On tests of linearity for dose response data: asymptotic, exact conditional and exact unconditional tests

The approximate chi-square statistic, X2Q, which is calculated as the difference between the usual chi-square statistic for heterogeneity and the Cochran-Armitage trend test statistic, has been widely applied to test the linearity assumption for dose-response data. This statistic can be shown to be asymptotically distributed as chi-square with K - 2 degrees of freedom. However, this asymptotic property could be quite questionable if the sample size is small, or if there is a high degree of sparseness or imbalance in the data. In this article, we consider how exact tests based on this X2Q statistic can be performed. Both the exact conditional and unconditional versions will be studied. Interesting findings include: (i) the exact conditional test is extremely sensitive to a small change in dosages, which may eventually produce a degenerate exact conditional distribution; and (ii) the exact unconditional test avoids the problem of degenerate distribution and is shown to be less sensitive to the change in dosages. A real example involving an animal carcinogenesis experiment as well as a fictitious data set will be used for illustration purposes.