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W W Piegorsch

Publications and source records attributed to W W Piegorsch.

At least 19 recordsLinked to original sources
PubMed1992

Assessing overdispersion and dose-response in the male dominant lethal assay.

In dominant lethal studies the primary variables of interest are typically expressed as discrete counts or proportions (e.g., live implants, resorptions, percent pregnant). Simple statistical sampling models for discrete data such as binomial or Poisson generally do not fit this type of data because of extra-binomial or extra-Poisson departures from variability predicted under these simple models. Extra-variability in the fetal response may originate from parental contributions. These can lead to over- or under-dispersion seen as, e.g., extra-binomial variability in the proportion response. Utilizing a large control database, we investigated the relative impact of extra-variability from male or female contributions on the endpoints of interest. Male-related effects did not seem to contribute to overdispersion in our database; female-related effects were, however, evidenced. Various statistical methods were considered to test for significant treatment differences under these forms of sampling variability. Computer simulations were used to evaluate these methods and to determine which are most appropriate for practical use in the evaluation of dominant lethal data. Our results suggest that distribution-free statistical methods such as a nonparametric permutation test or rank-based tests for trend can be recommended for use.

Analysis of Variance↗
PubMed1992

Concordance of carcinogenic response between rodent species: potency dependence and potential underestimation.

The use of average qualitative concordance between two bioassay endpoints is considered, with emphasis directed at agreement between rats and mice from results of long-term carcinogenicity studies. It is noted that concordance varies as a function of the underlying potency or toxicity of the chemicals over which the averaging is performed. Thus, the averaging process dilutes large observed concordances from potent chemicals, and possibly inflates lower observed concordances from weakly active chemicals. Stratification over some measure of potency is suggested as a method for taking these effects into account. Statistical simulations of concordance analyses limited to low-potency ranges are employed to examine the concordance measure in greater detail. It is seen that at low potencies, observed concordance is consistently underestimated, reaching maximum levels of only about 80%.

Animals↗
PubMed1992

Acrylamide: dermal exposure produces genetic damage in male mouse germ cells.

Acrylamide is used extensively in sewage and wastewater treatment plants, in the paper and pulp industry, in treatment of potable water, and in research laboratories for chromatography, electrophoresis, and electron microscopy. Dermal contact is a major route of human exposure. It has been shown that acrylamide is highly effective in breaking chromosomes of germ cells of male mice and rats when administered intraperitoneally or orally, resulting both in the early death of conceptuses and in the transmission of reciprocal translocations to live-born progeny. It is now reported that acrylamide is absorbed through the skin of male mice, reaches the germ cells, and induces chromosomal damage. The magnitude of genetic damage appears to be proportional to the dose administered topically.

Acrylamide↗
PubMed1991

Statistical methods for analyzing developmental toxicity data.

A description and review of methods for performing per-litter analyses involving extrabinomial proportion response is provided. It is stressed that the litter should be regarded as the appropriate experimental unit for quantitative analysis in studies for teratogenic or heritable mutagenic effects. Attention is directed at statistical identification of possible treatment effects, such as a positive dose response to a chemical stimulus. The methods range from distribution-free, nonparametric analyses to models involving parametric distributions such as the beta-binomial density. It is seen that most current methods require computer implementation. When concern is raised over misspecification of assumptions critical to the statistical analysis, it is argued that relatively parameter-free methods are appropriate for use. These include statistical bootstrapping and rank-based analyses.

Models, Statistical↗
PubMed1991

Multiple comparisons for analyzing dichotomous response.

Dichotomous response models are common in many experimental settings. Statistical parameters of interest are typically the probabilities, pi, that an experimental unit will respond at the various treatment levels. Herein, simultaneous procedures are considered for multiple comparisons among these probabilities, with attention directed at construction of simultaneous confidence intervals for various functions of the pi. The inferences are based on the asymptotic normality of the maximum likelihood estimator of pi. Specific applications include all pairwise comparisons and comparisons with a fixed (control) treatment. Monte Carlo evaluations are undertaken to examine the small-sample properties of the various procedures. It is seen that use of the usual estimates of variance consistently leads to less-than-nominal empirical coverage for most sample sizes examined. For very large samples (total size greater than about 300), nominal coverage is achieved. A reformulation of the pairwise comparisons using a construction noted by Beal (1987, Biometrics 43, 941-950) is shown to exhibit generally nominal empirical coverage characteristics, and is recommended for use with small-to-moderate sample sizes.

