Doctor of Philosophy, Case Western Reserve University, 2022, Clinical Translational Science

The translation of medical therapies from basic and preclinical research to efficacious human interventions is challenging. The majority of candidate therapies fail in early-stage human trials, after showing promise in preclinical work. The primary aim of the research presented herein is to explore the potential role that poor statistical practice in preclinical animal trials might play in contributing to translational failure. First, a comprehensive appraisal of current statistical practice in one area of preclinical neuroscience research was carried out. A close review of the current related literature is presented, and the appraisal includes a tutorial to explain how certain statistical mistakes might result in overly optimistic results, as well as practical recommendations for improvement. A majority of articles included in this appraisal failed to account for sources of non-independence in the data (74-93%) and/or did not analytically account for mid-treatment animal attrition (78%). Ordinal variables were often treated as continuous (37%), outliers were predominantly not mentioned (83%), and plots often concealed the distribution of the data (51%). Next, a sample including both successful and failed human trials for neurologic targets was identified, and rates of statistical mistakes in the associated preceding rodent trials were compared. Failed human trials were found to have higher rates of select sources of potential statistical bias in preceding rodent trials, compared to successful trials. This research provides evidence that a contributing factor to translational failure is statistical misapplication in preclinical animal research in the neurosciences. It provides the groundwork for future research that will provide practical solutions to translational researchers and funders, facilitating preclinical experimental validity to increase the translational success rate.

Committee: Mary Dolansky PhD RN FAAN (Committee Chair); Kenneth Baker PhD (Committee Member); Nancy Obuchowski PhD (Committee Member); Jill Barnholtz-Sloan PhD (Advisor) Subjects: Animal Sciences; Biostatistics; Neurosciences; Statistics