Multiple test procedures for identifying the maximum safe dose

Ajit C. Tamhane*, Charles W. Dunnett, John W. Green, Jeffrey D. Wetherington

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

We consider dose response studies for safety assessment of crop protection compounds and drugs, and we offer a hypothesis testing approach for identifying the maximum dose level that is guaranteed to be safe with preassigned confidence. The focus is on step-down (SD) multiple test procedures for identifying the maximum safe dose. We propose two classes of contrasts among the dose means as test statistics for these procedures: pairwise contrasts (PC) and Helmert contrasts (HC). The first procedure (SD2PC) consists of a sequence of ordinary t tests and is thus easy to apply, but it can have very low power for certain step response functions. The second procedure (SD1HC) does not suffer from this drawback, but it requires a weak monotonicity assumption for its mathematical validity. The powers of SD2PC and SD1HC are studied via Monte Carlo simulation. We recommend SD2PC for linear response functions and SD1HC for step response functions. The procedures are illustrated by applying them to data from an aquatic toxicity laboratory experiment conducted to assess the safe level of a pesticide.

Original languageEnglish (US)
Pages (from-to)835-843
Number of pages9
JournalJournal of the American Statistical Association
Volume96
Issue number455
DOIs
StatePublished - Sep 1 2001

Funding

Ajit C. Tame iPshfraeo,nDspaseortormSf tieacandtsDitset partment of Inustdrial Engineegr&iMnanagement ScienceNorths,western Ursnit, yive Enstovn, IaL6280. 0Charles W. Dunnett is Professor Emeritus, Department of Mathematics & Statistics and Dpartmente of CliniacEpildemiology & Bio- stistics,taMcMaster Urnts, yHamiltoiivn,eOntario L8S 4K1, Canada. John W. Green is Principal Reseh BaorisscttaiDctPniiuSoatna,H,flteehandtay EvironnmentExcellenceCent,eHaskellr LaboratoryforToxicology&Inus-d trial Medicine, Nwre, kDEa19714. JfeyrD.feWeertinghton is Di, Nornector Clinical/Phase I Biometrics, DuPont PhaeticalsrumComa,cWpimlaingtonn, y DE 19880. The authors thank Brent Logan, for suggesting the forumlation of hypotheses given in Section 8, and two editors and the rereffeeomsrany comntsmanseguedsogts. iThnis reasrwascesuphported in part by a grant from the DuPont Agriculturl Proaducts Dvisioni.

Keywords

  • Dose response
  • Familywise error rate
  • Minimum unsafe dose
  • Multiple comparisons
  • Multivariate
  • Step-down multiple testing procedure
  • T-distribution
  • Toxicology

ASJC Scopus subject areas

  • Statistics and Probability
  • Statistics, Probability and Uncertainty

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