Mendelian randomization implemented through instrumental variable analysis is frequently discussed in causality and recently the number of applications on real data is increasing. However, there are very few discussions to address modern biomedical questions such as the integration of large scale omics in causality. While in the age of large omics, we face several hundred or thousands of components with little knowledge about the underlying structures, the focus of the field is on small scales and mostly with known structures. The availability of large omic data accentuates the need for techniques to identify interconnectivity among the omic components and reveal the principles that govern the relationships. This study extends instrumental variable techniques to identify causal networks in large scales and assess the assumptions. Large-scale causal networks are complex and further analyses are required to uncover mechanisms by which the components are related within and between omics and linked to disease endpoints. This study will review these utilities of causal networks for mechanistic understanding.
Integrating summarized data from multiple genetic variants in Mendelian randomization: bias and coverage properties of inverse-variance weighted methods
Mendelian randomization 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 Mendelian randomization analyses with many correlated variants from a single gene region, and particularly on cis-Mendelian randomization 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 un…
Estimating the causal effect of an exposure on an outcome is an important task in many economical and biological studies. Mendelian randomization, in particular, uses genetic variants as instruments to estimate causal effects in epidemiological studies. However, conventional instrumental variable methods rely on some untestable assumptions, which may be violated in real problems. In this paper, we adopt a Bayesian framework and build hierarchical models to incorporate invalid effects of instruments. We introduce an empirical Bayes estimator for which some of the instruments are invalid by util…
Valid estimation of a causal effect using instrumental variables requires that all of the instruments are independent of the outcome conditional on the risk factor of interest and any confounders. In Mendelian randomization studies with large numbers of genetic variants used as instruments, it is unlikely that this condition will be met. Any given genetic variant could be associated with a large number of traits, all of which represent potential pathways to the outcome which bypass the risk factor of interest. Such pleiotropy can be accounted for using standard multivariable Mendelian randomiz…
Multivariable Mendelian randomization estimates the causal effect of multiple exposures on an outcome, typically using summary statistics of genetic variant associations. However, exposures of interest in Mendelian randomization applications will often be measured with error. The summary statistics will therefore not be of the genetic associations with the exposure, but with the exposure measured with error. Classical measurement error will not bias genetic association estimates but will increase their standard errors. With a single exposure, this will result in bias toward the null in a two s…
Methods have been developed for Mendelian randomization that can obtain consistent causal estimates while relaxing the instrumental variable assumptions. These include multivariable Mendelian randomization, in which a genetic variant may be associated with multiple risk factors so long as any association with the outcome is via the measured risk factors (measured pleiotropy), and the MR-Egger (Mendelian randomization-Egger) method, in which a genetic variant may be directly associated with the outcome not via the risk factor of interest, so long as the direct effects of the variants on the out…
The results from Genome-Wide Association Studies (GWAS) on thousands of phenotypes provide an unprecedented opportunity to infer the causal effect of one phenotype (exposure) on another (outcome). Mendelian randomization (MR), an instrumental variable (IV) method, has been introduced for causal inference using GWAS data. Due to the polygenic architecture of complex traits/diseases and the ubiquity of pleiotropy, however, MR has many unique challenges compared to conventional IV methods. We propose a Bayesian weighted Mendelian randomization (BWMR) for causal inference to address these challeng…
Mendelian randomization (MR) has become a popular approach to study the effect of a modifiable exposure on an outcome by using genetic variants as instrumental variables. A challenge in MR is that each genetic variant explains a relatively small proportion of variance in the exposure and there are many such variants, a setting known as many weak instruments. To this end, we provide a theoretical characterization of the statistical properties of two popular estimators in MR, the inverse-variance weighted (IVW) estimator and the IVW estimator with screened instruments using an independent select…
Mendelian randomization is the use of genetic variants to make causal inferences from observational data. The field is currently undergoing a revolution fuelled by increasing numbers of genetic variants demonstrated to be associated with exposures in genome-wide association studies, and the public availability of summarized data on genetic associations with exposures and outcomes from large consortia. A Mendelian randomization analysis with many genetic variants can be performed relatively simply using summarized data. However, a causal interpretation is only assured if each genetic variant sa…
