scholarly journals Semiparametric methods for estimation of a nonlinear exposure-outcome relationship using instrumental variables with application to Mendelian randomization

2017 ◽  
Vol 41 (4) ◽  
pp. 341-352 ◽  
Author(s):  
James R. Staley ◽  
Stephen Burgess
Keyword(s):  
Instrumental Variables ◽  
Mendelian Randomization ◽  
Semiparametric Methods ◽  
Outcome Relationship

scholarly journals Semiparametric methods for estimation of a non-linear exposure–outcome relationship using instrumental variables with application to Mendelian randomization

2017 ◽  
Author(s):  
James R Staley ◽  
Stephen Burgess
Keyword(s):  
Blood Pressure ◽  
Instrumental Variables ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Piecewise Linear ◽  
Linear Method ◽  
Piecewise Linear Function ◽  
Polynomial Method ◽  
Fractional Polynomial ◽  
Outcome Relationship

AbstractMendelian randomization, the use of genetic variants as instrumental variables (IV), can test for and estimate the causal effect of an exposure on an outcome. Most IV methods assume that the function relating the exposure to the expected value of the outcome (the exposure-outcome relationship) is linear. However, in practice this assumption may not hold. Indeed, often the primary question of interest is to assess the shape of this relationship. We present two novel IV methods for investigating the shape of the exposure-outcome relationship: a fractional polynomial method and a piecewise linear method. We divide the population into strata using the exposure distribution, and estimate a causal effect, referred to as a localized average causal effect (LACE), in each stratum of population. The fractional polynomial method performs meta-regression on these LACE estimates. The piecewise linear method estimates a continuous piecewise linear function, the gradient of which is the LACE estimate in each stratum. Both methods were demonstrated in a simulation study to estimate the true exposure-outcome relationship well, particularly when the relationship was a fractional polynomial (for the fractional polynomial method) or was piecewise linear (for the piecewise linear method). The methods were used to investigate the shape of relationship of body mass index with systolic blood pressure and diastolic blood pressure.Availability and implementation: https://github.com/jrs95/nlmr

scholarly journals Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 772
Author(s):  
João Botelho ◽  
Vanessa Machado ◽  
José João Mendes ◽  
Paulo Mascarenhas
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Instrumental Variables ◽  
Mendelian Randomization ◽  
Association Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
Bidirectional Association

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

scholarly journals Causal Inference Between Chronic Periodontitis and Chronic Kidney Disease: A Bidirectional Mendelian Randomization Analysis in a European Population

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Yang ◽  
Tianyi Chen ◽  
Yahong Zhu ◽  
Mingxia Bai ◽  
Xingang Li
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Causal Inference ◽  
Causal Relationship ◽  
Instrumental Variables ◽  
Chronic Periodontitis ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Summary Statistics

BackgroundPrevious epidemiological studies have shown significant associations between chronic periodontitis (CP) and chronic kidney disease (CKD), but the causal relationship remains uncertain. Aiming to examine the causal relationship between these two diseases, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis with multiple MR methods.MethodsFor the casual effect of CP on CKD, we selected seven single-nucleotide polymorphisms (SNPs) specific to CP as genetic instrumental variables from the genome-wide association studies (GWAS) in the GLIDE Consortium. The summary statistics of complementary kidney function measures, i.e., estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN), were derived from the GWAS in the CKDGen Consortium. For the reversed causal inference, six SNPs associated with eGFR and nine with BUN from the CKDGen Consortium were included and the summary statistics were extracted from the CLIDE Consortium.ResultsNo significant causal association between genetically determined CP and eGFR or BUN was found (all p > 0.05). Based on the conventional inverse variance-weighted method, one of seven instrumental variables supported genetically predicted CP being associated with a higher risk of eGFR (estimate = 0.019, 95% CI: 0.012–0.026, p < 0.001).ConclusionEvidence from our bidirectional causal inference does not support a causal relation between CP and CKD risk and therefore suggests that associations reported by previous observational studies may represent confounding.

scholarly journals Novel insights into the consequences of obesity: a phenotype-wide Mendelian randomization study

2022 ◽  
Author(s):  
Chang He ◽  
Miaoran Zhang ◽  
Jiuling Li ◽  
Yiqing Wang ◽  
Lanlan Chen ◽  
...  
Keyword(s):  
Instrumental Variables ◽  
Fixed Effects ◽  
Mendelian Randomization ◽  
Portion Size ◽  
Causal Effects ◽  
Calorie Intake ◽  
Smoking Behaviors ◽  
Prostate Cancers ◽  
The Uk ◽  
Consequences Of Obesity

