A Study on the Consistency Between Flagging by Statistical Tests and Biological Evaluation
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A STUDY ON THE CONSISTENCY BETWEEN FLAGGING BY STATISTICAL TESTS AND BIOLOGICAL EVALUATION TSUYOSHI TAKIZAWA, PHD, TOSHIJIIGARASHI,PHD, HIROSHIIMAMIZO, TAKASHI IKEDA,KATSUHIRO OMICHI,TOSHIHITOKADOTA,PHD, MITSUHIRO KAWATA,HIDEYUKISAKAKI,HIROSHITERAI, OSAMUTSUKAMOTO, K ~ z u TOTSUKA, o JUNHANDA,ATSUYOSHI HIRATA, HIDEYUKIMIZUMA,YOSHIKIMURAKAMI, MASAYUKIYAMADA, AND HIDEOYOKOUCHI Japan Pharmaceutical Manufacturers Association, Non-Clinical Evaluation Committee, The 1%Subcommittee, Statistics Working Group (1997-1998). Tokyo, Japan
Statistical hypothesis tests are used as a flagging device to highlight diferences 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 theirfinal 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 eflective for flagging unexpected ‘downturn’ dose response. Key Words: Williams’s test; Steel’s test: Biological significance; Dose-response relationship; Rat repeated dose toxicity study
INTRODUCTION THE PURPOSE OF THE repeated dose toxicity study in the rat is to define toxicity profiles of a drug on repeated administration and to determine the dose level that causes obvious toxic changes, and from that, the highest dose level at which no toxic changes are noted. Many observations and examination results are recorded on the following
Reprint address: Dr. Tsuyoshi Takizawa, Infomatics Office, Nippon Roche K.K.,200 Kajiura, Kamakura, Japan 247-8530. E-mail: [email protected].
items: general signs, body weight, food and water intake, organ weights, hematology, blood chemistry, urinalysis, and histopathological examination. As a result, numerous quantitative parameters are obtained. The customary intention is to check their values against a normal range. Sometimes, however, it is very difficult to establish values for a normal range. Instead, statistical hypothesis tests to compare a control group with several dose groups can be used as a flagging device to highlight differences worth further attention in evaluation of the parmeters. In the pharmaceutical industry, Dunnett’s
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Tsuyoshi Takizawa et al.
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sociation (JPMA) from 1995 to 1997. As shown in Table 1, all studies investigated cons
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