Machine Learning Techniques Outperform Conventional Statistical Methods in the Prediction of High Risk QTc Prolongation Related to a Drug-Drug Interaction

In clinical practice, many drug therapies are associated with prolongation of the QT interval. In literature, estimation of the risk of prescribing drug-induced QT prolongation is mainly executed by means of logistic regression; only one paper reported the use of machine learning techniques. In this paper, we compare the performance of both techniques on the same dataset. High risk for QT prolongation was defined as having a corrected QT interval (QTc) ≥ 450 ms or ≥ 470 ms for respectively male and female patients. Both conventional statistical methods (CSM) and machine learning techniques (MLT) were used. All algorithms were validated internally and with a hold-out dataset of respectively 512 and 102 drug-drug interactions with possible drug-induced QTc prolongation. MLT outperformed the best CSM in both internal and hold-out validation. Random forest and Adaboost classification performed best in the hold-out set with an equal harmonic mean of sensitivity and specificity (HMSS) of 81.2% and an equal accuracy of 82.4% in a hold-out dataset. Sensitivity and specificity were both high (respectively 75.6% and 87.7%). The most important features were baseline QTc value, C-reactive protein level, heart rate at baseline, age, calcium level, renal function, serum potassium level and the atrial fibrillation status. All CSM performed similarly with HMSS varying between 60.3% and 66.3%. The overall performance of logistic regression was 62.0%. MLT (bagging and boosting) outperform CSM in predicting drug-induced QTc prolongation. Additionally, 19.2% was gained in terms of performance by random forest and Adaboost classification compared to logistic regression (the most used technique in literature in estimating the risk for QTc prolongation). Future research should focus on testing the classification on fully external data, further exploring potential of other (new) machine and deep learning models and on generating data pipelines to automatically feed the data to the classifier used.