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    A RESAMPLING BASED APPROACH IN EVALUATION OF DOSE-RESPONSE MODELS

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    Genre
    Thesis/Dissertation
    Date
    2014
    Author
    Fu, Min
    Advisor
    Heiberger, Richard M., 1945-
    Committee member
    Sarkar, S. K. (Sanat K.)
    Han, Xu
    Pinheiro, José C.
    Department
    Statistics
    Subject
    Biostatistics
    Dose--response
    Mcp-mod
    Multiple Testing Procedures
    Permutation Test
    Proof-of-concept
    Resampliing
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/2886
    
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    DOI
    http://dx.doi.org/10.34944/dspace/2868
    Abstract
    In this dissertation, we propose a computational approach using a resampling based permutation test as an alternative to MCP-Mod (a hybrid framework integrating the multiple comparison procedure and the modeling technique) and gMCP-Mod (generalized MCP-Mod) [11], [29] in the step of identifying significant dose-response signals via model selection. We name our proposed approach RMCP-Mod or gRMCP-Mod correspondingly. The RMCP-Mod/gRMCP-Mod transforms the drug dose comparisons into a dose-response model selection issue via multiple hypotheses testing, an area where not much extended researches have been done, and solve it using resampling based multiple testing procedures [38]. The proposed approach avoids the inclusion of the prior dose-response knowledge known as "guesstimates" used in the model selection step of the MCP-Mod/gMCP-Mod framework, and therefore reduces the uncertainty in the significant model identification. When a new drug is being developed to treat patients with a specified disease, one of the key steps is to discover an optimal drug dose or doses that would produce the desired clinical effect with an acceptable level of toxicity. In order to nd such a dose or doses (different doses may be able to produce the same or better clinical effect with similar acceptable toxicity), the underlying dose-response signals need to be identified and thoroughly examined through statistical analyses. A dose-response signal refers to the fact that a drug has different clinical effects at many quantitative dose levels. Statistically speaking, the dose-response signal is a numeric relationship curve (shape) between drug doses and the clinical effects in quantitative measures. It's often been a challenge to nd correct and accurate efficacy and/or safety dose-response signals that would best describe the dose-effect relationship in the drug development process via conventional statistical methods because the conventional methods tend to either focus on a fixed, small number of quantitative dosages or evaluate multiple pre-denied dose-response models without Type I error control. In searching for more efficient methods, a framework of combining both multiple comparisons procedure (MCP) and model-based (Mod) techniques acronymed MCP-Mod was developed by F. Bretz, J. C. Pinheiro, and M. Branson [11] to handle normally distributed, homoscedastic dose response observations. Subsequently, a generalized version of the MCP- Mod named gMCP-Mod which can additionally deal with binary, counts, or time-to-event dose-response data as well as repeated measurements over time was developed by J. C. Pinheiro, B. Bornkamp, E. Glimm and F. Bretz [29]. The MCP-Mod/gMCP-Mod uses the guesstimates" in the MCP step to pre-specify parameters of the candidate models; however, in situations where the prior knowledge of the dose-response information is difficult to obtain, the uncertainties could be introduced into the model selection process, impacting on the correctness of the model identification. Throughout the evaluation of its application to the hypothetical and real study examples as well as simulation comparisons to the MCP-Mod/gMCP-Mod, our proposed approach, RMCP-Mod/gRMCP-Mod seems a viable method that can be used in the practice with some further improvements and researches that are still needed in applications to broader dose-response data types.
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