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B H Margolin

Publications and source records attributed to B H Margolin.

At least 37 records · Page 2Linked to original sources
PubMed1992

Methodological issues in epidemiologic studies using biologic markers.

Biologic markers are becoming prominent features of many classical epidemiologic studies. Their existence has also modified the character of some epidemiologic research such that the term "transitional epidemiologic studies" may be warranted. In the latter type of study, collaboration between laboratory and epidemiologic investigators is integral to the research. In this paper, goals, characteristics, and examples of transitional epidemiologic research are presented. Pertinent features are highlighted, including sources of misclassification and confounding, and elements of study design useful in reducing these potential biases. Sample size issues, transformation of variables, and sources of variability acquire enhanced importance. The study examples presented are intended to illustrate the altered substrate for these methodological features in studies using biologic markers.

Analysis of Variance↗
PubMed1992

Contributions to the design and statistical analysis of in vivo SCE experiments.

Two issues that arise in the design and statistical analysis of in vivo SCE and similar experiments are considered. First, with regard to analysis, the merits of various methods of data transformation are explored in depth. The conclusion drawn is that common transformations of the type studied here seemingly offer little advantage in the assessment of whether a test agent induces SCE in a dose-related manner. Second, a proposal is made for a method to determine, subject to budgetary constraints, the desired numbers of animals/dose group and cells scored/animal. The approach advocated also lends itself to discussions weighing the gains and losses from possible reductions in the number of animals below the 'desired' levels.

Analysis of Variance↗
PubMed1990

Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: confirmation of earlier results with 41 additional chemicals.

The effectiveness of four in vitro short-term tests (STT) for genetic toxicity, induction of mutations in Salmonella (SAL) and mouse lymphoma L5178Y cells (MLA), and induction of sister chromatid exchanges (SCE) and chromosome aberrations (ABS) in Chinese hamster ovary cells that are used for predicting rodent carcinogenicity were examined. The in vitro results were compared with the results from 41 rodent carcinogenicity studies performed by the National Toxicology Program. The predictive values of, and interrelationships among, the STT for these 41 chemicals were similar to those previously reported for 73 chemicals and confirm those earlier results [Tennant RW, Margolin BH, Shelby MD, Zeiger E, Haseman JK, Spalding J, Caspary W, Resnick M, Stasiewicz S, Anderson B, Minor R (1987): Science 236:933-941]. Because of this similarity among the two datasets, the chemicals were combined into a single dataset of 114. The results with 114 chemicals show that SAL had the lowest sensitivity (.48) and the highest specificity (.91), whereas MLA had the highest sensitivity (.72) and the lowest specificity (.40). The concordances of the test results with rodent carcinogenicity were .66, .61, .59, and .59, for SAL, ABS, SCE, and MLA, respectively. Salmonella was the most predictive for carcinogenicity; 89% of the chemicals mutagenic in SAL were carcinogenic in rodents, however a negative result in any or all of the STT was not indicative of noncarcinogenicity. The STT results reported here show good agreement with the potential electrophilicity of the chemicals, and the majority of carcinogens that are undetected by the STT do not have an electrophilic structure. There was no complementarity among the tests and no combination of the four tests was more effective than any single test for predicting carcinogenicity.

Animals↗
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

Differences in the rates of gene amplification in nontumorigenic and tumorigenic cell lines as measured by Luria-Delbrück fluctuation analysis.

It has been hypothesized that genomic fluidity is an important component of tumorigenesis. Previous studies described the relationship between tumorigenicity and one marker for genomic fluidity, gene amplification. In this report, these studies are extended with the rat liver epithelial cell lines to show that: (i) the amplification in these cells arises in a spontaneous fashion in the population (i.e., the variants detected are not preexisting in the population), and (ii) the rate of spontaneous amplification (mutation), as measured by Luria-Delbrück fluctuation analysis, is significantly lower in the nontumorigenic cells than in the tumorigenic cells. The rate was estimated by using the Po method and the method of means. The rate of spontaneous amplification of the gene encoding the multifunctional protein CAD (containing the enzymatic activities carbamoyl-phosphate synthase, aspartate transcarbamylase, and dihydroorotase) in the highly tumorigenic cells was significantly greater than that for the nontumorigenic cells, reaching almost 1 x 10(-4) events per cell per generation. The rate of this mutagenic event is high compared to the rate of point mutations usually reported in mammalian cells, and its potential contribution to the tumorigenic process will be discussed.