Mendelian randomization uses genetic variants to make causal inferences about a modifiable exposure. Subject to a genetic variant satisfying the instrumental variable assumptions, an association between the variant and outcome implies a causal effect of the exposure on the outcome. Complications arise with a binary exposure that is a dichotomization of a continuous risk factor (for example, hypertension is a dichotomization of blood pressure). This can lead to violation of the exclusion restriction assumption: the genetic variant can influence the outcome via the continuous risk factor even if…
Mendelian randomization (MR) is a statistical method exploiting genetic variants as instrumental variables to estimate the causal effect of modifiable risk factors on an outcome of interest. Despite wide uses of various popular two-sample MR methods based on genome-wide association study summary level data, however, those methods could suffer from potential power loss or/and biased inference when the chosen genetic variants are in linkage disequilibrium (LD), and also have relatively large direct effects on the outcome whose distribution might be heavy-tailed which is commonly referred to as t…
Mendelian randomization is a powerful tool for inferring the presence, or otherwise, of causal effects from observational data. However, the nature of genetic variants is such that pleiotropy remains a barrier to valid causal effect estimation. There are many options in the literature for pleiotropy robust methods when studying the effects of a single risk factor on an outcome. However, there are few pleiotropy robust methods in the multivariable setting, that is, when there are multiple risk factors of interest. In this paper we introduce three methods which build on common approaches in the …
Standard Mendelian randomization analysis can produce biased results if the genetic variant defining the instrumental variable (IV) is confounded and/or has a horizontal pleiotropic effect on the outcome of interest not mediated by the treatment. We provide novel identification conditions for the causal effect of a treatment in presence of unmeasured confounding, by leveraging an invalid IV for which both the IV independence and exclusion restriction assumptions may be violated. The proposed Mendelian Randomization Mixed-Scale Treatment Effect Robust Identification (MR MiSTERI) approach relies…
Mendelian randomization (MR) is a popular instrumental variable (IV) approach, in which one or several genetic markers serve as IVs that can sometimes be leveraged to recover valid inferences about a given exposure-outcome causal association subject to unmeasured confounding. A key IV identification condition known as the exclusion restriction states that the IV cannot have a direct effect on the outcome which is not mediated by the exposure in view. In MR studies, such an assumption requires an unrealistic level of prior knowledge about the mechanism by which genetic markers causally affect t…
Improving Mendelian Randomization Analysis by Instrument Borrowing from Auxiliary Outcome Traits
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health（约翰斯·霍普金斯彭博公共卫生学院生物统计系）；Department of Oncology, School of Medicine, Johns Hopkins University（约翰斯·霍普金斯大学医学院肿瘤系）
Mendelian randomization uses genetic variants to make causal inferences about the effect of a risk factor on an outcome. With fine-mapped genetic data, there may be hundreds of genetic variants in a single gene region any of which could be used to assess this causal relationship. However, using too many genetic variants in the analysis can lead to spurious estimates and inflated Type 1 error rates. But if only a few genetic variants are used, then the majority of the data is ignored and estimates are highly sensitive to the particular choice of variants. We propose an approach based on summari…
The Modified Egger Intercept Tests for Detecting Horizontal Pleiotropy in Two-Sample Summary-Data Mendelian Randomization
Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology（华中科技大学同济医学院公共卫生学院流行病学与生物统计系）
Towards more plausible point-identifying assumptions in two-sample Mendelian randomization
Federal University of Pelotas（佩洛塔斯联邦大学）；University of Bristol（布里斯托大学）；University College London（伦敦大学学院）；Norwegian University of Science and Technology（挪威科技大学）
Selection bias affects Mendelian randomization investigations when selection into the study sample depends on a collider between the genetic variant and confounders of the risk factor-outcome association. However, the relative importance of selection bias for Mendelian randomization compared to other potential biases is unclear. We performed an extensive simulation study to assess the impact of selection bias on a typical Mendelian randomization investigation. Selection bias had a severe impact on bias and Type 1 error rates in our simulation study, but only when selection effects were large. …
We expand Mendelian Randomization (MR) methodology to deal with randomly missing data on either the exposure or the outcome variable, and furthermore with data from nonindependent individuals (eg components of a family). Our method rests on the Bayesian MR framework proposed by Berzuini et al (2018), which we apply in a study of multiplex Multiple Sclerosis (MS) Sardinian families to characterise the role of certain plasma proteins in MS causation. The method is robust to presence of pleiotropic effects in an unknown number of instruments, and is able to incorporate inter-individual kinship in…
Background In a study performed on multiplex Multiple Sclerosis (MS) Sardinian families to identify disease causing plasma proteins, application of Mendelian Randomization (MR) methods encounters difficulties due to relatedness of individuals, correlation between finely mapped genotype instrumental variables (IVs) and presence of missing exposures. Method We specialize the method of Berzuini et al (2018) to deal with these difficulties. The proposed method allows pedigree structure to enter the specification of the outcome distribution via kinship matrix, and treating missing exposures as addi…
Background: Mendelian randomization (MR) has been widely applied to causal inference in medical research. It uses genetic variants as instrumental variables (IVs) to investigate putative causal relationship between an exposure and an outcome. Traditional MR methods have dominantly focussed on a two-sample setting in which IV-exposure association study and IV-outcome association study are independent. However, it is not uncommon that participants from the two studies fully overlap (one-sample) or partly overlap (overlapping-sample). Methods: We proposed a method that is applicable to all the th…
Two-sample summary-data Mendelian randomization (MR) has become a popular research design to estimate the causal effect of risk exposures. With the sample size of GWAS continuing to increase, it is now possible to utilize genetic instruments that are only weakly associated with the exposure. To maximize the statistical power of MR, we propose a genome-wide design where more than a thousand genetic instruments are used. For the statistical analysis, we use an empirical partially Bayes approach where instruments are weighted according to their strength, thus weak instruments bring less variation…
Mendelian Randomization (MR) is a popular method in epidemiology and genetics that uses genetic variation as instrumental variables for causal inference. Existing MR methods usually assume most genetic variants are valid instrumental variables that identify a common causal effect. There is a general lack of awareness that this effect homogeneity assumption can be violated when there are multiple causal pathways involved, even if all the instrumental variables are valid. In this article, we introduce a latent mixture model MR-PATH that groups instruments that yield similar causal effect estimat…
Mendelian randomization (MR) is a popular method in genetic epidemiology to estimate the effect of an exposure on an outcome by using genetic instruments. These instruments are often selected from a combination of prior knowledge from genome wide association studies (GWAS) and data-driven instrument selection procedures or tests. Unfortunately, when testing for the exposure effect, the instrument selection process done a priori is not accounted for. This paper studies and highlights the bias resulting from not accounting for the instrument selection process by focusing on a recent data-driven …
The use of genetic variants as instrumental variables - an approach known as Mendelian randomization - is a popular epidemiological method for estimating the causal effect of an exposure (phenotype, biomarker, risk factor) on a disease or health-related outcome from observational data. Instrumental variables must satisfy strong, often untestable assumptions, which means that finding good genetic instruments among a large list of potential candidates is challenging. This difficulty is compounded by the fact that many genetic variants influence more than one phenotype through different causal pa…
Mendelian randomization (MR) is a method of exploiting genetic variation to unbiasedly estimate a causal effect in presence of unmeasured confounding. MR is being widely used in epidemiology and other related areas of population science. In this paper, we study statistical inference in the increasingly popular two-sample summary-data MR design. We show a linear model for the observed associations approximately holds in a wide variety of settings when all the genetic variants satisfy the exclusion restriction assumption, or in genetic terms, when there is no pleiotropy. In this scenario, we der…
Background: Mendelian randomization (MR) is a useful approach to causal inference from observational studies when randomised controlled trials are not feasible. However, study heterogeneity of two association studies required in MR is often overlooked. When dealing with large studies, recently developed Bayesian MR is limited by its computational expensiveness. Methods: We addressed study heterogeneity by proposing a random effect Bayesian MR model with multiple exposures and outcomes. For large studies, we adopted a subset posterior aggregation method to tackle the problem of computation. In …
Integrating data from multiple heterogeneous sources has become increasingly popular to achieve a large sample size and diverse study population. This paper reviews development in causal inference methods that combines multiple datasets collected by potentially different designs from potentially heterogeneous populations. We summarize recent advances on combining randomized clinical trial with external information from observational studies or historical controls, combining samples when no single sample has all relevant variables with application to two-sample Mendelian randomization, distribu…
Mendelian randomization (MR) is a powerful method that uses genetic variants as instrumental variables (IVs) to infer the causal effect of a modifiable exposure on an outcome. Although recent years have seen many extensions of basic MR methods to be robust to certain violations of assumptions, few methods were proposed to infer bi-directional causal relationships, especially for phenotypes with limited biological understandings. The presence of horizontal pleiotropy adds another layer of complexity. In this article, we show that assumptions for common MR methods are often impossible or too str…
Instrumental variables have been widely used to estimate the causal effect of a treatment on an outcome. Existing confidence intervals for causal effects based on instrumental variables assume that all of the putative instrumental variables are valid; a valid instrumental variable is a variable that affects the outcome only by affecting the treatment and is not related to unmeasured confounders. However, in practice, some of the putative instrumental variables are likely to be invalid. This paper presents two tools to conduct valid inference and tests in the presence of invalid instruments. Fi…
