Software application profile: mrrobust—a tool for performing two-sample summary Mendelian randomization analyses.
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ABSTRACT:
SUBMITTER: Spiller W
PROVIDER: S-EPMC6659377 | biostudies-other | 2019 Jun
REPOSITORIES: biostudies-other
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Project description:Abstract Motivation Mendelian randomization methods that estimate non-linear exposure-outcome relationships typically require individual-level data. This package implements non-linear Mendelian randomization methods using stratified summarized data, facilitating analyses where individual-level data cannot easily be shared, and additionally increasing reproducibility as summarized data can be reported. Dependence on summarized data means the methods are independent of the form of the individual-level data, increasing flexibility to different outcome types (such as continuous, binary or time-to-event outcomes). Implementation SUMnlmr is available as an R package (version 3.1.0 or higher). General features The package implements the previously proposed fractional polynomial and piecewise linear methods on stratified summarized data that can either be estimated from individual-level data using the package or supplied by a collaborator. It constructs plots to visualize the estimated exposure-outcome relationship, and provides statistics to assess preference for a non-linear model over a linear model. Availability The package is freely available from GitHub [https://github.com/amymariemason/SUMnlmr].
| S-EPMC9749704 | biostudies-literature
Project description:MotivationEpidemiological cohorts typically contain a diverse set of phenotypes such that automation of phenome scans is non-trivial, because they require highly heterogeneous models. For this reason, phenome scans have to date tended to use a smaller homogeneous set of phenotypes that can be analysed in a consistent fashion. We present PHESANT (PHEnome Scan ANalysis Tool), a software package for performing comprehensive phenome scans in UK Biobank.General featuresPHESANT tests the association of a specified trait with all continuous, integer and categorical variables in UK Biobank, or a specified subset. PHESANT uses a novel rule-based algorithm to determine how to appropriately test each trait, then performs the analyses and produces plots and summary tables.ImplementationThe PHESANT phenome scan is implemented in R. PHESANT includes a novel Javascript D3.js visualization and accompanying Java code that converts the phenome scan results to the required JavaScript Object Notation (JSON) format.AvailabilityPHESANT is available on GitHub at [https://github.com/MRCIEU/PHESANT]. Git tag v0.5 corresponds to the version presented here.
| S-EPMC5837456 | biostudies-literature
Project description:Mendelian randomization (MR) uses genetic variants as instrumental variables to investigate the causal effect of a risk factor on an outcome. A collider is a variable influenced by two or more other variables. Naive calculation of MR estimates in strata of the population defined by a collider, such as a variable affected by the risk factor, can result in collider bias. We propose an approach that allows MR estimation in strata of the population while avoiding collider bias. This approach constructs a new variable, the residual collider, as the residual from regression of the collider on the genetic instrument, and then calculates causal estimates in strata defined by quantiles of the residual collider. Estimates stratified on the residual collider will typically have an equivalent interpretation to estimates stratified on the collider, but they are not subject to collider bias. We apply the approach in several simulation scenarios considering different characteristics of the collider variable and strengths of the instrument. We then apply the proposed approach to investigate the causal effect of smoking on bladder cancer in strata of the population defined by bodyweight. The new approach generated unbiased estimates in all the simulation settings. In the applied example, we observed a trend in the stratum-specific MR estimates at different bodyweight levels that suggested stronger effects of smoking on bladder cancer among individuals with lower bodyweight. The proposed approach can be used to perform MR studying heterogeneity among subgroups of the population while avoiding collider bias.
| S-EPMC9329404 | biostudies-literature
Project description:The summary-data-based Mendelian randomization (SMR) method is gaining popularity in estimating the causal effect of an exposure on an outcome. In practice, the instrument SNP is often selected from the genome-wide association study (GWAS) on the exposure but no correction is made for such selection in downstream analysis, leading to a biased estimate of the effect size and invalid inference. We address this issue by using the likelihood derived from the sampling distribution of the estimated SNP effects in the exposure GWAS and the outcome GWAS. This likelihood takes into account how the instrument SNPs are selected. Since the effective sample size is 1, the asymptotic theory does not apply. We use a support for a profile likelihood as an interval estimate of the causal effect. Simulation studies indicate that this support has robust coverage while the confidence interval implied by the SMR method has lower-than-nominal coverage. Furthermore, the variance of the two-stage least squares estimate of the causal effect is shown to be the same as the variance used for SMR for one-sample data when there is no selection.