Animals↗
PubMed1988

A statistical analysis for the mouse lymphoma cell forward mutation assay.

This paper illustrates the usefulness of solvent control trials and presents a statistical analysis for mouse L5178Y lymphoma data. Examination of solvent control trials establishes that the natural logarithm of mutant frequency is approximately normally distributed and that both the mean and variance of mutant frequency vary by trial. There is little evidence of downturns at higher doses in the dose-response curves studied; therefore, a trend test is proposed for the detection of an increasing dose-response curve. A Monte Carlo investigation confirms that the proposed trend test is better able to detect an increasing dose-response than 4 alternate methods of analysis.

Animals↗
PubMed1988

Exploring simple independent action in multifactor tables of proportions.

The problem of assessing synergistic or antagonistic departure from simple independent action in multifactor tables of proportions is discussed. A generalized linear model is employed in which additivity corresponds to simple independent action. Data-analytic strategies are proposed for exploring departures from simple independent action in various extensions of the 2 X 2 table of proportions. This methodology is illustrated with a series of models fitted to cellular differentiation and murine toxicity data.

Animals↗
PubMed1987

Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays.

Four widely used in vitro assays for genetic toxicity were evaluated for their ability to predict the carcinogenicity of selected chemicals in rodents. These assays were mutagenesis in Salmonella and mouse lymphoma cells and chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Seventy-three chemicals recently tested in 2-year carcinogenicity studies conducted by the National Cancer Institute and the National Toxicology Program were used in this evaluation. Test results from the four in vitro assays did not show significant differences in individual concordance with the rodent carcinogenicity results; the concordance of each assay was approximately 60 percent. Within the limits of this study there was no evidence of complementarity among the four assays, and no battery of tests constructed from these assays improved substantially on the overall performance of the Salmonella assay. The in vitro assays which represented a range of three cell types and four end points did show substantial agreement among themselves, indicating that chemicals positive in one in vitro assay tended to be positive in the other in vitro assays.

Animals↗
PubMed1986

Statistical analyses for in vitro cytogenetic assays using Chinese hamster ovary cells.

It is a widely held view that objective statistical criteria are needed for the evaluation of genetic toxicity assays. This paper presents statistical methods for the analysis of data from in vitro sister chromatid exchange (SCE) and chromosome aberration tests that use Chinese hamster ovary cells. For SCEs, an extensive study of solvent control results demonstrated that there is a substantial interday component of variability in the data, and that a Poisson sampling model is applicable to data generated via the protocol of Galloway et al [1985]. Consequently, a trend test for evidence of a dose response is proposed for such SCE data. As an illustration of this statistical method, analysis of data previously considered to be negative [Gulati et al, 1985] indicates that di(2-ethyl-hexyl) phthalate induces a weak, but reproducible, SCE dose response in CHO cells. Monte Carlo methods are used to show that the trend test is more sensitive than four other statistical procedures considered for the analysis of Poisson-distributed SCEs. A similar trend test for dose response in proportions is proposed for chromosome aberration data, where the percent of cells with chromosome aberrations is the response of interest. Sensitivity (or power) studies indicate that three doses and a control with 50 cells/dose point is a reasonable design for an in vitro SCE study that uses the Galloway et al protocol. For in vitro chromosome aberrations, however, three doses and a control with 100 cells/dose point appears to produce too insensitive an assay; an increase to 200 cells/dose point in the Galloway et al protocol seems worthy of serious consideration.

Animals↗
PubMed1985

Development of a standard protocol for in vitro cytogenetic testing with Chinese hamster ovary cells: comparison of results for 22 compounds in two laboratories.

