Continuous dose-response modeling and risk analysis with the gamma and reciprocal gamma distributions

Abstract

Kodell and West (1993) describe two methods for calculating pointwise upper confidence limits on the risk function with normally distributed responses and using a certain definition of adverse quantitative effect. But Banga et al. (2000) have shown that these normal theory methods break down when applied to skew data. We accordingly develop a risk analysis model and associated likelihood-based methodology when the response follows either a gamma or reciprocal gamma distribution. The model supposes that the shape (index) parameter k of the response distribution is held fixed while the logarithm of the scale parameter is a linear model in terms of the dose level. Existence and uniqueness of the maximum likelihood estimates is established. Asymptotic likelihood-based upper and lower confidence limits on the risk are solutions of the Lagrange equations associated with a constrained optimization problem. Starting values for an iterative solution are obtained by replacing the Lagrange equations by the lowest order terms in their asymptotic expansions. Three methods are then compared for calculating confidence limits on the risk: (i) the aforementioned starting values (LRAL method), (ii) full iterative solution of the Lagrange equations (LREL method), and (iii) bounds obtained using approximate normality of the maximum likelihood estimates with standard errors derived from the information matrix (MLE method). Simulation is used to assess coverage probabilities for the resulting upper confidence limits when the log of the scale parameter is quadratic in the dose level. Results indicate that coverage for the MLE method can be off by as much as 15% points and converges very slowly to nominal coverage levels as the sample size increases. Coverage for the LRAL and LREL methods, on the other hand, is close to nominal levels unless (a) the sample size is small, say N < 25, (b) the index parameter is small, say k ≤ 1, and (c) the direction of adversity is to the left for the gamma distribution or to the right for the reciprocal gamma distribution.