scholarly journals Selecting causal risk factors from high-throughput experiments using multivariable Mendelian randomization

2018 ◽  
Author(s):  
Verena Zuber ◽  
Johanna Maria Colijn ◽  
Caroline Klaver ◽  
Stephen Burgess
Keyword(s):  
Risk Factors ◽  
High Throughput ◽  
Bayesian Model Averaging ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Causal Effect ◽  
Model Averaging ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
High Throughput Experiments

AbstractModern high-throughput experiments provide a rich resource to investigate causal determinants of disease risk. Mendelian randomization (MR) is the use of genetic variants as instrumental variables to infer the causal effect of a specific risk factor on an outcome. Multivariable MR is an extension of the standard MR framework to consider multiple potential risk factors in a single model. However, current implementations of multivariable MR use standard linear regression and hence perform poorly with many risk factors.Here, we propose a novel approach to two-sample multivariable MR based on Bayesian model averaging (MR-BMA) that scales to high-throughput experiments. In a realistic simulation study, we show that MR-BMA can detect true causal risk factors even when the candidate risk factors are highly correlated. We illustrate MR-BMA by analysing publicly-available summarized data on metabolites to prioritise likely causal biomarkers for age-related macular degeneration.

scholarly journals Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Verena Zuber ◽  
Johanna Maria Colijn ◽  
Caroline Klaver ◽  
Stephen Burgess
Keyword(s):  
Risk Factors ◽  
High Throughput ◽  
Bayesian Model Averaging ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Causal Effect ◽  
Model Averaging ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
High Throughput Experiments

AbstractModern high-throughput experiments provide a rich resource to investigate causal determinants of disease risk. Mendelian randomization (MR) is the use of genetic variants as instrumental variables to infer the causal effect of a specific risk factor on an outcome. Multivariable MR is an extension of the standard MR framework to consider multiple potential risk factors in a single model. However, current implementations of multivariable MR use standard linear regression and hence perform poorly with many risk factors. Here, we propose a two-sample multivariable MR approach based on Bayesian model averaging (MR-BMA) that scales to high-throughput experiments. In a realistic simulation study, we show that MR-BMA can detect true causal risk factors even when the candidate risk factors are highly correlated. We illustrate MR-BMA by analysing publicly-available summarized data on metabolites to prioritise likely causal biomarkers for age-related macular degeneration.

scholarly journals Profile-likelihood Bayesian model averaging for two-sample summary data Mendelian randomization in the presence of horizontal pleiotropy

2020 ◽  
Author(s):  
Chin Yang Shapland ◽  
Qingyuan Zhao ◽  
Jack Bowden
Keyword(s):  
Bayesian Model ◽  
Bayesian Model Averaging ◽  
Causal Effect ◽  
Profile Likelihood ◽  
Model Averaging ◽  
Age Related Macular Degeneration ◽  
Mendelian Randomisation ◽  
Age Related ◽  
Adjusted Profile Likelihood ◽  
Summary Data

AbstractTwo-sample summary data Mendelian randomisation (MR) is a popular method for assessing causality in epidemiology, by using genetic variants as instrumental variables. If genes exert pleiotropic effects on the outcome not through the exposure of interest, this can lead to heterogeneous and (potentially) biased estimates of causal effect. We investigate the use of Bayesian model averaging (BMA) to preferentially search the space of models with the highest posterior likelihood. We develop a bespoke Metropolis-Hasting algorithm to perform the search using the recently developed Robust Adjusted Profile Likelihood (MR-RAPS) of Zhao et al as the basis for defining a posterior distribution that efficiently accounts for pleiotropic and weak instrument bias. We demonstrate how our general modelling approach can be extended from a standard one-parameter causal model to a two-parameter model, to allow a large proportion of SNPs to violate the Instrument Strength Independent of Direct Effect (InSIDE) assumption. We use Monte Carlo simulations to illustrate our methods and compare it to several related approaches. We finish by applying our approach in practice to investigate the changes in causal effect of their resulting high risk metabolite on the development age-related macular degeneration.

scholarly journals Age-related Macular Degeneration—Disease, Risk Factors, and Treatments