A major problem of cytogenetics testing in mammalian cells is lack of agreement of results among laboratories. Our objective was to develop a sensitive in vitro test protocol that was applicable to large-scale chemical screening and yielded comparable results in two laboratories. We used sister chromatid exchange (SCE) and chromosome aberration (CAb) tests in Chinese hamster ovary (CHO) cells. The initial protocol used standard cell densities, medium, batch of rat liver S9 for metabolic activation; positive, negative, and solvent controls; staining and scoring techniques; and fixation times. Treatment without S9 was for 8-12 hr (CAb) or 26 hr (SCE), and with S9 for 2 hr in serum-free medium. Bromodeoxyuridine (BrdUrd) (10 microM) was added to SCE cultures only, 2 hr after addition of the test chemical. Doses were based on the 50% toxicity level in a preliminary test of cell survival 24 hr after treatment. One hundred cells (CAb) or 50 cells (SCE) were scored from each control and from five dose levels. Five clastogens were tested in the first two-laboratory comparison: mitomycin-C, triethylenemelamine, N-methyl-N'-nitro-N-nitrosoguanidine, cyclophosphamide, and benzo(alpha)pyrene. There was quite good agreement between laboratories. Seventeen compounds were then tested "blind" in the two laboratories. As testing proceeded, some discrepancies occurred between the laboratories, and the protocol was modified in attempts to improve the resolution of marginal responses and make dose selection more consistent. The preliminary test for cell survival was omitted. A 10(5) dose range in a half-log series was tested, and cells were scored at the highest dose at which sufficient mitotic cells were obtained, and at the next two lower doses. By delaying fixation times, SCE and CAb were scored at doses that inhibited cell cycle progression. This protocol gave comparable results in the two laboratories in many cases and by testing up to a maximum dose, limited by solubility and/or toxicity, should detect a high proportion of clastogens and SCE inducers.

Animals↗
PubMed1985

Strategies to reduce the cost of mutagenicity screening with the Salmonella assay.

An extensive Salmonella assay database was analyzed in order to develop strategies to reduce costs of screening chemicals for mutagenicity. This database was obtained from testing 941 samples (representing 799 chemicals), 36% of which were judged mutagenic. Strains TA98, TA100, TA1535, and TA1537 without activation, with rat liver S-9, and with hamster liver S-9, make up the 12 strain/activation combinations considered here. The testing strategies examined consist of two or three stages; a positive result at any stage is regarded as definitive and stops the testing. Sequential testing improves efficiency by eliminating the need for further experimentation once a chemical has been found to be mutagenic. Consequently, costs and effort are reduced. For screening chemicals in the Salmonella assay, it is our recommendation that a sequential testing scheme be adopted whose initial stage consists of TA100.

Animals↗
PubMed1985

Sister chromatid exchanges: a reexamination of the evidence for sex and race differences in humans.

Published evidence for human sex and race differences in sister chromatid exchange (SCE) levels is reexamined. There is substantial support for the conclusion that women average approximately 0.5 SCE/cell higher than men among normal healthy adults. An index of heterogeneity for SCE counts for cells from a single subject is introduced, and this statistic is applied to the data of Butler [1981], who compared Caucasians, Blacks, Native Americans, and Orientals with regard to SCE levels. There is evidence in Butler's data of differences in the heterogeneity index among these four racial groups, but this finding needs independent verification in a larger study.

Adult↗
PubMed1985

Statistical studies in genetic toxicology: a perspective from the U.S. National Toxicology Program.

This paper surveys recent, as yet unpublished, statistical studies arising from research in genetic toxicology within the U.S. National Toxicology Program (NTP). These studies all involve analyses of data from Ames Salmonella/microsome mutagenicity tests, but the statistical methodologies are broadly applicable. Three issues are addressed: First, what is a tenable sampling model for Ames test data, and how does one best test the adequacy of the Poisson sampling assumption? Second, given that nonmonotone dose-response curves are fairly common in the Salmonella assay, what new statistical techniques or modifications of existing ones seem appropriate to accommodate to this reality? Finally, an intriguing question: How can the extensive NTP Ames test data base be used to assess the characteristics of any mutagen-nonmutagen decision rule? The last issue is illustrated with the commonly used "two-times background" rule.

Animals↗
PubMed1984

Sources of variability in Ames Salmonella typhimurium tester strains: analysis of the International Collaborative Study on 'genetic drift'.

