Application of the Marginal Structural Model to Account for Suboptimal Adherence in a Randomized Controlled Trial

James Rochon, Manjushri Bhapkar, Carl F Pieper, William E Kraus, James Rochon, Manjushri Bhapkar, Carl F Pieper, William E Kraus

Abstract

Background: There is considerable interest in adjusting for suboptimal adherence in randomized controlled trials. A per-protocol analysis, for example removes individuals who fail to achieve a minimal level of adherence. One can also reassign non-adherers to the control group, censor them at the point of non-adherence, or cross them over to the control. However, there are biases inherent in each of these methods. Here, we describe an application of causal modeling to address this issue.

Methods: The marginal structural model with inverse-probability weighting was implemented using a weighted generalized estimating equation model. Two ancillary models were developed to derive the weights. First, stepwise linear regression was used to model the observed percent weight loss, while stepwise logistic regression model was applied to model early discontinuation from the intervention. From these, participant- and time-specific weights were calculated.

Discussion: This model is complicated and requires careful attention to detail. Which variables to force into the ancillary models, how to construct interaction terms, and how to address time-dependent covariates must be considered. Nevertheless, it can be used to great effect to predict intervention effects at full adherence. Moreover, by contrasting these results against intention-to-treat results, insights can be gained into the intrinsic physiologic effect of the intervention.

Trial registration: ClinicalTrials.gov Identifier NCT00427193.

Keywords: adherence; aging; calorie restriction; causal modeling; marginal structural model; weighted GEE model.

Conflict of interest statement

None

Figures

Fig. 1
Fig. 1
Box-and-whisker plot of the percent weight change in the CR intervention over the four follow-up intervals.
Fig. 2
Fig. 2
Box-and-Whisker plots of the final stabilized weights, by time point, in the analysis of the adjusted resting metabolic rate.
Fig. 3
Fig. 3
Scatterplot of the adjusted resting metabolic rate against percent weight loss in the CR group at months 12 and 24 overlaid with the fitted quadratic curve. The vertical reference line corresponds to the targeted weight loss level.

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