title: Multilevel models improve precision and speed of IC50 estimates.
abstract: Experimental variation in dose-response data of drugs tested on cell lines result in inaccuracies in the estimate of a key drug sensitivity characteristic: the IC50. We aim to improve the precision of the half-limiting dose (IC50) estimates by simultaneously employing all dose-responses across all cell lines and drugs, rather than using a single drug-cell line response.
  
  
  
  We propose a multilevel mixed effects model that takes advantage of all available dose-response data.
  
  
  
  The new estimates are highly concordant with the currently used Bayesian model when the data are well behaved. Otherwise, the multilevel model is clearly superior.
  
  
  
  The multilevel model yields a significant reduction of extreme IC50 estimates, an increase in precision and it runs orders of magnitude faster.
authors.affiliation: Center for Personalized Cancer Treatment (CPCT), Utrecht/Amsterdam, The Netherlands.|Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Vis
authors.affiliation: Department of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Bombardelli
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Howard
authors.initials: H
authors.lastname: Lightfoot
authors.affiliation: European Molecular Biology Laboratory - European Bioinformatics Institute, Cambridge, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Iorio
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Garnett
authors.affiliation: Center for Personalized Cancer Treatment (CPCT), Utrecht/Amsterdam, The Netherlands.|Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Technical University Delft, Delft, The Netherlands.
authors.forename: Lodewyk Fa
authors.initials: LF
authors.lastname: Wessels
mesh_terms: D000465:Algorithms; D001499:Bayes Theorem; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D017711:Nonlinear Dynamics; D000071185:Pharmacogenomic Testing / Q000379:methods* / Q000706:statistics & numerical data; D057285:Precision Medicine
keywords: IC50; dose–response; mixed effects; nonlinear