Lange, Theis

Loeys, Tom

Moerkerke, Beatrijs

Steen, Johan

Vansteelandt, Stijn

English

Ghent University Academic Bibliography

Mediation analysis is routinely adopted in a wide range of applied disciplines as a statistical tool to disentangle the causal pathways by which an exposure X affects an outcome Y. Within the counterfactual framework, the mediation formula, can be considered the predominant vehicle for effect decomposition.§  Despite widespread application, the mediation formula often produces complex expressions for natural direct and indirect effects.§  For instance, even if no modification by X and/or covariate C levels are allowed for in the working models (for the outcome Y and mediator M), the resulting expressions may still depend on X and/or C in a complicated way. §  This makes results difficult to report and hypotheses infeasible (or even impossible) to test and may hence pose an impediment to routine application of the mediation formula.Medflex: flexible mediation analysis  using natural effect models in RJohan Steen1, Tom Loeys1, Beatrijs Moerkerke1, Theis Lange2, Stijn Vansteelandt1              1Ghent University, 2University of Copenhagen  	   expData <- neWeight(M~X+C, family=gaussian, data=data)fit a model for the mediator distribution and calculate regression weightsin a single R command:expData <- neImpute(Y~X*M+C, family=binomial, data=data)or fit a model for the outcome mean and  impute unobserved Yi(x0,Mi(x1)) within a single R command:WEIGHTING-BASED APPROACH2 IMPUTATION-BASED APPROACH3,4i Xi x0 x1 Yi(x0,Mi(x1)) wi1 1 1 1 Y1 11 1 1 0 Y1 p1(0)/p1(1)2 0 0 0 Y2 12 0 0 1 Y2 p2(1)/p2(0)⋮ ⋮ ⋮ ⋮ ⋮ ⋮i Xi x0 x1 Yi(x0,Mi(x1))1 1 1 1 Y11 1 0 1 Ŷ1(0,M1)2 0 0 0 Y22 0 1 0 Ŷ2(1,M2)⋮ ⋮ ⋮ ⋮ ⋮i Xi x0 x1 Yi(x0,Mi(x1))1 1 1 1 Y11 1 1 0 ?1 1 0 1 ?1 1 0 0 ?2 0 0 0 Y22 0 0 1 ?2 0 1 0 ?2 0 1 1 ?⋮ ⋮ ⋮ ⋮ ⋮Create a hypothetical dataset by expanding the original data along unobserved (x0, x1) combinations and …1 fit <- neModel(Y~X0*X1+C, family=binomial, expData=expData)Fit a natural effect model  to the expanded data:neEffdecomp(fit)Utility functions for  effect decomposition, neLht(fit)or general linear hypotheses2 3 XMYCBeyond the mediation formula: in search of flexibility and parsimonyFitting natural effect models and making statistical inferences using R package medflex1 in three simple stepsWhat’s in it for practitioners?medflex is freely available on CRAN: http://cran.r-project.org/web/packages/medflex/index.htmlcorrespondence: johan.steen@ugent.beü  handles a larger class of parametric working models than software applications that rely on closed-form expressionsü  embedded within framework of existing model-fitting functions in R (mainly glm), allowing estimation on most natural (mostly multiplicative) effect scale (e.g. odds ratios)ü  simplifies testing, especially when dealing with continuous  exposures or covariates, as hypotheses of interest can be captured by (a linear combination of) targeted model parametersü  provides robust standard errors (for glm working models):  less computer-intensive than bootstrap or Monte Carlo integration Alternatively, natural effect models focus on direct parameterization of the natural direct and indirect effects of interest (Lange, Vansteelandt & Bekaert, 2012; Vansteelandt, Bekaert & Lange, 2012).Fitting natural effect models entails the use of well-established missing data methods.	  1Steen, J., Loeys, T., Moerkerke, B., & Vansteelandt, S. (2015). Medflex: An R Package for Flexible Mediation Analysis Using Natural Effect Models. Submitted Manuscript.2Lange, T., Vansteelandt, S., & Bekaert, M. (2012). A Simple Unified Approach for Estimating Natural Direct and Indirect Effects. American Journal of Epidemiology, 176(3), 190–195.References3Vansteelandt, S., Bekaert, M., & Lange, T. (2012). Imputation Strategies for the Estimation of Natural Direct and Indirect Effects. Epidemiologic Methods, 1(1), Article 7. 