title: Evaluation of a statistics-based Ames mutagenicity QSAR model and interpretation of the results obtained.
abstract: The relative wealth of bacterial mutagenicity data available in the public literature means that in silico quantitative/qualitative structure activity relationship (QSAR) systems can readily be built for this endpoint. A good means of evaluating the performance of such systems is to use private unpublished data sets, which generally represent a more distinct chemical space than publicly available test sets and, as a result, provide a greater challenge to the model. However, raw performance metrics should not be the only factor considered when judging this type of software since expert interpretation of the results obtained may allow for further improvements in predictivity. Enough information should be provided by a QSAR to allow the user to make general, scientifically-based arguments in order to assess and overrule predictions when necessary. With all this in mind, we sought to validate the performance of the statistics-based in vitro bacterial mutagenicity prediction system Sarah Nexus (version 1.1) against private test data sets supplied by nine different pharmaceutical companies. The results of these evaluations were then analysed in order to identify findings presented by the model which would be useful for the user to take into consideration when interpreting the results and making their final decision about the mutagenic potential of a given compound.
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Barber
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK. Electronic address: alex.cayley@lhasalimited.org.
authors.forename: Alex
authors.initials: A
authors.lastname: Cayley
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Thierry
authors.initials: T
authors.lastname: Hanser
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Harding
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Crina
authors.initials: C
authors.lastname: Heghes
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Vessey
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Stephane
authors.initials: S
authors.lastname: Werner
authors.affiliation: Janssen Research & Development, 1400 McKean Road, Spring House, PA, 19477, United States.
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
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: Novartis Pharma AG, Pre-Clinical Safety, Werk Klybeck, CH-4057, Basel, Switzerland.
authors.forename: Alexis
authors.initials: A
authors.lastname: Parenty
authors.affiliation: Roche Pharmaceutical Research & Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Brigo
authors.affiliation: Sanofi-Aventis Deutschland GmbH, R&D DSAR/Preclinical Safety FF, Industriepark Hoechst, Bldg. H823, Room 116, D-65926, Frankfurt, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Spirkl
authors.affiliation: Sanofi-Aventis Deutschland GmbH, R&D DSAR/Preclinical Safety FF, Industriepark Hoechst, Bldg. H823, Room 116, D-65926, Frankfurt, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Amberg
authors.affiliation: Vertex Pharmaceuticals, Discovery and Investigative Toxicology, 50 Northern Ave, Boston, MA, United States.
authors.forename: Ray
authors.initials: R
authors.lastname: Kemper
authors.affiliation: Compound Safety Prediction, Pfizer Global Research & Development, 558 Eastern Point Road, Groton, CT, 06340, United States.
authors.forename: Nigel
authors.initials: N
authors.lastname: Greene
mesh_terms: D000465:Algorithms; D000818:Animals; D004269:DNA, Bacterial / Q000187:drug effects / Q000235:genetics; D016208:Databases, Factual; D003661:Decision Support Techniques; D006801:Humans; D015233:Models, Statistical; D016296:Mutagenesis; D009152:Mutagenicity Tests / Q000706:statistics & numerical data*; D009154:Mutation; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D018570:Risk Assessment; D012984:Software
chemical_list: D004269:DNA, Bacterial
keywords: ICH M7; In silico; Mutagenicity; QSAR; Sarah nexus