Biostatistical Methodology in Carcinogenicity Studies

Fairweather, William R.; Bhattacharyya, Amit; Ceuppens, Peter; Heimann, Guenter; Hothorn, Ludwig A.; Kodell, Ralph L.; Lin, Karl K.; Mager, H.; Middleton, Brian J.; Slob, Wout; Soper, Keith A.; Stallard, Nigel; Ventre, John; Wright, Jane

doi:10.1177/009286159803200212

Cited by 25 publications

(11 citation statements)

References 66 publications

(42 reference statements)

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“…A recent review of 13 carcinogenicity studies in the rat with dual control groups showed that on occasion, the presence of both groups assisted in the interpretation of tumor findings (Baldrick, 2005). Additional controls are reported as giving a better assessment of how rare each tumor type is and allows for a more accurate comparison to historical control data (Fairweather et al, 1998). It is also said that the results from 2 identical controls can be used as a mechanism for identifying the extent of control variability and to help evaluate the biological significance of increases in tumor incidence in the treated groups (CDER, 2001).…”

Section: Introductionmentioning

confidence: 99%

Carcinogenicity Evaluation: Comparison of Tumor Data from Dual Control Groups in the CD–1 Mouse

Baldrick

Reeve

2007

Toxicol Pathol

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Current regulatory thinking allows for the use of single control groups for rodent carcinogenicity testing although there has been a trend until recently to use dual control groups. To date, virtually nothing has been published on whether a shift from dual to single control groups will affect the identification of tumorigenic risk potential in these studies. A recent evaluation of dual control carcinogenicity data in the rat (Baldrick, Toxicol Pathol 2005, 33: 283-291) showed that although no major differences in tumor incidences between the control groups were found, some interstudy variation occurred and in cases were a notable difference was seen, the use of 2 control groups, as well as robust, contemporary background data, allowed an easier interpretation of findings in drug-treated groups. In this paper, the results of 10 mouse carcinogenicity studies, performed between 1991 and 2004, with 2 control groups, are presented. As in the rat, interstudy variation was seen and in some cases, the use of dual control groups assisted in the tumor risk assessment. Thus, the continued use of 2 control groups can have a vital role in mouse carcinogenicity studies. The paper also presents an update on survival, on the range and extent of background spontaneous neoplasms and comments on genetic drift in this commonly used mouse strain.

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Section: Introductionmentioning

confidence: 99%

Carcinogenicity Evaluation: Comparison of Tumor Data from Dual Control Groups in the CD–1 Mouse

Baldrick

Reeve

2007

Toxicol Pathol

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“…In some carcinogenicity studies, it may be useful to sacriÿce a few animals in the course of the study for obtaining more information about the tumour incidence rates among live animals. If a goal is to estimate the tumour onset rather than tumour death with low tumour lethality, a study could include interim sacriÿces at speciÿed time points to estimate the tumour incidence rate [33].…”

Section: Discussionmentioning

confidence: 99%

A dose–response test via closed‐form solutions for constrained MLEs in survival/sacrifice experiments

Kim

Ahn

Moon

2006

Statistics in Medicine

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In most survival-sacrifice experiments in animal carcinogenicity studies, the onset of the tumour of interest is not clinically observable. Due to the complexity of constraints for a biological justification, recently developed methods for estimating the tumour onset function and tumour-specific survival function employ computer-intensive numerical solutions. In this paper, closed-form solutions for nonparametric maximum likelihood estimators are derived under explicit and implicit inequality constraints obtained from the monotonicity of the survival functions. Our methods do not require cause-of-death information. The proposed methods can be used to estimate the tumour onset function and the survival function of the tumour of interest. We use the proposed estimators for the development of our new dose-response trend test. A modification of the Poly-k test is made by replacing the time-at-risk weight to a function of the tumour onset survival function. The weighted least square regression method is applied to the estimated survival functions in order to construct a dose-response trend test. A simulation study is conducted to evaluate the performance of the proposed test and compare it with existing trend tests. A real example is used to illustrate the methods.

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“…Permutation tests consider all possible assignments of animals to dose groups as equally likely, while fixing the rest of the information obtained in the experiment. Under the null hypothesis of no treatment effect, this results in an exact conditional distribution of the test statistic when intercurrent mortality patterns are equal across groups, and it is asymptotically correct when the mortality patterns are unequal (Fairweather et al, 1998;Heimann and Neuhaus, 1998). Given a data set, consider all, say M , possible allocations of animals to groups while keeping the observed data for each animal fixed.…”

Section: Permutational Distributionmentioning

confidence: 99%

Age-Adjusted Exact Trend Tests in the Event of Rare Occurrences

2002

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Preclinical animal carcinogenicity studies are usually concerned with testing the statistical significance of a dose-response relationship. When the response consists of a rare event such as the development of a certain type of tumor, exact statistical methods are often employed. The exact randomization trend test based on the multivariate hypergeometric distribution is less powerful in the presence of treatment-related risks other than the specified response. Particularly, the loss of power becomes more pronounced when competing risks cause progressively higher mortality rates with increasing dose, which is usual in practice. An age-adjusted form of the randomization test is proposed to adjust for this effect. Permutational distribution for Peto's cause-of-death (COD) test is also explored and compared with its asymptotic counterpart by simulation. The use of COD information has been a controversial issue due to the subjectivity in the pathologists' determinations as well as for economic reasons. The proposed age-adjusted exact test does not require COD, and it is shown to compare favorably to the COD tests via an extensive Monte Carlo simulation. Applications of the methods to two real data sets are included.

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Biostatistical Methodology in Carcinogenicity Studies

Cited by 25 publications

References 66 publications

Carcinogenicity Evaluation: Comparison of Tumor Data from Dual Control Groups in the CD–1 Mouse

Carcinogenicity Evaluation: Comparison of Tumor Data from Dual Control Groups in the CD–1 Mouse

A dose–response test via closed‐form solutions for constrained MLEs in survival/sacrifice experiments

Age-Adjusted Exact Trend Tests in the Event of Rare Occurrences

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