A comparison of methods for analysing multiple outcome measures in randomised controlled trials using a simulation study

• Published in: Biometrical journal Vol. 63; no. 3; pp. 599 - 615
• Main Authors: Vickerstaff, Victoria, Ambler, Gareth, Omar, Rumana Z.
• Format: Journal Article
• Language: English
• Published: Germany Wiley - VCH Verlag GmbH & Co. KGaA 01-03-2021; John Wiley and Sons Inc
• Subjects: Bias; Computer Simulation; Correlation analysis; Data Interpretation, Statistical; Evaluation; Missing data; multiple endpoints; multiple outcomes; Multivariate analysis; multivariate model; Outcome Assessment, Health Care; randomised controlled trials; Randomized Controlled Trials as Topic; Research Design; Research Paper; Simulation; Trial and Survey Methodology; multiple endpoints; multiple outcomes; multivariate model; randomised controlled trials
• ISSN: 0323-3847; 1521-4036; 1521-4036
• DOI: 10.1002/bimj.201900040

Multiple primary outcomes are sometimes collected and analysed in randomised controlled trials (RCTs), and are used in favour of a single outcome. By collecting multiple primary outcomes, it is possible to fully evaluate the effect that an intervention has for a given disease process. A simple approach to analysing multiple outcomes is to consider each outcome separately, however, this approach does not account for any pairwise correlations between the outcomes. Any cases with missing values must be ignored, unless an additional imputation step is performed. Alternatively, multivariate methods that explicitly model the pairwise correlations between the outcomes may be more efficient when some of the outcomes have missing values. In this paper, we present an overview of relevant methods that can be used to analyse multiple outcome measures in RCTs, including methods based on multivariate multilevel (MM) models. We perform simulation studies to evaluate the bias in the estimates of the intervention effects and the power of detecting true intervention effects observed when using selected methods. Different simulation scenarios were constructed by varying the number of outcomes, the type of outcomes, the degree of correlations between the outcomes and the proportions and mechanisms of missing data. We compare multivariate methods to univariate methods with and without multiple imputation. When there are strong correlations between the outcome measures (ρ > .4), our simulation studies suggest that there are small power gains when using the MM model when compared to analysing the outcome measures separately. In contrast, when there are weak correlations (ρ < .4), the power is reduced when using univariate methods with multiple imputation when compared to analysing the outcome measures separately.