title: An automated fitting procedure and software for dose-response curves with multiphasic features.
abstract: In cancer pharmacology (and many other areas), most dose-response curves are satisfactorily described by a classical Hill equation (i.e. 4 parameters logistical). Nevertheless, there are instances where the marked presence of more than one point of inflection, or the presence of combined agonist and antagonist effects, prevents straight-forward modelling of the data via a standard Hill equation. Here we propose a modified model and automated fitting procedure to describe dose-response curves with multiphasic features. The resulting general model enables interpreting each phase of the dose-response as an independent dose-dependent process. We developed an algorithm which automatically generates and ranks dose-response models with varying degrees of multiphasic features. The algorithm was implemented in new freely available Dr Fit software (sourceforge.net/projects/drfit/). We show how our approach is successful in describing dose-response curves with multiphasic features. Additionally, we analysed a large cancer cell viability screen involving 11650 dose-response curves. Based on our algorithm, we found that 28% of cases were better described by a multiphasic model than by the Hill model. We thus provide a robust approach to fit dose-response curves with various degrees of complexity, which, together with the provided software implementation, should enable a wide audience to easily process their own data.
authors.affiliation: CRUK Cambridge Institute, University of Cambridge, UK.
authors.forename: Giovanni Y
authors.initials: GY
authors.lastname: Di Veroli
authors.affiliation: CRUK Cambridge Institute, University of Cambridge, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fornari
authors.affiliation: CRUK Cambridge Institute, University of Cambridge, UK.|NIH Chemical Genomics Center, National Institutes of Health, Bethesda, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Goldlust
authors.affiliation: CRUK Cambridge Institute, University of Cambridge, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Mills
authors.affiliation: CRUK Cambridge Institute, University of Cambridge, UK.
authors.forename: Siang Boon
authors.initials: SB
authors.lastname: Koh
authors.affiliation: CRUK Cambridge Institute, University of Cambridge, UK.
authors.forename: Jo L
authors.initials: JL
authors.lastname: Bramhall
authors.affiliation: CRUK Cambridge Institute, University of Cambridge, UK.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Richards
authors.affiliation: CRUK Cambridge Institute, University of Cambridge, UK.
authors.forename: Duncan I
authors.initials: DI
authors.lastname: Jodrell
mesh_terms: D000465:Algorithms; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008962:Models, Theoretical; D012984:Software