Handling informative dropout in longitudinal analysis of health-related quality of life: application of three approaches to data from the esophageal cancer clinical trial PRODIGE 5/ACCORD 17

B Cuer, C Mollevi, A Anota, E Charton, B Juzyna, T Conroy, C Touraine, B Cuer, C Mollevi, A Anota, E Charton, B Juzyna, T Conroy, C Touraine

Abstract

Background: Health-related quality of life (HRQoL) has become a major endpoint to assess the clinical benefit of new therapeutic strategies in oncology clinical trials. Typically, HRQoL outcomes are analyzed using linear mixed models (LMMs). However, longitudinal analysis of HRQoL in the presence of missing data remains complex and unstandardized. Our objective was to compare the modeling alternatives that account for informative dropout.

Methods: We investigated three alternative methods-the selection model (SM), pattern-mixture model (PMM), and shared-parameters model (SPM)-in relation to the LMM. We first compared them on the basis of methodological arguments highlighting their advantages and drawbacks. Then, we applied them to data from a randomized clinical trial that included 267 patients with advanced esophageal cancer for the analysis of four HRQoL dimensions evaluated using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire.

Results: We highlighted differences in terms of outputs, interpretation, and underlying modeling assumptions; this methodological comparison could guide the choice of method according to the context. In the application, none of the four models detected a significant difference between the two treatment arms. The estimated effect of time on HRQoL varied according to the method: for all analyzed dimensions, the PMM estimated an effect that contrasted with those estimated by the SM and SPM; the LMM estimated effects were confirmed by the SM (on two of four HRQoL dimensions) and SPM (on three of four HRQoL dimensions).

Conclusions: The PMM, SM, or SPM should be used to confirm or invalidate the results of LMM analysis when informative dropout is suspected. Of these three alternative methods, the SPM appears to be the most interesting from both theoretical and practical viewpoints.

Trial registration: This study is registered with ClinicalTrials.gov , number NCT00861094 .

Keywords: Cancer clinical trial; Health-related quality of life; Informative dropout; Joint modeling; Pattern-mixture model; Selection model; Shared-parameters model.

Conflict of interest statement

The authors have declared no conflicts of interest.

Figures

Fig. 1
Fig. 1
Patients who dropped out after visits V0 to V6, or did not drop out (V7). Legend: Ratio calculated by treatment arm in evaluable patients for each of the four dimensions of EORTC QLQ-C30 (QL, global health status; PF, physical functioning; PA, pain; and FA, fatigue) during radiochemotherapy (RT), chemotherapy (CT), and follow-up visits (V)
Fig. 2
Fig. 2
Estimated parameters and 95% confidence intervals. Legend: Time effect β1 (slope in the control arm) and interaction effect β2 (slope difference between the experimental and control arm) for the four dimensions of the EORTC QLQ-C30 (QL, PF, PA, and FA) according to the LMM, PMM, SM, SPM
Fig. 3
Fig. 3
Predicted HRQoL score trajectories of the pattern-mixture model. Legend: Predictions over time by treatment arm regimen for the four dimensions of EORTC QLQ-C30 (QL, PF, PA, and FA). The linear trajectories are shown in pattern 1 (last measurement at visits V0 = 0, V1 = 1.25, or V2 = 3 months), pattern 2 (last measurement at visits V3 = 4 or V4 = 6 months), pattern 3 (last measurement at visits V5 = 12 months), pattern 4 (last measurement at visits V6 = 24 or V7 = 36 months, i.e., no dropout) and the overall patterns (marginal HRQoL scores). The solid line refers to the control fluorouracil-cisplatin regimen and the dashed line refers the experimental FOLFOX regimen
Fig. 4
Fig. 4
Predicted HRQoL score trajectories. Legend: Predictions for the four dimensions of the EORTC QLQ-C30 (QL, PF, PA, and FA) according to the LMM, PMM, SM, and SPM. The solid line refers to the control fluorouracil-cisplatin regimen and the dashed line refers the experimental FOLFOX regimen

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