Attribution of Tumor Lethality in the Absence of Cause-of-Death Information.pdf

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2017-04-09 发布于江苏
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Attribution of Tumor Lethality in the Absence of Cause-of-Death Information.pdf

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Attribution of Tumor Lethality in the Absence of Cause-of-Death Information

Attribution of Tumor Lethality in the Absence of Cause-of-DeathInformationHongshik Ahn1, Ralph L. Kodell2, and Hojin Moon11Department of Applied Mathematics and StatisticsState University of New York at Stony BrookStony Brook, NY 11794-36002Division of Biometry and Risk AssessmentNational Center for Toxicological ResearchFood and Drug AdministrationJeerson, AR 72079AbstractA new statistical approach is developed for estimating the carcinogenic potential of drugsand other chemical substances used by humans. Improved statistical methods are developedfor rodent tumorigenicity assays that have interval sacrices but not cause-of-death data. Forsuch experiments, this paper proposes a nonparametric maximum likelihood estimation methodfor estimating the distributions of time-to-onset-of and the time-to-death-from the tumor. Thelog-likelihood function is optimized using a constrained direct-search procedure. Using the max-imum likelihood estimators, the number of fatal tumors in an experiment can be imputed. AMonte Carlo Simulation study is conducted for illustration. The accuracy of cause of deathattributed by the proposed method tends to increase as the competing risks survival rate in-creases. By applying the proposed procedure to a real data set, the eect of calorie restriction isinvestigated. In this study, we found calorie restriction delays the tumor-onset time signicantlyfor pituitary tumors. The present method can result in substantial economic savings by relievingthe need for case-by-case assignment of cause of death or context of observation by pathologists.The ultimate goal of the proposed method is to use the imputed number of fatal tumors tomodify Petos IARC test for application to tumorigenicity assays that lack cause-of-death data.Keywords: Bioassay; Competing risk; Incidental tumor; Interval sacrice; Likelihood1 1 IntroductionIn an animal carcinogenicity study, information about onset of a specic disease is confoundedwith information about the eect of