Abstract
Pleiotropy, the phenomenon of a single genetic variant influencing multiple traits, is likely widespread in the human genome. If pleiotropy arises because the single nucleotide polymorphism ...(SNP) influences one trait, which in turn influences another ('vertical pleiotropy'), then Mendelian randomization (MR) can be used to estimate the causal influence between the traits. Of prime focus among the many limitations to MR is the unprovable assumption that apparent pleiotropic associations are mediated by the exposure (i.e. reflect vertical pleiotropy), and do not arise due to SNPs influencing the two traits through independent pathways ('horizontal pleiotropy'). The burgeoning treasure trove of genetic associations yielded through genome wide association studies makes for a tantalizing prospect of phenome-wide causal inference. Recent years have seen substantial attention devoted to the problem of horizontal pleiotropy, and in this review we outline how newly developed methods can be used together to improve the reliability of MR.
Inference about the causal structure that induces correlations between two traits can be achieved by combining genetic associations with a mediation-based approach, as is done in the causal inference ...test (CIT). However, we show that measurement error in the phenotypes can lead to the CIT inferring the wrong causal direction, and that increasing sample sizes has the adverse effect of increasing confidence in the wrong answer. This problem is likely to be general to other mediation-based approaches. Here we introduce an extension to Mendelian randomisation, a method that uses genetic associations in an instrumentation framework, that enables inference of the causal direction between traits, with some advantages. First, it can be performed using only summary level data from genome-wide association studies; second, it is less susceptible to bias in the presence of measurement error or unmeasured confounding. We apply the method to infer the causal direction between DNA methylation and gene expression levels. Our results demonstrate that, in general, DNA methylation is more likely to be the causal factor, but this result is highly susceptible to bias induced by systematic differences in measurement error between the platforms, and by horizontal pleiotropy. We emphasise that, where possible, implementing MR and appropriate sensitivity analyses alongside other approaches such as CIT is important to triangulate reliable conclusions about causality.
Abstract
Mendelian randomization (MR) is gaining in recognition and popularity as a method for strengthening causal inference in epidemiology by utilizing genetic variants as instrumental variables. ...Concurrently with the explosion in empirical MR studies, there has been the steady production of new approaches for MR analysis. The recently proposed “global and individual tests for direct effects” (GLIDE) approach fits into a family of methods that aim to detect horizontal pleiotropy—at the individual single nucleotide polymorphism level and at the global level—and to adjust the analysis by removing outlying single nucleotide polymorphisms. In this commentary, we explain how existing methods can (and indeed are) being used to detect pleiotropy at the individual and global levels, although not explicitly using this terminology. By doing so, we show that the true comparator for GLIDE is not MR-Egger regression (as Dai et al., the authors of the accompanying article (Am J Epidemiol. 2018;187(12):2672–2680), claim) but rather the humble heterogeneity statistic.
Abstract
Background
Mendelian 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 results
We 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.
Conclusion
MVMR 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.
We investigate the behavior of the Lasso for selecting invalid instruments in linear instrumental variables models for estimating causal effects of exposures on outcomes, as proposed recently by Kang ...et al. Invalid instruments are such that they fail the exclusion restriction and enter the model as explanatory variables. We show that for this setup, the Lasso may not consistently select the invalid instruments if these are relatively strong. We propose a median estimator that is consistent when less than 50% of the instruments are invalid, and its consistency does not depend on the relative strength of the instruments, or their correlation structure. We show that this estimator can be used for adaptive Lasso estimation, with the resulting estimator having oracle properties. The methods are applied to a Mendelian randomization study to estimate the causal effect of body mass index (BMI) on diastolic blood pressure, using data on individuals from the UK Biobank, with 96 single nucleotide polymorphisms as potential instruments for BMI. Supplementary materials for this article are available online.
The number of Mendelian randomization analyses including large numbers of genetic variants is rapidly increasing. This is due to the proliferation of genome-wide association studies, and the desire ...to obtain more precise estimates of causal effects. However, some genetic variants may not be valid instrumental variables, in particular due to them having more than one proximal phenotypic correlate (pleiotropy).
