TY - JOUR TI - Design of primary and sensitivity analyses for handling non-future dependence missing data in clinical trials with an emphasis on the type-i error rate using multiple imputation and pattern mixture model approach DO - https://doi.org/doi:10.7282/T3514138 PY - 2015 AB - Missing data is a common problem in longitudinal clinical trials. Substantial missing data could introduce potential biases and undermine the scientific credibility of causal conclusions from clinical trials. To handle the missing data issue, it is always required by the regulatory agencies to pre-specify a primary analysis and sensitivity analysis in protocol or statistical analysis plan (SAP). Recent National Research Council (NRC) report questioned the reasonableness of the missing at random (MAR) setting as the primary analysis since MAR is a very special and doubtful assumption for the missing data mechanism, and the report encourages to use not missing at random (NMAR) setting as the primary analysis. One of the NMAR mechanisms is non-future dependence missing data (NFD-NMAR). It is also one of the recommended methods in the NRC report. This dissertation addressed this issue and proposed a process to investigate the mean-shift model with NFD-NMAR mechanism (NFD-Delta method). The goal is to provide, via the investigation process, a method of finding an appropriate shift parameter to specify the primary NMAR analysis in study protocol or SAP based on the maintenance of the type-I error rate for any late phase trial by simulations. The simulation set-up should be based on either early phase data or information from interim data of the current trial. The shift parameter of the NFD-Delta method constitutes the sensitivity analysis. Several components were considered for the NFD shift parameter in this dissertation: the metric/unit, magnitude, and the algorithm to place the shift to examine the effect of these components on the type-I error rate (alpha) under the null hypothesis of no treatment effect. For the metric factor, four different metric units were considered: constant STD1, constant RSD1, STDk, RSDk; for the magnitude factor, different values of shift parameter f were considered to investigate which f value is the appropriate shift parameter to control the type-I error rate to the nominal level; for the algorithm to implement the delta shift, three different methods were proposed: sequential, non-sequential and single adjustment method. Extensive simulations were conducted to investigate the type-I error rate. Correctness and robustness of the results were examined. KW - Statistics and Biostatistics KW - Sensitivity theory (Mathematics) KW - Missing observations (Statistics) KW - Clinical trials LA - eng ER -