Estimation of the number of studies with positive trends when studies with negative trends are present

A two-point estimator is proposed for the proportion of studies with positive trends among a collection of studies, some of which may demonstrate negative trends. The proposed estimator is the y-intercept of the secant line joining the points (a, F?(a)) and (b, F?(b)), where F?(p) is the empirical distribution function of p-values from one-tailed tests for positive trend derived from the individual studies. Although this estimator is negatively biased for any choice of the points 0 ≤ a < b ≤ 1, the bias is less than that of the previously proposed one-point estimator defined by setting b = 1. The bias of the two-point estimator is smallest when a and b approach the inflection point of the true distribution function, E [F?(p)]. The utility of the two-point estimator is demonstrated by using it to estimate the number of male-mouse liver carcinogens among carcinogenicity studies conducted by the National Toxicology Program.     

Cancer Risk Assessment with Intermittent Exposure

Applications of methods for carcinogenic risk assessment often focus on estimating lifetime cancer risk. With intermittent or time-dependent exposures, lifetime risk is often approximated on the basis of a lifetime average daily dose (LADD). In this article, we show that there exists a lifetime equivalent constant dose (LECD) which leads to the same lifetime risk as the actual time-dependent exposure pattern. The ratio C = LECD/LADD then provides a measure of accuracy of risk estimates based on the LADD, as well as a basis for correcting such estimates. Theoretical results derived under the classical multistage model and the two-stage birth-death-mutation model suggest that the maximum value of C, which represents the factor by which the LADD may lead to underestimates of risk, will often lie in the range of 2- to 5-fold. The practical application of these results is illustrated in the case of astronauts subjected to relatively short-term exposure to volatile organics in a closed space station environment, and in the case of the ingestion of pesticide residues in food where consumption patterns vary with age.     

A Comparison of Methods for Estimating the Benchmark Dose Based on Overdispersed Data from Developmental Toxicity Studies

Developmental anomalies resulting from prenatal toxicity can be manifested in terms of both malformations among surviving offspring and prenatal death. Although these two endpoints have traditionally been analyzed separately in the assessment of risk, multivariate methods of risk characterization have recently been proposed. We examined this and other issues in developmental toxicity risk assessment by evaluating the accuracy and precision of estimates of the effective dose ( ED ₀₅) and the benchmark dose ( BMD ₀₅) using computer simulation. Our results indicated that different variance structures (Dirichlet-trinomial and generalized linear model) used to characterize overdispersion yielded comparable results when fitting joint dose response models based on generalized estimating equations. (The choice of variance structure in separate modeling was also not critical.) However, using the Rao-Scott transformation to eliminate overdispersion tended to produce estimates of the ED ₀₅ with reduced bias and mean squared error. Because joint modeling ensures that the ED ₀₅ for overall toxicity (based on both malformations and prenatal death) is always less than the ED ₀₅ for either malformations or prenatal death, joint modeling is preferred to separate modeling for risk assessment purposes.     

On the estimation of the proportion of positives in a sequence of screening experiments

A metaanalytic estimator of the proportion of positives in a sequence of screening experiments is proposed. The distribution-free estimator is based on the empirical distribution of P-values from individual experiments, which is uniform under the global null hypotheses of no positives in the sequence of experiments performed. Under certain regularity conditions, the proportion of positives corresponds to the derivative of this distribution under the alternative hypothesis of the existence of some positives. The statistical properties of the estimator are established, including its bias, variance, and rate of convergence to normality. Optimal estimators with minimum mean squared error are also developed under specific alternative hypotheses. The application of the proposed methods is illustrated using data from a sequence of screening experiments with chemicals to determine their carcinogenic potential.     

An Overview of the Report: Correlation Between Carcinogenic Potency and the Maximum Tolerated Dose: Implications for Risk Assessment

Current practice in carcinogen bioassay calls for exposure of experimental animals at doses up to and including the maximum tolerated dose (MTD). Such studies have been used to compute measures of carcinogenic potency such as the TD₅₀ as well as unit risk factors such as q ₁ * for predicting low-dose risks. Recent studies have indicated that these measures of carcinogenic potency are highly correlated with the MTD. Carcinogenic potency has also been shown to be correlated with indicators of mutagenicity and toxicity. Correlation of the MTDs for rats and mice implies a corresponding correlation in TD₅₀ values for these two species. The implications of these results for cancer risk assessment are examined in light of the large variation in potency among chemicals known to induce tumors in rodents.     

Conditional and unconditional tests with historical controls

Score statistics utilizing historical control data have been proposed to test for increasing trend in tumour occurrence rates in laboratory carcinogenicity studies. Novel invariance arguments are used to confirm, under slightly weaker conditions, previously established asymptotic distributions (mixtures of normal distributions) of tests unconditional on the tumor response rate in the concurrent control group. Conditioning on the control response rate, an ancillary statistic, leads to a new conditional limit theorem in which the test statistic converges to an unknown random variable. Because of this, a subasymptotic approximation to the conditional limiting distribution is also considered. The adequacy of these large-sample approximations in finite samples is evaluated using computer simulation. Bootstrap methods for use in finite samples are also proposed. The application of the conditional and unconditional tests is illustrated using bioassay data taken from the literature. The results presented in this paper are used to formulate recommendations for the use of tests for trend with historical controls in practice.