2014 ◽  
Vol 07 (02) ◽  
pp. 154
Author(s):  
Clyde Schultz ◽  
Keyword(s):  
Risk Factors ◽  
Macular Degeneration ◽  
Genetic Factors ◽  
Progressive Disease ◽  
Disease Risk ◽  
Treatment Options ◽  
Current Treatment ◽  
Posterior Segment ◽  
Age Related Macular Degeneration ◽  
Age Related

Age-related macular degeneration (AMD) is a progressive disease of the posterior segment of the eye. It is has been diagnosed worldwide and primarily affects individuals over 50 years of age. The incidence of the disease increases with age and with the presence of certain genetic factors, which may indicate a disposition for disease progression. In addition to genetic factors and age, other factors may be involved in developing AMD. These include obesity and smoking, which are also linked to various cardiovascular conditions. There are two forms of AMD: wet and dry. Both forms may involve the build-up of drusen deposits in the posterior segment of the eye, but the wet form tends to be more severe due to the proliferation of blood vessels into the macula and retinal areas of the back of the eye, thus causing an individual’s vision to become ‘blocked’ or ‘shaded’ usually beginning at the center of the visual field. There are a variety of treatment options for AMD including surgery in the form of laser or photo therapy. The most current treatment options involve the injection of a biologic into the posterior segment of the eye. There are some severe adverse events with this approach but they tend to be rare.

scholarly journals Inferring the direction of a causal link and estimating its effect via a Bayesian Mendelian randomization approach

2019 ◽  
Vol 29 (4) ◽  
pp. 1081-1111 ◽  
Author(s):  
Ioan Gabriel Bucur ◽  
Tom Claassen ◽  
Tom Heskes
Keyword(s):  
Instrumental Variables ◽  
Genetic Variants ◽  
Bayesian Model Averaging ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Model Averaging ◽  
Causal Link ◽  
Reverse Direction ◽  
Causal Pathways ◽  
Health Related

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 pathways, a phenomenon called horizontal pleiotropy. This leads to errors not only in estimating the magnitude of the causal effect but also in inferring the direction of the putative causal link. In this paper, we propose a Bayesian approach called BayesMR that is a generalization of the Mendelian randomization technique in which we allow for pleiotropic effects and, crucially, for the possibility of reverse causation. The output of the method is a posterior distribution over the target causal effect, which provides an immediate and easily interpretable measure of the uncertainty in the estimation. More importantly, we use Bayesian model averaging to determine how much more likely the inferred direction is relative to the reverse direction.

scholarly journals The impact of vascular risk factors on the thickness and volume of the choroid in AMD patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Elżbieta Krytkowska ◽  
Aleksandra Grabowicz ◽  
Katarzyna Mozolewska-Piotrowska ◽  
Zofia Ulańczyk ◽  
Krzysztof Safranow ◽  
...  
Keyword(s):  
Risk Factors ◽  
Vascular Risk Factors ◽  
Age Related Macular Degeneration ◽  
Control Group ◽  
Vascular Risk ◽  
Average Volume ◽  
Central Ring ◽  
Age Related ◽  
The Impact ◽  
Wet Amd

AbstractDisturbances in choroidal microcirculation may lead to the onset and progression of age-related macular degeneration (AMD). We aimed to assess changes in the choroidal volume and thickness in the macular region in AMD eyes and to investigate whether coexisting vascular risk factors alter choroidal status. We enrolled 354 AMD patients (175 dry, 179 wet AMD) and 121 healthy controls. All participants underwent a complete ophthalmologic examination and assessment of choroidal thickness and volume. A multivariate analysis adjusted for age, sex, and smoking status revealed that wet AMD was an independent factor associated with higher average thickness of the central ring area (ATC) and average volume of the central ring area (AVC) and lower choroidal vascularity index (CVI) compared to controls (β =  + 0.18, p = 0.0007, β =  + 0.18, p = 0.0008, respectively) and to dry AMD (β =  + 0.17, p = 0.00003 for both ATC and AVC and β =  − 0.30 p < 0.0001 for CVI). ATC, AVC and average volume (AV) were lower in AMD patients with hypertension and ischaemic heart disease (IHD). The duration of hypertension was inversely correlated with ATC, AVC and AV (Rs =  − 0.13, p < 0.05; Rs =  − 0.12; p < 0.05, Rs =  − 0.12; p < 0.05, respectively) while IHD duration negatively correlated with AV (Rs =  − 0.15, p < 0.05). No such associations were observed in the control group. Our findings show that the choroidal vascular system in eyes with AMD is much more susceptible to damage in the presence than in the absence of systemic vascular disease.