4Loeys, T., Moerkerke, B., De Smet, O., Buysse, A., Steen, J., & Vansteelandt, S. (2013). Flexible Mediation Analysis in   the Presence of Nonlinear Relations: Beyond the Mediation Formula. Multivariate Behavioral Research, 48(6), 871–894.mediation formulaworking modelslogitP{Y = 1|X ,M,C}=q0+q1X+q2M+q3XM+q4CE(M|X ,C) = g0+ g1X+ g2CZE(Y |X = x0,M = m,C)⇥dF(M = m|X = x1,C)natural direct effect odds rationatural indirect effect odds rationatural effect modellogitP{Y (x0,M(x1)) = 1|C}=b0+b1x0+b2x1+b3x0x1+b4Codds{Y (1,M(x1))|C}odds{Y (0,M(x1))|C} = exp(b1+b3x1)odds{Y (x0,M(1))|C}odds{Y (x0,M(0))|C} = exp(b2+b3x0)Johan Steen, Tom Loeys, Beatrijs Moerkerke, Stijn Vansteelandt 29Applying the plot function to a natural e↵ect model object automatically retains the causale↵ect estimates of interest, generates a linear hypothesis object using neEffdecomp and thenplots its corresponding estimates and confidence intervals, as shown in Figure 4.R> par(mfrow = c(1, 2))R> plot(neMod2, xlab = "log odds ratio")R> plot(neMod2, xlab = "odds ratio", transf = exp)95% sandwich CIslog odds ratio0.0 0.4 0.8total effecttotal indirect effectpure indirect effecttotal direct effectpure direct effect95% sandwich CIsodds ratio1.0 1.5 2.0 2.5total effecttotal indirect effectpure indirect effecttotal direct effectpure direct effectFigure 4: E↵ect decomposition on the log odds ratio and odds ratio scales.The default exposure reference and covariate levels for these plots are the same as for then Effdecomp unction, but can again b altered via the corresponding arguments xRef andcovLev.7. Population-average natural e↵ectsIn all previous sections, we defined natural e↵ects as conditional or stratum-specific e↵ects(i.e., conditional on baseline covariates). However, themedflex package also allows to estimatepopulation-average natural e↵ects. As demonstrated in Appendix A.3 and A.4, rewritingthe mediation formula reveals that estimation of these population-average e↵ects requiresweighting by the reciprocal of the conditional exposure distribution in order to adjust forconfounding (also see Albert 2012; Vansteelandt 2012).As a consequence, a model for the exposure distribution needs to be fitted and specified asan additional working model, e.g.,R> expFit <- glm(att ~ gender + educ + age, data = UPBdata)Since specifying population-average natural e↵ect models using the neModel is equivalent forthe weighting- and imputation-based approaches, in the remainder of this section, we demon-strate how to proceed when adhering to the imputation-based approach. Moreover, whenestimating population-average natural e↵ects, incoherence between imputation and naturale↵ect models is less of a concern as the latter does not require modeling the relation be-tween outcome and covariates. The (first) working model can again be fitted using the samecommands as before:R> impData <- neImpute(UPB ~ att + negaff + gender + educ + age,+ family = binomial("logit"), data = UPBdata)Many thanks to Patrick Corrigan for granting  permission to reproduce his cartoon                      Estimatepure direct effect      0.4790total direct effect     0.5578pure indirect effect    0.1824total indirect effect   0.2613total effect            0.7403Yˆi(x0,Mi) = Eˆ(Yi|Xi = x0,Mi,Ci).wi = pi(x1)/pi(x0) =Pˆ(Mi|Xi = x1,Ci)Pˆ(Mi|Xi = x0,Ci).Natural effect models

Medflex: flexible mediation analysis using natural effect models in R

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Medflex: flexible mediation analysis using natural effect models in R

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