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Mendelian randomization analysis of a time-varying exposure for binary disease outcomes using functional data analysis methods.

ABSTRACT: A Mendelian randomization (MR) analysis is performed to analyze the causal effect of an exposure variable on a disease outcome in observational studies, by using genetic variants that affect the disease outcome only through the exposure variable. This method has recently gained popularity among epidemiologists given the success of genetic association studies. Many exposure variables of interest in epidemiological studies are time varying, for example, body mass index (BMI). Although longitudinal data have been collected in many cohort studies, current MR studies only use one measurement of a time-varying exposure variable, which cannot adequately capture the long-term time-varying information. We propose using the functional principal component analysis method to recover the underlying individual trajectory of the time-varying exposure from the sparsely and irregularly observed longitudinal data, and then conduct MR analysis using the recovered curves. We further propose two MR analysis methods. The first assumes a cumulative effect of the time-varying exposure variable on the disease risk, while the second assumes a time-varying genetic effect and employs functional regression models. We focus on statistical testing for a causal effect. Our simulation studies mimicking the real data show that the proposed functional data analysis based methods incorporating longitudinal data have substantial power gains compared to standard MR analysis using only one measurement. We used the Framingham Heart Study data to demonstrate the promising performance of the new methods as well as inconsistent results produced by the standard MR analysis that relies on a single measurement of the exposure at some arbitrary time point.

SUBMITTER: Cao Y

PROVIDER: S-EPMC5123677 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Mendelian randomization analysis of a time-varying exposure for binary disease outcomes using functional data analysis methods.

Cao Ying Y Rajan Suja S SS Wei Peng P

Genetic epidemiology 20161104 8

A Mendelian randomization (MR) analysis is performed to analyze the causal effect of an exposure variable on a disease outcome in observational studies, by using genetic variants that affect the disease outcome only through the exposure variable. This method has recently gained popularity among epidemiologists given the success of genetic association studies. Many exposure variables of interest in epidemiological studies are time varying, for example, body mass index (BMI). Although longitudinal ...[more]

PMID: 27813215

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Project description:BackgroundFindings from Mendelian randomization (MR) studies are conventionally interpreted as lifelong effects, which typically do not provide insight into the molecular mechanisms underlying the effect of an exposure on an outcome. In this study, we apply two recently developed MR approaches (known as 'lifecourse' and 'tissue-partitioned' MR) to investigate lifestage-specific effects and tissues of action in the relationship between adiposity and circulating leptin levels.MethodsGenetic instruments for childhood and adult adiposity were incorporated into a multivariable MR (MVMR) framework to estimate lifestage-specific effects on leptin levels measured during early life (mean age: 10 y) in the Avon Longitudinal Study of Parents and Children and in adulthood (mean age: 55 y) using summary-level data from the deCODE Health study. This was followed by partitioning body mass index (BMI) instruments into those whose effects are putatively mediated by gene expression in either subcutaneous adipose or brain tissues, followed by using MVMR to simultaneously estimate their separate effects on childhood and adult leptin levels.ResultsThere was strong evidence that childhood adiposity has a direct effect on leptin levels at age 10 y in the lifecourse (β = 1.10 SD change in leptin levels, 95% CI = 0.90-1.30, p=6 × 10-28), whereas evidence of an indirect effect was found on adulthood leptin along the causal pathway involving adulthood body size (β = 0.74, 95% CI = 0.62-0.86, p=1 × 10-33). Tissue-partitioned MR analyses provided evidence to suggest that BMI exerts its effect on leptin levels during both childhood and adulthood via brain tissue-mediated pathways (β = 0.79, 95% CI = 0.22-1.36, p=6 × 10-3 and β = 0.51, 95% CI = 0.32-0.69, p=1 × 10-7, respectively).ConclusionsOur findings demonstrate the use of lifecourse MR to disentangle direct and indirect effects of early-life exposures on time-varying complex outcomes. Furthermore, by integrating tissue-specific data, we highlight the etiological importance of appetite regulation in the effect of adiposity on leptin levels.FundingThis work was supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1).

Project description:Intersectionality recognizes that in the context of sociohistorically shaped structural power relations, an individual's multiple social positions or identities (e.g., gender, ethnicity) can interact to affect health-related outcomes. Despite limited methodological guidance, intersectionality frameworks have increasingly been incorporated into epidemiological studies, both to describe health disparities and to examine their causes. This study aimed to advance methods in intersectional estimation of binary outcomes in descriptive health disparities research through evaluation of 7 potentially intersectional data analysis methods: cross-classification, regression with interactions, multilevel analysis of individual heterogeneity (MAIHDA), and decision trees (CART, CTree, CHAID, random forest). Accuracy of estimated intersection-specific outcome prevalence was evaluated across 192 intersections using simulated data scenarios. For comparison we included a non-intersectional main effects regression. We additionally assessed variable selection performance amongst decision trees. Example analyses using National Health and Nutrition Examination Study data illustrated differences in results between methods. At larger sample sizes, all methods except for CART performed better than non-intersectional main effects regression. In smaller samples, MAIHDA was the most accurate method but showed no advantage over main effects regression, while random forest, cross-classification, and saturated regression were the least accurate, and CTree and CHAID performed moderately well. CART performed poorly for estimation and variable selection. Sensitivity analyses examining the bias-variance tradeoff suggest MAIHDA as the preferred unbiased method for accurate estimation of high-dimensional intersections at smaller sample sizes. Larger sample sizes are more imperative for other methods. Results support the adoption of an intersectional approach to descriptive epidemiology.

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Mendelian randomization analysis of a time-varying exposure for binary disease outcomes using functional data analysis methods.

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Mendelian randomization analysis of a time-varying exposure for binary disease outcomes using functional data analysis methods.

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