Sage Journals: Discover world-class research

Abstract

Statistical hypothesis tests are used as a flagging device to highlight differences worth further attention in the evaluation of repeated dose toxicity studies in the rat. Raw data of quantitative parameters of 19 regulatory toxicity studies were collected with their final interpretation of each study. An investigation was done on the consistency between flagging by statistical tests and biological significance by final interpretation. Williams's test at 2.5% of the significance level showed as much accuracy (correct results compared with the sum of false negative and false positive results) as the rate of Dunnett's test at the 5% significance level. Since a monotonic dose-response relationship is usually assumed in selection of dose levels, Williams's test with ordered alternative hypotheses is recommended as a routine procedure instead of the currently used Dunnett's test. A supplementary procedure, using Steel's test, was shown to be effective for flagging unexpected ‘downturn’ dose response.

Keywords

Williams's test Steel's test: Biological significance Dose-response relationship Rat repeated dose toxicity study

Get full access to this article

View all access options for this article.

References

Dunnett

A multiple comparison procedure for comparing several treatments with a control. J Am Stat Assn. 1955;50:1096–1121.

Steel

RGD

A multiple comparison rank sum test: Treatments versus control. Biometrics. 1959;15: 560–572.

Hamada

Three types of algorithm for statistical analysis in chronic toxicity studies. J Toxicol Sci. 1998;23:173–181.

Healey

How to achieve standardization of statistical methods in toxicology. Drug Inf J. 1997;31: 395–401.

Ministry of Health and Welfare Guidelines for Toxicity Studies of Drugs In: Ministry of Health and Welfare ed. Guidelines for Non-Clinical Studies of Drugs. Tokyo, Japan: Yakuji-Nippou-Sya; 1997: 147–175.

Williams

The comparison of several dose levels with a zero dose control. Biometrics. 1972,28:519–531.

Shirley

EAC

A non-parametric equivalent of Williams test for contrasting increasing dose levels of a treatment. Biometrics. 1977;33:386–389.

Williams

A note on SHIRLEY'S nonparametric test for comparing several dose levels with a zero-dose control. Biometrics. 1986;42:183–186.

Hsu

Multiple Comparisons: Theory and Methods. New York, NY: Chapman & Hall; 1996.

10.

Joncreeheere

A distribution k-sample test against ordered alternatives. Biometrika. 1954;41: 133–145.

11.

SAS Institute Inc. SAS/STAT User's Guide Version 6 Fourth Edition. Cary, NC: SAS Institute Inc.; 1992.

12.

Kadota

General consideration for assessment of no-observed adverse effect level (NOAEL). J Toxicol Sci. 1993;18:343–345.

13.

Hothorn

Robustness study on Williams and Shirley procedure with applications in toxicology. Biometr J. 1989;31:891–903.

14.

Hochberg

Tamhane

Multiple Comparison Procedures. New York, NY: John Wiley & Sons; 1987.

15.

Hamada

A study on the consistency between statistical evaluation and toxicological judgment. Drug Inf J. 1997;31:413–421.

A Study on the Consistency between Flagging by Statistical Tests and Biological Evaluation

Abstract

Keywords

Get full access to this article

References