| S-EPMC9859138 | biostudies-literature
Project description:Two-sample summary data Mendelian randomization is a popular method for assessing causality in epidemiology, by using genetic variants as instrumental variables. If genes exert pleiotropic effects on the outcome not entirely through the exposure of interest, this can lead to heterogeneous and (potentially) biased estimates of causal effect. We investigate the use of Bayesian model averaging to preferentially search the space of models with the highest posterior likelihood. We develop a Metropolis-Hasting algorithm to perform the search using the recently developed MR-RAPS as the basis for defining a posterior distribution that efficiently accounts for pleiotropic and weak instrument bias. We demonstrate how our general modeling approach can be extended from a standard one-component causal model to a two-component model, which allows a large proportion of SNPs to violate the InSIDE assumption. We use Monte Carlo simulations to illustrate our methods and compare it to several related approaches. We finish by applying our approach to investigate the causal role of cholesterol on the development age-related macular degeneration.
| S-EPMC9303808 | biostudies-literature
Project description:MendelianRandomization is a software package for the R open-source software environment that performs Mendelian randomization analyses using summarized data. The core functionality is to implement the inverse-variance weighted, MR-Egger and weighted median methods for multiple genetic variants. Several options are available to the user, such as the use of robust regression, fixed- or random-effects models and the penalization of weights for genetic variants with heterogeneous causal estimates. Extensions to these methods, such as allowing for variants to be correlated, can be chosen if appropriate. Graphical commands allow summarized data to be displayed in an interactive graph, or the plotting of causal estimates from multiple methods, for comparison. Although the main method of data entry is directly by the user, there is also an option for allowing summarized data to be incorporated from the PhenoScanner database of genotype-phenotype associations. We hope to develop this feature in future versions of the package. The R software environment is available for download from [https://www.r-project.org/]. The MendelianRandomization package can be downloaded from the Comprehensive R Archive Network (CRAN) within R, or directly from [https://cran.r-project.org/web/packages/MendelianRandomization/]. Both R and the MendelianRandomization package are released under GNU General Public Licenses (GPL-2|GPL-3).
| S-EPMC5510723 | biostudies-literature
Project description:Mendelian randomization (MR) is the use of genetic variants to assess the existence of a causal relationship between a risk factor and an outcome of interest. Here, we focus on two-sample summary-data MR analyses with many correlated variants from a single gene region, particularly on cis-MR studies which use protein expression as a risk factor. Such studies must rely on a small, curated set of variants from the studied region; using all variants in the region requires inverting an ill-conditioned genetic correlation matrix and results in numerically unstable causal effect estimates. We review methods for variable selection and estimation in cis-MR with summary-level data, ranging from stepwise pruning and conditional analysis to principal components analysis, factor analysis, and Bayesian variable selection. In a simulation study, we show that the various methods have comparable performance in analyses with large sample sizes and strong genetic instruments. However, when weak instrument bias is suspected, factor analysis and Bayesian variable selection produce more reliable inferences than simple pruning approaches, which are often used in practice. We conclude by examining two case studies, assessing the effects of low-density lipoprotein-cholesterol and serum testosterone on coronary heart disease risk using variants in the HMGCR and SHBG gene regions, respectively.
| S-EPMC7614127 | biostudies-literature
Project description:Mendelian randomization (MR) is becoming more and more popular for inferring causal relationship between an exposure and a trait. Typically, instrument SNPs are selected from an exposure GWAS based on their summary statistics and the same summary statistics on the selected SNPs are used for subsequent analyses. However, this practice suffers from selection bias and can invalidate MR methods, as showcased via two popular methods: the summary data-based MR (SMR) method and the two-sample MR Steiger method. The SMR method is conservative while the MR Steiger method can be either conservative or liberal. A simple and yet more powerful alternative to SMR is proposed.
| S-EPMC8027662 | biostudies-literature
Project description:BackgroundTwo-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables.MethodsWe performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR.ResultsIn the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index.ConclusionsOur findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.
| S-EPMC8580279 | biostudies-literature
Project description:BackgroundMendelian randomization (MR) is a powerful tool in epidemiology that can be used to estimate the causal effect of an exposure on an outcome in the presence of unobserved confounding, by utilizing genetic variants that are instrumental variables (IVs) for the exposure. This has been extended to multivariable MR (MVMR) to estimate the effect of two or more exposures on an outcome.Methods and resultsWe use simulations and theory to clarify the interpretation of estimated effects in a MVMR analysis under a range of underlying scenarios, where a secondary exposure acts variously as a confounder, a mediator, a pleiotropic pathway and a collider. We then describe how instrument strength and validity can be assessed for an MVMR analysis in the single-sample setting, and develop tests to assess these assumptions in the popular two-sample summary data setting. We illustrate our methods using data from UK Biobank to estimate the effect of education and cognitive ability on body mass index.ConclusionMVMR analysis consistently estimates the direct causal effect of an exposure, or exposures, of interest and provides a powerful tool for determining causal effects in a wide range of scenarios with either individual- or summary-level data.
| S-EPMC6734942 | biostudies-literature