega-analysis model, using data from 38 cohorts including 3,665 participants of the ENIGMA-OCD consortium. We assessed the effect sizes and standard errors, and the fit of the models, to evaluate the performance of the different methods. Results: The mega-analytical models showed lower standard errors and narrower confidence intervals than the meta-analysis. Similar standard errors and confidence intervals were found for the linear regression and linear mixed-effects random-intercept models. Moreover, the linear mixed-effects random-intercept models showed better fit indices compared to linear regression mega-analytical models. Conclusions: Our findings indicate that results obtained by meta- and mega-analysis differ, in favor of the latter. In multi-center studies with a moderate amount of variation between cohorts, a linear mixed-effects random-intercept mega-analytical framework appears to be the better approach to investigate structural neuroimaging dat

A mega-analysis of memory reports from eight peer-reviewed false memory implantation studies

Understanding that suggestive practices can promote false beliefs and false memories forchildhood events is important in many settings (e.g., psychotherapeutic, medical, legal). The generalizability of findings from memory implantation studies has been questioned due to variability in estimates across studies. Such variability is partly due to false memories having been operationalized differently across studies and to differences in memory induction techniques. We explored ways of defining false memory based on memory science and developed a reliable coding system that we applied to reports from eight published implantation studies (N=423). Independent raters coded transcripts using seven criteria: accepting the suggestion, elaboration beyond the suggestion, imagery, coherence, emotion, memory statements, and not rejecting the suggestion. Using this scheme, 30.4% of cases were classified as false memories and another 23% were classified as having accepted the event to some degree. When the suggestion included self-relevant information, an imagination procedure, and was not accompanied by a photo depicting the event, the memory formation rate was 46.1%. Our research demonstrates a useful procedure for systematically combining data that are not amenable to meta-analysis, and provides the most valid estimate of false memory formation and associated moderating factors within the implantation literature to date

Pooling fMRI Data: Meta-Analysis, Mega-Analysis and Multi-Center Studies

The quantitative analysis of pooled data from related functional magnetic resonance imaging (fMRI) experiments has the potential to significantly accelerate progress in brain mapping. Such data-pooling can be achieved through meta-analysis (the pooled analysis of published results), mega-analysis (the pooled analysis of raw data) or multi-site studies, which can be seen as designed mega-analyses. Current limitations in function-location brain mapping and how data-pooling can be used to remediate them are reviewed, with particular attention to power aggregation and mitigation of false positive results. Some recently developed analysis tools for meta- and mega-analysis are also presented, and recommendations for the conduct of valid fMRI data pooling are formulated

An empirical comparison of meta-analysis and mega-analysis of individual participant data for identifying gene-environment interactions

pre-printMeta-analysis combining results from multiple studies is a standard practice in GWAS. For genetic main effects, meta-analysis has been shown to provide comparable results as mega-analysis that jointly analyzes the pooled data from the available studies. Gene-environment interaction (GEI) studies are an important component of genetic epidemiology research since they can explain a part of the missing heritability, elucidate the biological networks underlying disease risk, and identify individuals at high risk for disease. However, it is not known whether meta- and mega-analyses of interactions also yield comparable results. In this study, we investigate whether both approaches provide comparable results for identifying interaction effects using empirical data from 4 studies: the Framingham Heart Study, GENOA, HERITAGE and HyperGEN. We performed meta-analysis of cohort-specific results and mega-analysis by analyzing the pooled data from all 4 studies. We used the standard 1 degree of freedom (df) test of main effect only, the 1 df test of the interaction effect (in the presence of main effect), and the joint 2 df test of main and interaction effects. We found that the results from meta- and mega-analyses were highly consistent for all three tests. The correlation between -log (p) values from the two analyses was 0.89 for the 1 df main effect, 0.90 for the 1 df interaction test, and 0.91 for the joint 2 df test. Although mega-analysis provided slightly better results as expected, both yielded very similar results for the most promising SNPs. Moreover, mega-analysis is not always feasible especially in very large and diverse consortia since pooling of raw data may be limited by the terms of the informed consent. Our study illustrates that meta-analysis can be an effective approach also for identifying interactions in very large consortia without losing appreciable power

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

sem informaçãoThe epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant91sem informaçãosem informaçãosem informaçã

Multi-site genetic analysis of diffusion images and voxelwise heritability analysis : a pilot project of the ENIGMA–DTI working group

The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium was set up to analyze brain measures and genotypes from multiple sites across the world to improve the power to detect genetic variants that influence the brain. Diffusion tensor imaging (DTI) yields quantitative measures sensitive to brain development and degeneration, and some common genetic variants may be associated with white matter integrity or connectivity. DTI measures, such as the fractional anisotropy (FA) of water diffusion, may be useful for identifying genetic variants that influence brain microstructure. However, genome-wide association studies (GWAS) require large populations to obtain sufficient power to detect and replicate significant effects, motivating a multi-site consortium effort. As part of an ENIGMA–DTI working group, we analyzed high-resolution FA images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites. Four hundred images of healthy adults aged 18–85 from four sites were used to create a template and corresponding skeletonized FA image as a common reference space. Using twin and pedigree samples of different ethnicities, we used our common template to evaluate the heritability of tract-derived FA measures. We show that our template is reliable for integrating multiple datasets by combining results through meta-analysis and unifying the data through exploratory mega-analyses. Our results may help prioritize regions of the FA map that are consistently influenced by additive genetic factors for future genetic discovery studies. Protocols and templates are publicly available at (http://enigma.loni.ucla.edu/ongoing/dti-working-group/)

An overview of the first 5 years of the ENIGMA obsessive–compulsive disorder working group: The power of worldwide collaboration

Abstract Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive?compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors