arXiv subjects

George Davey Smith

Publications and source records attributed to George Davey Smith.

5 recordsLinked to original sources

arXiv2025

Empirically assessing the plausibility of unconfoundedness in observational studies

The possibility of unmeasured confounding is one of the main limitations for causal inference from observational studies. There are different methods for (partially) empirically assessing the plausibility of unconfoundedness. However, most currently available methods require (at least partial) assumptions about the confounding structure, which may be difficult to know in practice. In this paper we describe a simple strategy for empirically assessing the plausibility of conditional unconfoundedness (i.e., whether the candidate adjustment set of covariates suffices for confounding adjustment) which does not require any explicit assumptions about the confounding structure, relying instead on assumptions related to temporal ordering between covariates, exposure and outcome (which can be guaranteed by design) and selection into the study. The proposed method essentially relies on testing the association between a subset of the covariates included in the adjustment set (those associated with the exposure, given all other covariates) and the outcome conditional on the remaining covariates and the exposure. We describe the assumptions underlying the method, provide proofs, use simulations to corroborate the theory and illustrate the method with an applied example assessing the causal effect of delivery mode and intelligence quotient measured in adulthood using data from the 1982 Pelotas (Brazil) birth cohort. We also discuss the implications of measurement error and some important limitations of the suggested approach.

stat.ME↗

arXiv2023

Woolf et als GWAS by subtraction is not useful for cross-generational Mendelian randomization studies

Mendelian randomization (MR) is an epidemiological method that can be used to strengthen causal inference regarding the relationship between a modifiable environmental exposure and a medically relevant trait and to estimate the magnitude of this relationship1. Recently, there has been considerable interest in using MR to examine potential causal relationships between parental phenotypes and outcomes amongst their offspring. In a recent issue of BMC Research Notes, Woolf et al (2023) present a new method, GWAS by subtraction, to derive genome-wide summary statistics for paternal smoking and other paternal phenotypes with the goal that these estimates can then be used in downstream (including two sample) MR studies. Whilst a potentially useful goal, Woolf et al. (2023) focus on the wrong parameter of interest for useful genome-wide association studies (GWAS) and downstream cross-generational MR studies, and the estimator that they derive is neither efficient nor appropriate for such use.

q-bio.QM↗

arXiv2023

Almost exact Mendelian randomization

Mendelian randomization (MR) is a natural experimental design based on the random transmission of genes from parents to offspring. However, this inferential basis is typically only implicit or used as an informal justification. As parent-offspring data becomes more widely available, we advocate a different approach to MR that is exactly based on this natural randomization, thereby formalizing the analogy between MR and randomized controlled trials. We begin by developing a causal graphical model for MR which represents several biological processes and phenomena, including population structure, gamete formation, fertilization, genetic linkage, and pleiotropy. This causal graph is then used to detect biases in population-based MR studies and identify sufficient confounder adjustment sets to correct these biases. We then propose a randomization test in the within-family MR design using the exogenous randomness in meiosis and fertilization, which is extensively studied in genetics. Besides its transparency and conceptual appeals, our approach also offers some practical advantages, including robustness to misspecified phenotype models, robustness to weak instruments, and elimination of bias arising from population structure, assortative mating, dynastic effects, and horizontal pleiotropy. We conclude with an analysis of a pair of negative and positive controls in the Avon Longitudinal Study of Parents and Children. The accompanying R package can be found at https://github.com/matt-tudball/almostexactmr.

stat.ME↗

arXiv2022

Homogeneity in the instrument-treatment association is not sufficient for the Wald estimand to equal the average causal effect for a binary instrument and a continuous exposure

Background: Interpreting instrumental variable results often requires further assumptions in addition to the core assumptions of relevance, independence, and the exclusion restriction. Methods: We assess whether instrument-exposure additive homogeneity renders the Wald estimand equal to the average derivative effect (ADE) in the case of a binary instrument and a continuous exposure. Results: Instrument-exposure additive homogeneity is insufficient for ADE identification when the instrument is binary, the exposure is continuous and the effect of the exposure on the outcome is non-linear on the additive scale. For a binary exposure, the exposure-outcome effect is necessarily additive linear, so the homogeneity condition is sufficient. Conclusions: For binary instruments, instrument-exposure additive homogeneity identifies the ADE if the exposure is also binary. Otherwise, additional assumptions (such as additive linearity of the exposure-outcome effect) are required.

stat.ME↗

arXiv2021

How to estimate heritability, a guide for epidemiologists

Traditionally, heritability has been estimated using family-based methods such as twin studies. Advancements in molecular genomics have facilitated the development of alternative methods that utilise large samples of unrelated or related individuals. Yet, specific challenges persist in the estimation of heritability such as epistasis, assortative mating and indirect genetic effects. Here, we provide an overview of common methods applied in genetic epidemiology to estimate heritability i.e., the proportion of phenotypic variation explained by genetic variation. We provide a guide to key genetic concepts required to understand heritability estimation methods from family-based designs (twin and family studies), genomic designs based on unrelated individuals (LD score regression, GREML), and family-based genomic designs (Sibling regression, GREML-KIN, Trio-GCTA, MGCTA, RDR). For each method, we describe how heritability is estimated, the assumptions underlying its estimation, and discuss the implications when these assumptions are not met. We further discuss the benefits and limitations of estimating heritability within samples of unrelated individuals compared to samples of related individuals. Overall, this article is intended to help the reader determine the circumstances when each method would be appropriate and why.

stat.AP↗