This application addresses broad Challenge Area (05): Comparative Effectiveness Research and specific Challenge Topic: 05-AA-102 Adaptive Designs and Person-Centered Data Analysis for Alcohol Treatment Research. As the challenge topic implies, statistical analyses using variable-centered approaches (e.g., comparison of means) are insufficient in many clinical studies of alcohol dependence. For example, statistical assumptions (e.g., normality) are routinely violated. Also, such methods can not adequately account for variability in drinking outcome. Similarly, simple trials comparing a treatment and a placebo often do not answer questions of particular import to clinicians, who have to make a series of decisions in the same patient based upon response to initial and subsequent treatment. Recently, there has been substantially increased interest in - and research on - the use of various pharmacological agents as promising adjuncts to psychosocial treatment to reduce alcohol consumption. Many of these studies collected person-centered drinking data using retrospective method, e.g., the timeline follow-back method to recall and record the daily drinking outcome for the past week. These daily drinking records were then summarized and analyzed. For example, Johnson et al. (2003) condensed the daily drinking records in the treatment assessment periods, while Johnson et al. (2007) condensed them in the weekly format. However, such condensed outcomes are not as informative as the original daily drinking record. Also, normality is often assumed for these outcomes, which could be violated. Third, the trajectory of the drinking outcome can not be fully captured in these analyses. In this grant proposal we will develop new statistical methods to analyze person-centered data for alcohol treatment research. First, we will use the original daily drinking level as the response variable, thus our method is more efficient than those using the condensed outcomes. Second, we tackle the non-normality of the daily drinking outcome by two- part models (2PM) to separately describe the odds of daily drinking being zero and the actual number of drinks in a drinking day. We also propose new methods to tackle the skewness and possible heteroscedasticity in the positive daily drinking level. Third, we are interested in the trajectory of the drinking outcome over time to better capture differences in outcomes. We will use both parametric and semiparametric methods (e.g., splines) to describe such temporal patterns. In many simple trials, we compare two arms, often a treatment arm and a control arm, to determine the efficacy of the intervention. However, such studies are insufficient when we are interested in determining the optimal dose from a range of doses. For example, Johnson et al. (2003, 2007) used a dose escalation scheme (from 25 mg to 300 mg) in the topiramate trials. In these proof of concept trials, they established the overall topiramate treatment effect at improving drinking outcomes. However, the topiramate effect at different dose levels remains to be ascertained so that we can identify the best dose which has the satisfactory efficacy while minimizing the rate of adverse events. Adaptive designs can offer a potential solution. The motivation behind adaptive designs is to bring together the statistical advantages of a sequential design with the ethical imperative of treating as many patients as possible at a dose judged to be the best, in the light of prior knowledge and the current accumulated data. In this context, the continual reassessment method (CRM) opened up the field to the use of working statistical models which have some optimal characteristics (O'Quigley, Pepe and Fisher, 1990). New methods to find the most successful dose (MSD) will be proposed to identify the optimal dose in a cost-effective way.
(provided by applicant): In this grant proposal we will propose and apply several innovative models to analyze the person-centered data for alcohol treatment research. We will also introduce new adaptive designs to identify optimal dose in a cost-effective way. We expect that the completion of this study will speed the process of comparing effectiveness of different treatments in alcohol dependence studies.
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