title: Linear-rank testing of a non-binary, responder-analysis, efficacy score to evaluate pharmacotherapies for substance use disorders.
abstract: The design of pharmacological trials for management of substance use disorders is shifting toward outcomes of successful individual-level behavior (abstinence or no heavy use). While binary success/failure analyses are common, McCann and Li (CNS Neurosci Ther 2012; 18: 414-418) introduced "number of beyond-threshold weeks of success" (NOBWOS) scores to avoid dichotomized outcomes. NOBWOS scoring employs an efficacy "hurdle" with values reflecting duration of success. Here, we evaluate NOBWOS scores rigorously. Formal analysis of mathematical structure of NOBWOS scores is followed by simulation studies spanning diverse conditions to assess operating characteristics of five linear-rank tests on NOBWOS scores. Simulations include assessment of Fisher's exact test applied to hurdle component. On average, statistical power was approximately equal for five linear-rank tests. Under none of conditions examined did Fisher's exact test exhibit greater statistical power than any of the linear-rank tests. These linear-rank tests provide good Type I and Type II error control for comparing distributions of NOBWOS scores between groups (e.g. active vs. placebo). All methods were applied to re-analyses of data from four clinical trials of differing lengths and substances of abuse. These linear-rank tests agreed across all trials in rejecting (or not) their null (equality of distributions) at ≤ 0.05.
authors.affiliation: 1 Human Immune Monitoring Center, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Tyson H
authors.initials: TH
authors.lastname: Holmes
authors.affiliation: 2 Division of Therapeutics and Medical Consequences, National Institute on Drug Abuse (NIDA), National Institutes of Health, Bethesda, MD, USA.
authors.forename: Shou-Hua
authors.initials: SH
authors.lastname: Li
authors.affiliation: 2 Division of Therapeutics and Medical Consequences, National Institute on Drug Abuse (NIDA), National Institutes of Health, Bethesda, MD, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: McCann
mesh_terms: D015982:Bias; D004358:Drug Therapy / Q000706:statistics & numerical data; D006801:Humans; D016014:Linear Models; D009010:Monte Carlo Method; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D019966:Substance-Related Disorders / Q000188:drug therapy*
keywords: Linear-rank tests; Type I error; pharmacotherapy development; randomized clinical trial; statistical power; substance use disorders