title: Estimating treatment efficacy over time: a logistic regression model for binary longitudinal outcomes.
abstract: This paper presents a case study in longitudinal data analysis where the goal is to estimate the efficacy of a new drug for treatment of a severe chronic constipation. Data consist of long sequences of binary outcomes (relief/no relief) on each of a large number of patients randomized to treatment (low and high dose) or placebo. Data characteristics indicate: (1) the treatment effects vary non-linearly with time; (2) there is substantial heterogeneity across subjects in their responses to treatment; and (3) there is a high proportion of subjects who never experience any relief (the non-responders). To overcome these challenges, we develop a hierarchical model for binary longitudinal data with a mixture distribution on the probability of response to account for the high frequency of non-responders. While the model is specified conditionally on subject-specific latent variables, we also draw inferences on key population-average parameters for the assessment of the treatments' efficacy in a population. In addition we employ a model-checking method to compare the goodness-of-fit for our model against simpler modelling approaches for aggregated counts, such as the zero-inflated Poisson and zero-inflated negative binomial models. We estimate subject-specific and population-average rate ratios of relief for the treatment with respect to the placebo as functions of time (RR(t)), and compare them with the rate ratios estimated from the models for aggregated counts. We find that: (1) the treatment is effective with respect to the placebo with higher efficacy at the beginning of the study; (2) the estimated rate ratios from the models for aggregated counts appear to be similar to the average across time of the population-average rate ratios estimated under our model; and (3) model-checking suggests that the hierarchical and zero-inflated negative binomial model fit the data best. If we are mainly interested to establish the overall efficacy (or safety) of a new drug, it is appropriate to aggregate the longitudinal data over time and analyse the count data by use of standard statistical methods. However, the models for aggregated counts cannot capture time trend of treatment such as the initial treatment benefit or the development of tolerance during the early stage of the treatment which may be important information to physicians to predict the treatment effects for their patients.
authors.affiliation: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA. lchoi@jhsph.edu
authors.forename: Leena
authors.initials: L
authors.lastname: Choi
authors.forename: Francesca
authors.initials: F
authors.lastname: Dominici
authors.forename: Scott L
authors.initials: SL
authors.lastname: Zeger
authors.forename: Peter
authors.initials: P
authors.lastname: Ouyang
mesh_terms: D001699:Biometry; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D003248:Constipation / Q000188:drug therapy; D003627:Data Interpretation, Statistical; D004311:Double-Blind Method; D006801:Humans; D016013:Likelihood Functions; D016015:Logistic Models; D008137:Longitudinal Studies; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D016896:Treatment Outcome