Excess significance bias in repetitive transcranial magnetic stimulation literature for neuropsychiatric disorders, bioRxiv, 2019-04-23
ABSTRACTIntroductionRepetitive transcranial magnetic stimulation (rTMS) has been widely tested and promoted for use in multiple neuropsychiatric conditions, but as for many other medical devices, some gaps may exist in the literature and the evidence base for rTMS clinical efficacy remains under debate. We aimed to empirically test for an excess number of statistically significant results in the literature on rTMS therapeutic efficacy across a wide range of meta-analyses and to characterize the power of studies included in these meta-analyses.MethodsBased on power calculations, we computed the expected number of “positive” datasets for a medium effect-size (standardized mean difference, SMD=0.30) and compared it with the number of observed “positive” datasets. Sensitivity analyses considered small (SMD=0.20), modest (SMD=0.50), and large (SMD=0.80) effect sizes.Results14 meta-analyses with 228 datasets (110 for neurological disorders and 118 for psychiatric disorders) were assessed. For SMD=0.3, the number of observed “positive” studies (n=94) was larger than expected (n=35). We found evidence for an excess of significant findings overall (p<0.0001) and in 814 meta-analyses. Evidence for an excess of significant findings was also observed for SMD=0.5 for neurological disorders. 0 (0 %), 0 (0 %), 3 (1 %), and 53 (23 %) of the 228 datasets had power >0.80, respectively for SMDs of 0.30, 0.20, 0.50, and 0.80.ConclusionMost studies in the rTMS literature are underpowered. This results in fragmentation and waste of research efforts. The somewhat high frequency of “positive” results seems spurious and may reflect bias.Trial Registration PROSPERO 2017 CRD42017056694
biorxiv scientific-communication-and-education 0-100-users 2019ModelTest-NG a new and scalable tool for the selection of DNA and protein evolutionary models, bioRxiv, 2019-04-23
AbstractModelTest-NG is a re-implementation from scratch of jModelTest and ProtTest, two popular tools for selecting the best-fit nucleotide and amino acid substitution models, respectively. ModelTest-NG is one to two orders of magnitude faster than jModelTest and ProtTest but equally accurate, and introduces several new features, such as ascertainment bias correction, mixture and FreeRate models, or the automatic processing of partitioned datasets. ModelTest-NG is available under a GNU GPL3 license at <jatsext-link xmlnsxlink=httpwww.w3.org1999xlink ext-link-type=uri xlinkhref=httpsgithub.comddarribamodeltest>httpsgithub.comddarribamodeltest<jatsext-link>.
biorxiv bioinformatics 0-100-users 2019pathwayPCA an R package for integrative pathway analysis with modern PCA methodology and gene selection, bioRxiv, 2019-04-23
ABSTRACTWith the advance in high-throughput technology for molecular assays, multi-omics datasets have become increasingly available. However, most currently available pathway analysis software provide little or no functionalities for analyzing multiple types of -omics data simultaneously. In addition, most tools do not provide sample-specific estimates of pathway activities, which are important for precision medicine. To address these challenges, we present pathwayPCA, a unique R package for integrative pathway analysis that utilizes modern statistical methodology including supervised PCA and adaptive elastic-net PCA for principal component analysis. pathwayPCA can analyze continuous, binary, and survival outcomes in studies with multiple covariate andor interaction effects. We provide three case studies to illustrate pathway analysis with gene selection, integrative analysis of multi-omics datasets to identify driver genes, estimating and visualizing sample-specific pathway activities in ovarian cancer, and identifying sex-specific pathway effects in kidney cancer. pathwayPCA is an open source R package, freely available to the research community. We expect pathwayPCA to be a useful tool for empowering the wide scientific community on the analyses and interpretation of the wealth of multiomics data recently made available by TCGA, CPTAC and other large consortiums.
