An application of a pattern-mixture model with multiple imputation for the analysis of longitudinal trials with protocol deviations.

Background: The benefit of a given treatment can be evaluated via a randomized clinical trial design. However, protocol deviations may severely compromise treatment effect since such deviations often lead to missing values. The assumption that methods of analysis can account for the missing data cannot be justified and hence methods of analysis based on plausible assumptions should be used. An alternative analysis to the simple imputation methods requires unverifiable assumptions about the missing data. Therefore sensitivity analysis should be performed to investigate the robustness of statistical inferences to alternative assumptions about the missing data.

Aims: In this paper, we investigate the effect of tuberculosis pericarditis treatment (prednisolone) on CD4 count changes over time and draw inferences in the presence of missing data. The data come from a multicentre clinical trial (the IMPI trial).

Methods: We investigate the effect of prednisolone on CD4 count changes by adjusting for baseline and time-dependent covariates in the fitted model. To draw inferences in the presence of missing data, we investigate sensitivity of statistical inferences to missing data assumptions using the pattern-mixture model with multiple imputation (PM-MI) approach. We also performed simulation experiment to evaluate the performance of the imputation approaches.

Results: Our results showed that the prednisolone treatment has no significant effect on CD4 count changes over time and that the prednisolone treatment does not interact with time and anti-retroviral therapy (ART). Also, patients' CD4 count levels significantly increase over the study period and patients on ART treatment have higher CD4 count levels compared with those not on ART. The results also showed that older patients had lower CD4 count levels compared with younger patients, and parameter estimates under the MAR assumption are robust to NMAR assumptions.

Conclusions: Since the parameter estimates under the MAR analysis are robust to NMAR analyses, the process that generated the missing data in the CD4 count measurements is missing at random (MAR). The implication is that valid inferences can be obtained using either the likelihood-based methods or multiple imputation approaches.