Data from 38 laboratories using 5 strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537, and TA1538) were analyzed to determine sources and magnitudes of test data variability. Each laboratory tested the mutagenicity of 4-nitroquinoline-N-oxide by the same protocol, using both its in-house cultures and a set of reference cultures provided to all laboratories. It was found that neither plate-to-plate nor day-to-day variability within a laboratory differed substantially between the in-house and reference cultures for any strain; this indicated no difference in the laboratories' handling of the two cultures. Not surprisingly, on average, plate-to-plate variability was substantially smaller than day-to-day variability within a laboratory, which, in turn, was substantially smaller than inter-laboratory variability. The solvent DMSO was found to have a small (6-7%) but statistically significant depressive effect on the spontaneous mutant frequency for the two plasmid-containing strains, TA98 and TA100, but not for the other three strains. When the mean value and variance of all laboratories for the in-house culture were compared with the corresponding reference culture values for each dose and strain, no major differences were seen. Any increase in mean or variance in the distribution of laboratory means in one of the two cultures could be ascribed largely to a small number of laboratories. Laboratories that reported 'high' or 'low' levels of spontaneous or induced revertants per plate tended to deviate in the same direction for most strains and for both in-house and reference cultures. If 'genetic drift' contributed to the inter-laboratory variability in this collaborative study, it was a minor component that went undetected in our analyses.

4-Nitroquinoline-1-oxide↗
PubMed1983

Statistical analysis and sample-size determinations for mutagenicity experiments with binomial responses.

Two statistical analyses are studied for their applicability to mutagenicity experiments that produce binomial responses from a control group and a single treated group. Attention is focused on experiments with (1) group sample sizes greater than 500 and (2) a probability less than .05 for a binary observation from any experimental unit being "positive." In addition, it is assumed that historical control data will not be included in the statistical analysis. The first analysis is a conditional binomial test, which has been tabulated extensively by Kastenbaum and Bowman [1970], while the second is based on a standard normal approximation to the distribution of the difference between two sample proportions. A formula is presented for each analysis that relates the associated probability of detecting a mutagen to the mutant frequencies and sample sizes of the two groups. Based on extensive numerical results, the conclusion is drawn that the normal test is the preferred analysis for experiments in which the ratio of the two sample sizes is between 0.80 and 1.25. On the further assumption that an experiment is to be conducted with equal experimental group sample sizes, recommendations are offered for values of this common sample size needed to achieve a specified power, ie, a degree of assurance of detecting a postulated level of mutagenic effect.

Animals↗
PubMed1981

Statistical analysis of the Ames Salmonella/microsome test.

A family of statistical models for analysis of Ames Salmonella/microsome test data is constructed that considers mutation and toxicity as competing risks and allows hyper-Poisson variability. These models have a parameter than can be employed as a mutagenic index because it approximates the slope at zero dose of a dose-response curve adjusted for toxicity. A second parameter quantifies plate-to-plate variability and lends itself to the study of factors affecting internal test reproducibility. The detection of aberrant plate counts is also addressed. This methodology is illustrated with data from a Salmonella test.

Animals↗
PubMed1981

Analyses for binomial data, with application to the fluctuation test for mutagenicity.

The fluctuation test proposed by Green, Muriel and Bridges (1976, Mutation Research 38, 33-42), a short-term microbial test for mutagenicity, yields binomial observations for which the probability of success varies with the background mutation rate, the total number of microbial growth cycles for which a microbe is at risk of mutation, and the rate of induced mutation for the compound being tested. A standard one-tailed two-sample binomial test is preferable to the two-tailed test adopted by Green et al. for analyzing data from a control versus single positive dose fluctuation test. Based on exact power computations, recommendations are offered for the design of such a fluctuation test. A simple method of guarding against the impact of a small number of aberrant observations in a multisample binomial problem is studied; it is applicable to the fluctuation test when the protocol involves replicate measurements . Finally, the case of more than one positive dose of the test compound is investigated. Two statistical tests for this situation, both extensions of one-tailed two-sample test, are extensively compared. A departure from monotonicity at high doses has a more serious effect on the power of the 'regression' test than on that of the 'isotonic' test. A variant of the isotonic test, based on the angular transformation, should be avoided.

Microbial Sensitivity Tests↗