title: Interlaboratory evaluation of genomic signatures for predicting carcinogenicity in the rat.
abstract: The Critical Path Institute recently established the Predictive Safety Testing Consortium, a collaboration between several companies and the U.S. Food and Drug Administration, aimed at evaluating and qualifying biomarkers for a variety of toxicological endpoints. The Carcinogenicity Working Group of the Predictive Safety Testing Consortium has concentrated on sharing data to test the predictivity of two published hepatic gene expression signatures, including the signature by Fielden et al. (2007, Toxicol. Sci. 99, 90-100) for predicting nongenotoxic hepatocarcinogens, and the signature by Nie et al. (2006, Mol. Carcinog. 45, 914-933) for predicting nongenotoxic carcinogens. Although not a rigorous prospective validation exercise, the consortium approach created an opportunity to perform a meta-analysis to evaluate microarray data from short-term rat studies on over 150 compounds. Despite significant differences in study designs and microarray platforms between laboratories, the signatures proved to be relatively robust and more accurate than expected by chance. The accuracy of the Fielden et al. signature was between 63 and 69%, whereas the accuracy of the Nie et al. signature was between 55 and 64%. As expected, the predictivity was reduced relative to internal validation estimates reported under identical test conditions. Although the signatures were not deemed suitable for use in regulatory decision making, they were deemed worthwhile in the early assessment of drugs to aid decision making in drug development. These results have prompted additional efforts to rederive and evaluate a QPCR-based signature using these samples. When combined with a standardized test procedure and prospective interlaboratory validation, the accuracy and potential utility in preclinical applications can be ascertained.
authors.affiliation: Roche Palo Alto, Palo Alto, California 94304, USA. mark.fielden@roche.com
authors.forename: Mark R
authors.initials: MR
authors.lastname: Fielden
authors.forename: Alex
authors.initials: A
authors.lastname: Nie
authors.forename: Michael
authors.initials: M
authors.lastname: McMillian
authors.forename: Chandi S
authors.initials: CS
authors.lastname: Elangbam
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Trela
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dunn
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dragan
authors.forename: Ronny
authors.initials: R
authors.lastname: Fransson-Stehen
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogdanffy
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Adams
authors.forename: William R
authors.initials: WR
authors.lastname: Foster
authors.forename: Shen-Jue
authors.initials: SJ
authors.lastname: Chen
authors.forename: Phil
authors.initials: P
authors.lastname: Rossi
authors.forename: Peter
authors.initials: P
authors.lastname: Kasper
authors.forename: David
authors.initials: D
authors.lastname: Jacobson-Kram
authors.forename: Kay S
authors.initials: KS
authors.lastname: Tatsuoka
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Wier
authors.forename: Jeremy
authors.initials: J
authors.lastname: Gollub
authors.forename: Donald N
authors.initials: DN
authors.lastname: Halbert
authors.forename: Alan
authors.initials: A
authors.lastname: Roter
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Young
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Sina
authors.forename: Jennifer
authors.initials: J
authors.lastname: Marlowe
authors.forename: Hans-Joerg
authors.initials: HJ
authors.lastname: Martus
authors.forename: Jiri
authors.initials: J
authors.lastname: Aubrecht
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Olaharski
authors.forename: Nigel
authors.initials: N
authors.lastname: Roome
authors.forename: Paul
authors.initials: P
authors.lastname: Nioi
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pardo
authors.forename: Ron
authors.initials: R
authors.lastname: Snyder
authors.forename: Richard
authors.initials: R
authors.lastname: Perry
authors.forename: Peter
authors.initials: P
authors.lastname: Lord
authors.forename: William
authors.initials: W
authors.lastname: Mattes
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Car
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D020869:Gene Expression Profiling; D023281:Genomics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley