Mendelian Randomization with Incomplete Exposure Data: a Bayesian Approach
Teresa Fazia, Leonardo Egidi, Burcu Ayoglu, Ashley Beecham, Pier Paolo Bitti, Anna Ticca, Hui Guo, Jacob L. McCauley, Peter Nilsson, Rosanna Asselta, Carlo Berz… 展开作者
Teresa Fazia, Leonardo Egidi, Burcu Ayoglu, Ashley Beecham, Pier Paolo Bitti, Anna Ticca, Hui Guo, Jacob L. McCauley, Peter Nilsson, Rosanna Asselta, Carlo Berzuini, Luisa Bernardinelli
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 information. Introduction of missing data allows us to overcome the bias introduced by the (reverse) effect of treatment (in MS cases) on level of protein. From a substantive point of view, our study results confirm recent suspicion that an increase in circulating IL12A and STAT4 protein levels does not cause an increase in MS risk, as originally believed, suggesting that these two proteins may not be suitable drug targets for MS.
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…
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…
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…
Multivariable Mendelian randomization with weak instruments: a comparison of Bayesian and frequentist methods
Sydney School of Public Health, University of Sydney（悉尼大学公共卫生学院）；MRC Biostatistics Unit, University of Cambridge（剑桥大学医学研究委员会生物统计单元）；Cardiovascular Epidemiology Unit, University of Cambridge（剑桥大学心血管流行病学单元）
Our approach to Mendelian Randomization (MR) analysis is designed to increase reproducibility of causal effect "discoveries" by: (i) using a Bayesian approach to inference; (ii) replacing the point null hypothesis with a region of practical equivalence consisting of values of negligible magnitude for the effect of interest, while exploiting the ability of Bayesian analysis to quantify the evidence of the effect falling inside/outside the region; (iii) rejecting the usual binary decision logic in favour of a ternary logic where the hypothesis test may result in either an acceptance or a rejecti…
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 …
Our Bayesian approach to Mendelian Randomisation uses multiple instruments to assess the putative causal effect of an exposure on an outcome. The approach is robust to violations of the (untestable) Exclusion Restriction condition, and hence it does not require instruments to be independent of the outcome conditional on the exposure and on the confounders of the exposure-outcome relationship. The Bayesian approach offers a rigorous handling of the uncertainty (e.g. about the estimated instrument-exposure associations), freedom from asymptotic approximations of the null distribution and the pos…
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. …
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 techni…
Mendelian randomization is the use of genetic variants as instrumental variables to assess whether a risk factor is a cause of a disease outcome. Increasingly, Mendelian randomization investigations are conducted on the basis of summarized data, rather than individual-level data. These summarized data comprise the coefficients and standard errors from univariate regression models of the risk factor on each genetic variant, and of the outcome on each genetic variant. A causal estimate can be derived from these associations for each individual genetic variant, and a combined estimate can be obta…
The funnel plot is a graphical visualisation of summary data estimates from a meta-analysis, and is a useful tool for detecting departures from the standard modelling assumptions. Although perhaps not widely appreciated, a simple extension of the funnel plot can help to facilitate an intuitive interpretation of the mathematics underlying a meta-analysis at a more fundamental level, by equating it to determining the centre of mass of a physical system. We used this analogy, with some success, to explain the concepts of weighing evidence and of biased evidence to a young audience at the Cambridg…
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…
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 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 …
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) 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…
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…
