title: D-optimal experimental designs to test for departure from additivity in a fixed-ratio mixture ray.
abstract: Traditional factorial designs for evaluating interactions among chemicals in a mixture may be prohibitive when the number of chemicals is large. Using a mixture of chemicals with a fixed ratio (mixture ray) results in an economical design that allows estimation of additivity or nonadditive interaction for a mixture of interest. This methodology is extended easily to a mixture with a large number of chemicals. Optimal experimental conditions can be chosen that result in increased power to detect departures from additivity. Although these designs are used widely for linear models, optimal designs for nonlinear threshold models are less well known. In the present work, the use of D-optimal designs is demonstrated for nonlinear threshold models applied to a fixed-ratio mixture ray. For a fixed sample size, this design criterion selects the experimental doses and number of subjects per dose level that result in minimum variance of the model parameters and thus increased power to detect departures from additivity. An optimal design is illustrated for a 2:1 ratio (chlorpyrifos:carbaryl) mixture experiment. For this example, and in general, the optimal designs for the nonlinear threshold model depend on prior specification of the slope and dose threshold parameters. Use of a D-optimal criterion produces experimental designs with increased power, whereas standard nonoptimal designs with equally spaced dose groups may result in low power if the active range or threshold is missed.
authors.affiliation: Department of Biostatistics, Virginia Commonwealth University, Richmond, 23298, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Coffey
authors.forename: Chris
authors.initials: C
authors.lastname: Gennings
authors.forename: Jane Ellen
authors.initials: JE
authors.lastname: Simmons
authors.forename: David W
authors.initials: DW
authors.lastname: Herr
mesh_terms: D000818:Animals; D012721:Carbaryl / Q000633:toxicity; D004390:Chlorpyrifos / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008962:Models, Theoretical; D051381:Rats; D020318:Rats, Long-Evans; D012107:Research Design / Q000592:standards*; D018675:Toxicity Tests / Q000191:economics / Q000379:methods*; D015262:Xenobiotics / Q000633:toxicity*
chemical_list: D002800:Cholinesterase Inhibitors; D004338:Drug Combinations; D015262:Xenobiotics; D004390:Chlorpyrifos; D012721:Carbaryl