AbstractObesity is thought to significantly impact the quality of life. In this study, we sought to evaluate the health consequences of obesity on the risk of a broad spectrum of human diseases. The causal effects of exposing to obesity on health outcomes were inferred using Mendelian randomization (MR) analyses using a fixed effects inverse-variance weighted model. The instrumental variables were SNPs associated with obesity as measured by body mass index (BMI) reported by GIANT consortium. The spectrum of outcome consisted of the phenotypes from published GWAS and the UK Biobank. The MR-Egger intercept test was applied to estimate horizontal pleiotropic effects, along with Cochran’s Q test to assess heterogeneity among the causal effects of instrumental variables. Our MR results confirmed many putative disease risks due to obesity, such as diabetes, dyslipidemia, sleep disorder, gout, smoking behaviors, arthritis, myocardial infarction, and diabetes-related eye disease. The novel findings indicated that elevated red blood cell count was inferred as a mediator of BMI-induced type 2 diabetes in our bidirectional MR analysis. Intriguingly, the effects that higher BMI could decrease the risk of both skin and prostate cancers, reduce calorie intake, and increase the portion size warrant further studies. Our results shed light on a novel mechanism of the disease-causing roles of obesity.

Circulating adiponectin levels and systemic lupus erythematosus: a two-sample Mendelian randomization study

Rheumatology ◽  
2020 ◽  
Author(s):  
Yi-Lin Dan ◽  
Peng Wang ◽  
Zhongle Cheng ◽  
Qian Wu ◽  
Xue-Rong Wang ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Instrumental Variables ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Causal Effects ◽  
European Ancestry ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Inverse Variance ◽  
Weighted Median

Abstract Objectives Several studies have reported increased serum/plasma adiponectin levels in SLE patients. This study was performed to estimate the causal effects of circulating adiponectin levels on SLE. Methods We selected nine independent single-nucleotide polymorphisms that were associated with circulating adiponectin levels (P < 5 × 10−8) as instrumental variables from a published genome-wide association study (GWAS) meta-analysis. The corresponding effects between instrumental variables and outcome (SLE) were obtained from an SLE GWAS analysis, including 7219 cases with 15 991 controls of European ancestry. Two-sample Mendelian randomization (MR) analyses with inverse-variance weighted, MR-Egger regression, weighted median and weight mode methods were used to evaluate the causal effects. Results The results of inverse-variance weighted methods showed no significantly causal associations of genetically predicted circulating adiponectin levels and the risk for SLE, with an odds ratio (OR) of 1.38 (95% CI 0.91, 1.35; P = 0.130). MR-Egger [OR 1.62 (95% CI 0.85, 1.54), P = 0.195], weighted median [OR 1.37 (95% CI 0.82, 1.35), P = 0.235) and weighted mode methods [OR 1.39 (95% CI 0.86, 1.38), P = 0.219] also supported no significant associations of circulating adiponectin levels and the risk for SLE. Furthermore, MR analyses in using SLE-associated single-nucleotide polymorphisms as an instrumental variable showed no associations of genetically predicted risk of SLE with circulating adiponectin levels. Conclusion Our study did not find evidence for a causal relationship between circulating adiponectin levels and the risk of SLE or of a causal effect of SLE on circulating adiponectin levels.

scholarly journals Application of Mendelian Randomization to Investigate the Association of Body Mass Index with Health Care Costs

2020 ◽  
Vol 40 (2) ◽  
pp. 156-169 ◽  
Author(s):  
Christoph F. Kurz ◽  
Michael Laxy
Keyword(s):  
Health Care ◽  
Body Mass Index ◽  
Body Mass ◽  
Health Care Costs ◽  
Instrumental Variables ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Omitted Variables ◽  
Care Costs ◽  
Genetic Instruments

Causal effect estimates for the association of obesity with health care costs can be biased by reversed causation and omitted variables. In this study, we use genetic variants as instrumental variables to overcome these limitations, a method that is often called Mendelian randomization (MR). We describe the assumptions, available methods, and potential pitfalls of using genetic information and how to address them. We estimate the effect of body mass index (BMI) on total health care costs using data from a German observational study and from published large-scale data. In a meta-analysis of several MR approaches, we find that models using genetic instruments identify additional annual costs of €280 for a 1-unit increase in BMI. This is more than 3 times higher than estimates from linear regression without instrumental variables (€75). We found little evidence of a nonlinear relationship between BMI and health care costs. Our results suggest that the use of genetic instruments can be a powerful tool for estimating causal effects in health economic evaluation that might be superior to other types of instruments where there is a strong association with a modifiable risk factor.

scholarly journals Factorial Mendelian randomization: using genetic variants to assess interactions

2019 ◽  
Vol 49 (4) ◽  
pp. 1147-1158 ◽  
Author(s):  
Jessica M B Rees ◽  
Christopher N Foley ◽  
Stephen Burgess
Keyword(s):  
Risk Factors ◽  
Instrumental Variables ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Real Data ◽  
Uk Biobank ◽  
Pharmacological Interventions ◽  
Natural Break ◽  
Using Data ◽  
Randomization Analysis

Abstract Background Factorial Mendelian randomization is the use of genetic variants to answer questions about interactions. Although the approach has been used in applied investigations, little methodological advice is available on how to design or perform a factorial Mendelian randomization analysis. Previous analyses have employed a 2 × 2 approach, using dichotomized genetic scores to divide the population into four subgroups as in a factorial randomized trial. Methods We describe two distinct contexts for factorial Mendelian randomization: investigating interactions between risk factors, and investigating interactions between pharmacological interventions on risk factors. We propose two-stage least squares methods using all available genetic variants and their interactions as instrumental variables, and using continuous genetic scores as instrumental variables rather than dichotomized scores. We illustrate our methods using data from UK Biobank to investigate the interaction between body mass index and alcohol consumption on systolic blood pressure. Results Simulated and real data show that efficiency is maximized using the full set of interactions between genetic variants as instruments. In the applied example, between 4- and 10-fold improvement in efficiency is demonstrated over the 2 × 2 approach. Analyses using continuous genetic scores are more efficient than those using dichotomized scores. Efficiency is improved by finding genetic variants that divide the population at a natural break in the distribution of the risk factor, or else divide the population into more equal-sized groups. Conclusions Previous factorial Mendelian randomization analyses may have been underpowered. Efficiency can be improved by using all genetic variants and their interactions as instrumental variables, rather than the 2 × 2 approach.

scholarly journals Exploring and mitigating potential bias when genetic instrumental variables are associated with multiple non-exposure traits in Mendelian randomization

2019 ◽  
Author(s):  
Qian Yang ◽  
Eleanor Sanderson ◽  
Kate Tilling ◽  
M Carolina Borges ◽  
Deborah A Lawlor
Keyword(s):  
Population Structure ◽  
Instrumental Variables ◽  
Population Stratification ◽  
Mendelian Randomization ◽  
Mr Studies ◽  
Sensitivity Analyses ◽  
List Type ◽  
Genome Wide Association Studies ◽  
Inverse Association ◽  
Genome Wide

AbstractBackgroundOur aim is to produce guidance on exploring and mitigating possible bias when genetic instrumental variables (IVs) associate with traits other than the exposure of interest in Mendelian randomization (MR) studies.MethodsWe use causal diagrams to illustrate scenarios that could result in IVs being related to (non-exposure) traits. We recommend that MR studies explore possible IV-non-exposure associations across a much wider range of traits than is usually the case. Where associations are found, confounding by population stratification should be assessed through adjusting for relevant population structure variables. To distinguish vertical from horizontal pleiotropy we suggest using bidirectional MR between the exposure and non-exposure traits and MR of the effect of the non-exposure traits on the outcome of interest. If vertical pleiotropy is plausible, standard MR methods should be unbiased. If horizontal pleiotropy is plausible, we recommend using multivariable MR to control for observed pleiotropic traits and conducting sensitivity analyses which do not require prior knowledge of specific invalid IVs or pleiotropic paths.ResultsWe applied our recommendations to an illustrative example of the effect of maternal insomnia on offspring birthweight in the UK Biobank. We found little evidence that unexpected IV-non-exposure associations were driven by population stratification. Three out of six observed non-exposure traits plausibly reflected horizontal pleiotropy. Multivariable MR and sensitivity analyses suggested an inverse association of insomnia with birthweight, but effects were imprecisely estimated in some of these analyses.ConclusionsWe provide guidance for MR studies where genetic IVs associate with non-exposure traits.Key messagesGenetic variants are increasingly found to associate with more than one social, behavioural or biological trait at genome-wide significance, which is a challenge in Mendelian randomization (MR) studies.Four broad scenarios (i.e. population stratification, vertical pleiotropy, horizontal pleiotropy and reverse causality) could result in an IV-non-exposure trait association.Population stratification can be assessed through adjusting for population structure with individual data, while two-sample MR studies should check whether the original genome-wide association studies have used robust methods to properly account for it.We apply currently available MR methods for discriminating between vertical and horizontal pleiotropy and mitigating against horizontal pleiotropy to an example exploring the effect of maternal insomnia on offspring birthweight.Our study highlights the pros and cons of relying more on sensitivity analyses without considering particular pleiotropic paths versus systematically exploring and controlling for potential pleiotropic paths via known characteristics.

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