Incorporating Historical Control Data When Comparing Tumor Incidence Rates

• Published in: Journal of the American Statistical Association 2007-12, Vol.102 (480), p.1212-1220
• Main Authors: Peddada, Shyamal D, Dinse, Gregg E, Kissling, Grace E
• Format: Article
• Language: English
• Subjects: Animals; Applications; Applications and Case Studies; Bayesian method; Benzophenones; Biology, psychology, social sciences; Biometrics; Cancer; Cancer bioassay; Carcinogenicity; Carcinogenicity experiment; Carcinogens; Control data; Control groups; Dosage; Exact sciences and technology; Gallium; General topics; Mathematics; Medical care; Medical sciences; Methodology; Mortality; National Toxicology Program; Nonparametric inference; Order-restricted inference; Poly-3; Probability and statistics; Public health; Quantal response; Rats; Sciences and techniques of general use; Statistical analysis; Statistical inference; Statistical methods; Statistics; Survival; Survival adjustment; Survival analysis; Toxicity; Trends; Tumors
• ISSN: 0162-1459; 1537-274X
• DOI: 10.1198/016214506000001356

Animal carcinogenicity studies, such as those conducted by the U.S. National Toxicology Program (NTP), focus on detecting trends in tumor rates across dose groups. Over time, the NTP has compiled vast amounts of data on tumors in control animals. Currently, this information is used informally, without the benefit of statistical tests for carcinogenicity that directly incorporate historical data on control animals. This article proposes a survival-adjusted test for detecting dose-related trends in tumor incidence rates, which incorporates data on historical control rates and formally accounts for variation in these rates among studies. An extensive simulation, based on a wide range of realistic situations, demonstrates that the proposed test performs well compared with the current NTP test, which does not incorporate historical control data. In particular, our test can aid in interpreting the occurrence of a few tumors in treated animals that are rarely seen in controls. One such example, which motivates our work, concerns the analysis of histiocytic sarcoma in the NTP's 2-year cancer bioassay of benzophenone. Whereas the occurrence of three histiocytic sarcomas in female rats was not significant according to the current NTP testing procedure (p = .074), it was highly significant (p = .004) when control data from six recent historical studies were included and our test was applied to the combined data.