title: It's difficult, but important, to make negative predictions.
abstract: At the confluence of predictive and regulatory toxicologies, negative predictions may be the thin green line that prevents populations from being exposed to harm. Here, two novel approaches to making confident and robust negative in silico predictions for mutagenicity (as defined by the Ames test) have been evaluated. Analyses of 12 data sets containing >13,000 compounds, showed that negative predictivity is high (∼90%) for the best approach and features that either reduce the accuracy or certainty of negative predictions are identified as misclassified or unclassified respectively. However, negative predictivity remains high (and in excess of the prevalence of non-mutagens) even in the presence of these features, indicating that they are not flags for mutagenicity.
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK. Electronic address: richard.williams@lhasalimited.org.
authors.forename: Richard V
authors.initials: RV
authors.lastname: Williams
authors.affiliation: Sanofi-Aventis Deutschland GmbH, R&D DSAR/Preclinical Safety FF, Industriepark Hoechst, Bldg. H823, D-65926 Frankfurt am Main, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Amberg
authors.affiliation: Roche Pharmaceutical Research & Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Brigo
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Laurence
authors.initials: L
authors.lastname: Coquin
authors.affiliation: GlaxoSmithKline Pre-Clinical Development, Park Road, Ware, Hertfordshire SG12 0DP, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Giddings
authors.affiliation: Novartis Pharma AG, Pre-clinical Safety, Werk Klybeck, CH-4057 Basel, Switzerland.
authors.forename: Susanne
authors.initials: S
authors.lastname: Glowienke
authors.affiliation: Compound Safety Prediction, Pfizer Global Research & Development, 558 Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Nigel
authors.initials: N
authors.lastname: Greene
authors.affiliation: Health/Safety/Environmental, Lilly Research Laboratories, Indianapolis, IN, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Jolly
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston MA, USA.
authors.forename: Ray
authors.initials: R
authors.lastname: Kemper
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: O'Leary-Steele
authors.affiliation: Novartis Pharma AG, Pre-clinical Safety, Werk Klybeck, CH-4057 Basel, Switzerland.
authors.forename: Alexis
authors.initials: A
authors.lastname: Parenty
authors.affiliation: Sanofi-Aventis Deutschland GmbH, R&D DSAR/Preclinical Safety FF, Industriepark Hoechst, Bldg. H823, D-65926 Frankfurt am Main, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Spirkl
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Stalford
authors.affiliation: Janssen Research & Development, 1400 McKean Road, Spring House, PA 19477, USA.
authors.forename: Sandy K
authors.initials: SK
authors.lastname: Weiner
authors.affiliation: Bayer Pharma AG, Investigational Toxicology, Muellerstr. 178, S 116, D-13353, Berlin, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Wichard
mesh_terms: D000818:Animals; D003198:Computer Simulation; D004269:DNA, Bacterial / Q000187:drug effects* / Q000235:genetics; D005188:False Negative Reactions; D006801:Humans; D051188:Knowledge Bases; D008958:Models, Molecular; D016296:Mutagenesis; D009152:Mutagenicity Tests / Q000379:methods*; D009154:Mutation; D010363:Pattern Recognition, Automated; D021281:Quantitative Structure-Activity Relationship; D018570:Risk Assessment
chemical_list: D004269:DNA, Bacterial
keywords: (Q)SAR; Expert assessment; Expert system; ICH M7; In silico toxicology; Negative predictions