Biometry↗
PubMed1990

Detection of induced mitotic chromosome loss in Saccharomyces cerevisiae--an interlaboratory assessment of 12 chemicals.

Induced mitotic chromosome loss was assayed using diploid yeast strain S. cerevisiae D61.M. The test relies upon the uncovering and expression of multiple recessive markers reflecting the presumptive loss of the chromosome VII homologue carrying the corresponding wild-type alleles. An interlaboratory study was performed in which 12 chemicals were tested under code in 2 laboratories. The results generated by the Berkeley and the Darmstadt laboratories were in close agreement. The solvents benzonitrile and methyl ethyl ketone induced significantly elevated chromosome loss levels. However, a treatment regime that included overnight storage at 0 degree C was required to optimize chromosome loss induction. Hence, these agents are postulated to induce chromosome loss via perturbation of microtubular assembly. Fumaronitrile yielded inconsistent results: induction of chromosome loss and respiratory deficiency was observed in both laboratories, but the response was much more pronounced in the Darmstadt trial than that observed in Berkeley. The mammalian carcinogens, benzene, acrylonitrile, trichloroethylene, 1,1,1-trichloroethane and 1,1,1,2-tetrachloroethane failed to induce chromosome loss but elicited high levels of respiratory deficiency, reflecting anti-mitochondrial activity. Trifluralin, cyclophosphamide monohydrate, diazepam and diethylstilbestrol dipropionate failed to induce any detectable genetic effects. These data suggest that the D61.M system is a reproducible method for detecting induced chromosome loss in yeast.

Alleles↗
PubMed1990

The detection of mitotic and meiotic chromosome gain in the yeast Saccharomyces cerevisiae: effects of methyl benzimidazol-2-yl carbamate, methyl methanesulfonate, ethyl methanesulfonate, dimethyl sulfoxide, propionitrile and cyclophosphamide monohydrate.

The diploid yeast strain BR1669 was used to study induction of mitotic and meiotic chromosome gain by selected chemical agents. The test relies on a gene dosage selection system in which hyperploidy is detected by the simultaneous increase in copy number of two alleles residing on the right arm of chromosome VIII: arg4-8 and cup1S (Rockmill and Fogel. 1988; Whittaker et al., 1988). Methyl methanesulfonate (MMS) induced mitotic, but not meiotic, chromosome gain. Methyl benzimidazol-2-yl carbamate (MBC) and ethyl methanesulfonate (EMS) induced both mitotic and meiotic chromosome gain. Propionitrile, a polar aprotic solvent, induced only mitotic chromosome gain; a reliable response was only achieved by overnight incubation of treated cultures at 0 degrees C. MBC is postulated to act by binding directly to tubulin. The requirement for low-temperature incubation suggests that propionitrile also induces aneuploidy by perturbation of microtubular dynamics. The alkylating agents MMS and EMS probably induce recombination which might in turn perturb chromosome segregation. Cyclophosphamide monohydrate and dimethyl sulfoxide (DMSO) failed to induce mitotic or meiotic chromosome gain.

Aneuploidy↗
PubMed1990

Estimating integrals using quadrature methods with an application in pharmacokinetics.

The estimation of integrals using numerical quadrature is common in many biological studies. For instance, in biopharmaceutical research the area under curves is a useful quantity in deriving pharmacokinetic parameters and in providing a surrogate measure of the total dose of a compound at a particular site. In this paper, statistical issues as separate from numerical issues are considered in choosing a quadrature rule. The class of Newton-Côtes numerical quadrature procedures is examined from the perspective of minimizing mean squared error (MSE). The MSE are examined for a variety of functions commonly encountered in pharmacokinetics. It is seen that the simplest Newton-Côtes procedure, the trapezoidal rule, frequently provides minimum MSE for a variety of concentration-time shapes and under a variety of response variance conditions. A biopharmaceutical example is presented to illustrate these considerations.

Animals↗
PubMed1990

Fisher's contributions to genetics and heredity, with special emphasis on the Gregor Mendel controversy.

R. A. Fisher is widely respected for his contributions to both statistics and genetics. For instance, his 1930 text on The Genetical Theory of Natural Selection remains a watershed contribution in that area. Fisher's subsequent research led him to study the work of (Johann) Gregor Mendel, the 19th century monk who first developed the basic principles of heredity with experiments on garden peas. In examining Mendel's original 1865 article, Fisher noted that the conformity between Mendel's reported and proposed (theoretical) ratios of segregating individuals was unusually good, "too good" perhaps. The resulting controversy as to whether Mendel "cooked" his data for presentation has continued to the current day. This review highlights Fisher's most salient points as regards Mendel's "too good" fit, within the context of Fisher's extensive contributions to the development of genetical and evolutionary theory.

Animals↗
PubMed1990

One-sided significance tests for generalized linear models under dichotomous response.

Dichotomous response models are common in many experimental settings. Often, concomitant explanatory variables are recorded, and a generalized linear model, such as a logit model, is fit. In some cases, interest in specific model parameters is directed only at one-sided departures from some null effect. In these cases, procedures can be developed for testing the null effect against a one-sided alternative. These include Bonferroni-type adjustments of univariate Wald tests, and likelihood ratio tests that employ inequality-constrained multivariate theory. This paper examines such tests of significance. Monte Carlo evaluations are undertaken to examine the small-sample properties of the various procedures. The procedures are seen to perform fairly well, generally achieving their nominal sizes at total sample sizes near 100 experimental units. Extensions to the problem of one-sided tests against a control or standard are also considered.

Biometry↗
PubMed1989

Optimal design allocations for estimating area under curves for studies employing destructive sampling.

Optimal allocations of experimental resources for the estimation of integrals is considered for experiments that use destructive sampling. Given a set of sampling times, a minimum mean square error rule is given for the allotment of fixed experimental resources to the independent variable. The results are seen to be functionally dependent upon the pattern of underlying variability assumed in the model and upon the quadrature rule used to estimate the integral. Extensions to other optimality criteria, including a minimum mean absolute deviation criterion, and to cases involving multiple treatment groups, are also noted.

Models, Biological↗
PubMed1989

Quantitative methods for assessing a synergistic or potentiated genotoxic response.

The problem of assessing chemical interactions in studies of genotoxicity is discussed. Attention is focused on assessing possible synergism or potentiation when the observed genotoxic response is binary (yes-no). Different forms of enhancement are distinguished based upon different assumptions on the genotoxic activity of the experimental treatments. A generalized linear statistical model is considered that links the probability of the binary response to the doses, and data-analytic strategies are described for detecting synergy and potentiation in factorially designed experiments. This approach is illustrated with a series of analyses of various genotoxicity data-sets.

Aminacrine↗
PubMed1989

Quantitative approaches for assessing chromosome loss in Saccharomyces cerevisiae: general methods for analyzing downturns in dose response.

Statistical methods are considered for analysis of data arising from a mitotic chromosome loss assay in Saccharomyces cerevisiae strain D61.M. The methods make use of reproducibility trial data from the assay (presented herein) and previous data, which suggest a unimodal, 'umbrella-patterned' dose response. Computer simulations are employed to illustrate the operating characteristics of the umbrella response methods. These methods are generally applicable to any toxicity assay that exhibits a downturn in dose response. Experimental design considerations are also discussed. These include applications of 2-stage sampling rules to first gauge the dose window of peak response, then test if the response deviates significantly from untreated levels.

Alleles↗
PubMed1989

Detection of induced mitotic chromosome loss in Saccharomyces cerevisiae--an interlaboratory study.

The diploid yeast strain D61.M was used to study induction of mitotic chromosome loss. The test relies upon the uncovering and expression of multiple recessive markers reflecting the presumptive loss of the chromosome VII homologue carrying the corresponding wild-type alleles. The underlying 'loss event' is probably complex since the predicted centromere-linked lethal tetrad segregations for chromosome VII are not recovered. Instead, the homologue bearing the multiple recessive markers is patently homozygous. An interlaboratory study was performed in which 16 chemicals were tested under code in 2 laboratories. The results generated by the Berkeley and Darmstadt laboratories were in close agreement. Acetonitrile, ethyl acetate, 4-acetylpyridine, propionitrile and nocodazole were identified as potent inducers of mitotic chromosome loss. Acetone, dimethyl sulfoxide and 2-methoxyethyl acetate either elicited weak responses or yielded ambiguous results. Water, carbon tetrachloride, 4-fluoro-D,L-phenylalanine, amphotericin B, griseofulvin, cadmium chloride, ethyl methanesulfonate and methylmercury(II) chloride failed to induce chromosome loss. These data suggest that the system described herein represents a reliable assay for chemically induced chromosome loss in yeast.

Alleles↗
PubMed1989

Influence of viral infections on body weight, survival, and tumor prevalence of B6C3F1 (C57BL/6N x C3H/HeN) mice in carcinogenicity studies.

Sendai virus (SV), mouse hepatitis virus (MHV), and pneumonia virus of mice (PVM) are common viral infections of mice. Influence of these viral infections on the prevalence of liver tumors, lung tumors, and lymphoma is of concern in chemical carcinogenicity studies. Body weight, survival, and tumor prevalence of B6C3F1 mice with and without viral infections in 33 male and 34 female untreated control groups and 32 male and 32 female low- and high-dose groups of 2-year chemical carcinogenicity studies were evaluated. In male mice, the SV infection was associated with significantly (p less than 0.05) higher survival of control, low-dose, and high-dose groups, and higher prevalence of liver tumors and lymphoma. The increases in tumor prevalence are possibly due to an increase in the survival of male mice that had SV infection. However, when interlaboratory variability and time-related effects were taken into account, the number of significant effects was consistent with the expected false-positive rate inherent to the statistical procedures. The MHV and PVM infections did not cause consistent changes in body weight, survival, and tumor prevalences in the control and chemical treatment groups of male mice. Viral infections did not cause consistent increases or decreases in body weight, survival, or tumor prevalence in the control and chemical treatment groups of female B6C3F1 mice.

Animals↗
PubMed1989

Quantification of toxic response and the development of the median effective dose (ED50)--a historical perspective.

The development of the widely-used median effective (or lethal) dose as a summary measure in quantifying toxic response to chemical stimuli is reviewed. Attention is directed at those mathematical properties noted by the originator of the median effective dose, the English physiologist John William Trevan, that make the measure a useful summary statistic for toxicological studies. Consideration is also given to the development of precursor measures to the median effective dose, such as minimal effective dose.

Animals↗
PubMed1988

Exploring relationships between mutagenic and carcinogenic potencies.

Salmonella mutagenic and rodent carcinogenic potencies are calculated for 112 compounds recently studied by the U.S. National Toxicology Program. 28 of the 112 compounds are seen to exhibit simultaneous non-zero mutagenic and carcinogenic potencies. These are combined with an earlier list of mutagenic and carcinogenic compounds (McCann et al., 1988) in order to study possible trends in the data. A significant positive correlation is exhibited between mutagenic and carcinogenic potencies in the combined data, although the observed scatter is too great for the overall result to be predictive. Classification by chemical class further indicates positive correlations near one for chemicals classified as nitroaromatic and related compounds. Patterns in mutagenic and carcinogenic potency over time are also examined. Mean potencies of recently-studied compounds are seen to trend lower than those of compounds studied 10 or more years ago.

Animals↗