Missing data imputation in clinical trials using recurrent neural network facilitated by clustering and oversampling

In clinical practice, the composition of missing data may be complex, for example, a mixture of missing at random (MAR) and missing not at random (MNAR) assumptions. Many methods under the assumption of MAR are available. Under the assumption of MNAR, likelihood-based methods require specification of the joint distribution of the data, and the missingness mechanism has been introduced as sensitivity analysis. These classic models heavily rely on the underlying assumption, and, in many realistic scenarios, they can produce unreliable estimates. In this paper, we develop a machine learning based missing data prediction framework with the aim of handling more realistic missing data scenarios. We use an imbalanced learning technique (i.e., oversampling of minority class) to handle the MNAR data. To implement oversampling in longitudinal continuous variable, we first perform clustering via <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:semantics><mml:mi>k</mml:mi><mml:annotation>$k$</mml:annotation></mml:semantics></mml:math> -mean trajectories. And use the recurrent neural network (RNN) to model the longitudinal data. Further, we apply bootstrap aggregating to improve the accuracy of prediction and also to consider the uncertainty of a single prediction. We evaluate the proposed method using simulated data. The prediction result is evaluated at the individual patient level and the overall population level. We demonstrate the powerful predictive capability of RNN for longitudinal data and its flexibility for nonlinear modeling. Overall, the proposed method provides an accurate individual prediction for both MAR and MNAR data and reduce the bias of missing data in treatment effect estimation when compared to standard methods and classic models. Finally, we implement the proposed method in a real dataset from an antidepressant clinical trial. In summary, this paper offers an opportunity to encourage the integration of machine learning strategies for handling of missing data in the analysis of randomized clinical trials.