arXiv subjects

Zhonghua Liu

Publications and source records attributed to Zhonghua Liu.

22 records · Page 2Linked to original sources

arXiv2022

Semiparametric Efficient G-estimation with Invalid Instrumental Variables

The instrumental variable method is widely used in the health and social sciences for identification and estimation of causal effects in the presence of potentially unmeasured confounding. In order to improve efficiency, multiple instruments are routinely used, leading to concerns about bias due to possible violation of the instrumental variable assumptions. To address this concern, we introduce a new class of g-estimators that are guaranteed to remain consistent and asymptotically normal for the causal effect of interest provided that a set of at least $γ$ out of $K$ candidate instruments are valid, for $γ\leq K$ set by the analyst ex ante, without necessarily knowing the identities of the valid and invalid instruments. We provide formal semiparametric efficiency theory supporting our results. Both simulation studies and applications to the UK Biobank data demonstrate the superior empirical performance of our estimators compared to competing methods.

stat.ME↗

arXiv2021

A Two-Sample Robust Bayesian Mendelian Randomization Method Accounting for Linkage Disequilibrium and Idiosyncratic Pleiotropy with Applications to the COVID-19 Outcome

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 the idiosyncratic pleiotropy phenomenon. To resolve those two issues, we propose a novel Robust Bayesian Mendelian Randomization (RBMR) model that uses the more robust multivariate generalized t-distribution to model such direct effects in a probabilistic model framework which can also incorporate the LD structure explicitly. The generalized t-distribution can be represented as a Gaussian scaled mixture so that our model parameters can be estimated by the EM-type algorithms. We compute the standard errors by calibrating the evidence lower bound using the likelihood ratio test. Through extensive simulation studies, we show that our RBMR has robust performance compared to other competing methods. We also apply our RBMR method to two benchmark data sets and find that RBMR has smaller bias and standard errors. Using our proposed RBMR method, we find that coronary artery disease is associated with increased risk of critically ill coronavirus disease 2019 (COVID-19). We also develop a user-friendly R package RBMR for public use.

stat.ME↗

arXiv2021

On Mendelian Randomization Mixed-Scale Treatment Effect Robust Identification (MR MiSTERI) and Estimation for Causal Inference

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 on (i) an assumption that the treatment effect does not vary with the invalid IV on the additive scale; and (ii) that the selection bias due to confounding does not vary with the invalid IV on the odds ratio scale; and (iii) that the residual variance for the outcome is heteroscedastic and thus varies with the invalid IV. We formally establish that their conjunction can identify a causal effect even with an invalid IV subject to pleiotropy. MiSTERI is shown to be particularly advantageous in presence of pervasive heterogeneity of pleiotropic effects on additive scale, a setting in which two recently proposed robust estimation methods MR GxE and MR GENIUS can be severely biased. In order to incorporate multiple, possibly correlated and weak IVs, a common challenge in MR studies, we develop a MAny Weak Invalid Instruments (MR MaWII MiSTERI) approach for strengthened identification and improved accuracy MaWII MiSTERI is shown to be robust to horizontal pleiotropy, violation of IV independence assumption and weak IV bias. Both simulation studies and real data analysis results demonstrate the robustness of the proposed MR MiSTERI methods.

stat.ME↗

arXiv2018

A Geometric Perspective on the Power of Principal Component Association Tests in Multiple Phenotype Studies

Joint analysis of multiple phenotypes can increase statistical power in genetic association studies. Principal component analysis, as a popular dimension reduction method, especially when the number of phenotypes is high-dimensional, has been proposed to analyze multiple correlated phenotypes. It has been empirically observed that the first PC, which summarizes the largest amount of variance, can be less powerful than higher order PCs and other commonly used methods in detecting genetic association signals. In this paper, we investigate the properties of PCA-based multiple phenotype analysis from a geometric perspective by introducing a novel concept called principal angle. A particular PC is powerful if its principal angle is $0^o$ and is powerless if its principal angle is $90^o$. Without prior knowledge about the true principal angle, each PC can be powerless. We propose linear, non-linear and data-adaptive omnibus tests by combining PCs. We show that the omnibus PC test is robust and powerful in a wide range of scenarios. We study the properties of the proposed methods using power analysis and eigen-analysis. The subtle differences and close connections between these combined PC methods are illustrated graphically in terms of their rejection boundaries. Our proposed tests have convex acceptance regions and hence are admissible. The $p$-values for the proposed tests can be efficiently calculated analytically and the proposed tests have been implemented in a publicly available R package {\it MPAT}. We conduct simulation studies in both low and high dimensional settings with various signal vectors and correlation structures. We apply the proposed tests to the joint analysis of metabolic syndrome related phenotypes with data sets collected from four international consortia to demonstrate the effectiveness of the proposed combined PC testing procedures.

stat.AP↗