biorxiv bioinformatics 0-100-users 2019Stacks 2 Analytical Methods for Paired-end Sequencing Improve RADseq-based Population Genomics, bioRxiv, 2019-04-23
AbstractFor half a century population genetics studies have put type II restriction endonucleases to work. Now, coupled with massively-parallel, short-read sequencing, the family of RAD protocols that wields these enzymes has generated vast genetic knowledge from the natural world. Here we describe the first software capable of using paired-end sequencing to derive short contigs from de novo RAD data natively. Stacks version 2 employs a de Bruijn graph assembler to build contigs from paired-end reads and overlap those contigs with the corresponding single-end loci. The new architecture allows all the individuals in a meta population to be considered at the same time as each RAD locus is processed. This enables a Bayesian genotype caller to provide precise SNPs, and a robust algorithm to phase those SNPs into long haplotypes – generating RAD loci that are 400-800bp in length. To prove its recall and precision, we test the software with simulated data and compare reference-aligned and de novo analyses of three empirical datasets. We show that the latest version of Stacks is highly accurate and outperforms other software in assembling and genotyping paired-end de novo datasets.
biorxiv genomics 100-200-users 2019Assessment of Glyphosate Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations Generational Toxicology, Scientific Reports, 2019-04-22
Ancestral environmental exposures to a variety of factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. One of the most widely used agricultural pesticides worldwide is the herbicide glyphosate (N-(phosphonomethyl)glycine), commonly known as Roundup. There are an increasing number of conflicting reports regarding the direct exposure toxicity (risk) of glyphosate, but no rigorous investigations on the generational actions. The current study using a transient exposure of gestating F0 generation female rats found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed. The transgenerational pathologies observed include prostate disease, obesity, kidney disease, ovarian disease, and parturition (birth) abnormalities. Epigenetic analysis of the F1, F2 and F3 generation sperm identified differential DNA methylation regions (DMRs). A number of DMR associated genes were identified and previously shown to be involved in pathologies. Therefore, we propose glyphosate can induce the transgenerational inheritance of disease and germline (e.g. sperm) epimutations. Observations suggest the generational toxicology of glyphosate needs to be considered in the disease etiology of future generations.
scientific reports genetics 500+-users 2019Alzheimer’s patient brain myeloid cells exhibit enhanced aging and unique transcriptional activation, bioRxiv, 2019-04-19
AbstractGene expression changes in brain microglia from mouse models of Alzheimer’s disease (AD) are highly characterized and reflect specific myeloid cell activation states that could modulate AD risk or progression. While some groups have produced valuable expression profiles for human brain cells1–4, the cellular clarity with which we now view transcriptional responses in mouse AD models has not yet been realized for human AD tissues due to limited availability of fresh tissue samples and technological hurdles of recovering transcriptomic data with cell-type resolution from frozen samples. We developed a novel method for isolating multiple cell types from frozen post-mortem specimens of superior frontal gyrus for RNA-Seq and identified 66 genes differentially expressed between AD and control subjects in the myeloid cell compartment. Myeloid cells sorted from fusiform gyrus of the same subjects showed similar changes, and whole tissue RNA analyses further corroborated our findings. The changes we observed did not resemble the “damage-associated microglia” (DAM) profile described in mouse AD models5, or other known activation states from other disease models. Instead, roughly half of the changes were consistent with an “enhanced human aging” phenotype, whereas the other half, including the AD risk gene APOE, were altered in AD myeloid cells but not differentially expressed with age. We refer to this novel profile in human Alzheimer’s microgliamyeloid cells as the HAM signature. These results, which can be browsed at <jatsext-link xmlnsxlink=httpwww.w3.org1999xlink ext-link-type=uri xlinkhref=httpresearch-pub.gene.comBrainMyeloidLandscapereviewVersion>research-pub.gene.comBrainMyeloidLandscapereviewVersion<jatsext-link>, highlight considerable differences between myeloid activation in mouse models and human disease, and provide a genome-wide picture of brain myeloid activation in human AD.
biorxiv neuroscience 100-200-users 2019