scholarly journals Incidence of elevated intraocular pressure after intravitreal injection in Japanese patients with age-related macular degeneration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maiko Maruyama-Inoue ◽  
Tatsuya Inoue ◽  
Shaheeda Mohamed ◽  
Yoko Kitajima ◽  
Shoko Ikeda ◽  
...  
Keyword(s):  
Risk Factors ◽  
Intraocular Pressure ◽  
Macular Degeneration ◽  
Intravitreal Injection ◽  
Odds Ratio ◽  
Japanese Patients ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Elevated Intraocular Pressure ◽  
History Of

AbstractThe purpose of this study was to report the incidence of elevated intraocular pressure (IOP) after intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF) in Japanese patients with age-related macular degeneration (AMD). A retrospective study of chart review of patients who underwent ≥ 10 intravitreal anti-VEGF injections between April 2009 and December 2019 was conducted. Elevated IOP was defined as IOP ≥ 25 mmHg at one visit. Cases with elevated IOP resulting from IVI were identified. Furthermore, the association between elevated IOP and some parameters, as the risk factors that influence elevated IOP, was investigated. A total of 402 eyes of 370 patients were included in this study. Twenty-eight eyes of 26 patients (7.0%) were identified as cases with elevated IOP after IVI. The mean time of elevation after baseline was 50.6 ± 26.5 months. History of glaucoma (p = 0.021; odds ratio, 5.85), treatment modality (p = 0.019; odds ratio, 6.32), and total number of injections (p = 0.003; odds ratio, 1.03) were significantly associated with elevated IOP. A late complication of elevated IOP is associated with IVI in patients with AMD. Particularly, history of glaucoma and treat and extend regimen with frequent injections were found to be risk factors of elevated IOP.

scholarly journals Neovascular Macular Degeneration: A Review of Etiology, Risk Factors, and Recent Advances in Research and Therapy

2021 ◽  
Vol 22 (3) ◽  
pp. 1170
Author(s):  
Arunbalaji Pugazhendhi ◽  
Margaret Hubbell ◽  
Pooja Jairam ◽  
Balamurali Ambati
Keyword(s):  
Risk Factors ◽  
Macular Degeneration ◽  
Kinase Inhibitors ◽  
Rho Kinase ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Gene Therapies ◽  
Rho Kinase Inhibitors ◽  
Age Related ◽  
Endothelial Growth Factor

Neovascular age-related macular degeneration (exudative or wet AMD) is a prevalent, progressive retinal degenerative macular disease that is characterized by neovascularization of the choroid, mainly affecting the elderly population causing gradual vision impairment. Risk factors such as age, race, genetics, iris color, smoking, drinking, BMI, and diet all play a part in nvAMD’s progression, with anti-vascular endothelial growth factor (anti-VEGF) therapy being the mainstay of treatment. Current therapeutic advancements slow the progression of the disease but do not cure or reverse its course. Newer therapies such as gene therapies, Rho-kinase inhibitors, and levodopa offer potential new targets for treatment.

scholarly journals Progression from Early/Intermediate to Advanced Forms of Age-Related Macular Degeneration in a Large UK Cohort: Rates and Risk Factors

2020 ◽  
Vol 4 (7) ◽  
pp. 662-672 ◽  
Author(s):  
Usha Chakravarthy ◽  
Clare C. Bailey ◽  
Peter H. Scanlon ◽  
Martin McKibbin ◽  
Rehna S. Khan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Age Related

scholarly journals Five-Year Incidence, Progression, and Risk Factors for Age-Related Macular Degeneration

Ophthalmology ◽  
2014 ◽  
Vol 121 (9) ◽  
pp. 1766-1772 ◽  
Author(s):  
Fridbert Jonasson ◽  
Diana E. Fisher ◽  
Gudny Eiriksdottir ◽  
Sigurdur Sigurdsson ◽  
Ronald Klein ◽  
...  
Keyword(s):  
Risk Factors ◽  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Age Related
Sign in / Sign up

Export Citation Format

Share Document