We view Mendelian randomization with multiple instruments as a meta-analysis, and show that bias caused by pleiotropy can be regarded as analogous to small study bias. Causal estimates using each instrument can be displayed visually by a funnel plot to assess potential asymmetry. Egger regression, a tool to detect small study bias in meta-analysis, can be adapted to test for bias from pleiotropy, and the slope coefficient from Egger regression provides an estimate of the causal effect. Under the assumption that the association of each genetic variant with the exposure is independent of the pleiotropic effect of the variant (not via the exposure), Egger's test gives a valid test of the null causal hypothesis and a consistent causal effect estimate even when all the genetic variants are invalid instrumental variables.
We illustrate the use of this approach by re-analysing two published Mendelian randomization studies of the causal effect of height on lung function, and the causal effect of blood pressure on coronary artery disease risk. The conservative nature of this approach is illustrated with these examples.
An adaption of Egger regression (which we call MR-Egger) can detect some violations of the standard instrumental variable assumptions, and provide an effect estimate which is not subject to these violations. The approach provides a sensitivity analysis for the robustness of the findings from a Mendelian randomization investigation.
Numerous observational studies have attempted to identify risk factors for infection with SARS-CoV-2 and COVID-19 disease outcomes. Studies have used datasets sampled from patients admitted to ...hospital, people tested for active infection, or people who volunteered to participate. Here, we highlight the challenge of interpreting observational evidence from such non-representative samples. Collider bias can induce associations between two or more variables which affect the likelihood of an individual being sampled, distorting associations between these variables in the sample. Analysing UK Biobank data, compared to the wider cohort the participants tested for COVID-19 were highly selected for a range of genetic, behavioural, cardiovascular, demographic, and anthropometric traits. We discuss the mechanisms inducing these problems, and approaches that could help mitigate them. While collider bias should be explored in existing studies, the optimal way to mitigate the problem is to use appropriate sampling strategies at the study design stage.
Mendelian randomization (MR) is being increasingly used to strengthen causal inference in observational studies. Availability of summary data of genetic associations for a variety of phenotypes from ...large genome-wide association studies (GWAS) allows straightforward application of MR using summary data methods, typically in a two-sample design. In addition to the conventional inverse variance weighting (IVW) method, recently developed summary data MR methods, such as the MR-Egger and weighted median approaches, allow a relaxation of the instrumental variable assumptions.
Here, a new method - the mode-based estimate (MBE) - is proposed to obtain a single causal effect estimate from multiple genetic instruments. The MBE is consistent when the largest number of similar (identical in infinite samples) individual-instrument causal effect estimates comes from valid instruments, even if the majority of instruments are invalid. We evaluate the performance of the method in simulations designed to mimic the two-sample summary data setting, and demonstrate its use by investigating the causal effect of plasma lipid fractions and urate levels on coronary heart disease risk.
The MBE presented less bias and lower type-I error rates than other methods under the null in many situations. Its power to detect a causal effect was smaller compared with the IVW and weighted median methods, but was larger than that of MR-Egger regression, with sample size requirements typically smaller than those available from GWAS consortia.
The MBE relaxes the instrumental variable assumptions, and should be used in combination with other approaches in sensitivity analyses.
Abstract
In the last third of the 20th century, etiological epidemiology within academia in high-income countries shifted its primary concern from attempting to tackle the apparent epidemic of ...noncommunicable diseases to an increasing focus on developing statistical and causal inference methodologies. This move was mutually constitutive with the failure of applied epidemiology to make major progress, with many of the advances in understanding the causes of noncommunicable diseases coming from outside the discipline, while ironically revealing the infectious origins of several major conditions. Conversely, there were many examples of epidemiologic studies promoting ineffective interventions and little evident attempt to account for such failure. Major advances in concrete understanding of disease etiology have been driven by a willingness to learn about and incorporate into epidemiology developments in biology and cognate data science disciplines. If fundamental epidemiologic principles regarding the rooting of disease risk within populations are retained, recent methodological developments combined with increased biological understanding and data sciences capability should herald a fruitful post–Modern Epidemiology world.
The past decade has been proclaimed as a hugely successful era of gene discovery through the high yields of many genome-wide association studies (GWAS). However, much of the perceived benefit of such ...discoveries lies in the promise that the identification of genes that influence disease would directly translate into the identification of potential therapeutic targets, but this has yet to be realized at a level reflecting expectation. One reason for this, we suggest, is that GWAS, to date, have generally not focused on phenotypes that directly relate to the progression of disease and thus speak to disease treatment.
PDF
