Response Letter to the Editor: “Assumption Checking Before Application of the Prespecified QT Linear Mixed Effect Model is Essential”
Yeamin Huh, Steve Riley, Timothy Nicholas · CPT Pharmacometrics & Systems Pharmacology · 2020
To the Editor: In the Letter to the Editor regarding: “Assumption checking is essential,” the authors questioned satisfaction of assumptions required for applying the prespecified linear mixed effect (LME) model, and our conclusion on reconsidering the LME model when drug-induced circadian rhythm change is expected.1 We appreciate the authors’ investigation of exploratory plots. We believe the basic assumptions are met in part (i) and consideration of exploring alternative models based on known pharmacology is warranted in part (ii) because exploratory plots may not be sensitive to identify all characteristics of drug effects on QT. Hysteresis plot of simulation data, where “truth” is no hysteresis, were additionally investigated in part (ii) (Figure 1b). This could be interpreted as counterclockwise hysteresis, even though none exists. Given the possible conflicting interpretation of graphical analyses, further work is needed to develop definitive criteria for hysteresis checking. Regarding part (ii), we investigated exploratory plots for randomly sampled simulation datasets in the worst scenario (1.2-fold period lengthening). Because only QTcF was simulated, HR-related plots were not examined. As seen in Figure S5, basic assumptions were met, and the LME model would be deemed acceptable. However, because drug-induced circadian rhythm change cannot be identified in the current set of plots but can significantly affect ∆∆QTcF inference, additional modeling should be undertaken given the known pharmacology. We acknowledge that basic assumption checking should be satisfied before applying a LME model. Given the highly variable nature of QT data, graphical analysis may not always be sensitive to identify all characteristics of drug effects on QT. Drug-induced circadian rhythm change may be one case misinformed by graphical analysis alone. None. No funding was received for this work. Y.H., S.R., and T.N. are employees and shareholders of Pfizer Inc. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.