title: Not Just a Sum? Identifying Different Types of Interplay between Constituents in Combined Interventions.
abstract: BACKGROUND
  Experiments in which the effect of combined manipulations is compared with the effects of their pure constituents have received a great deal of attention. Examples include the study of combination therapies and the comparison of double and single knockout model organisms. Often the effect of the combined manipulation is not a mere addition of the effects of its constituents, with quite different forms of interplay between the constituents being possible. Yet, a well-formalized taxonomy of possible forms of interplay is lacking, let alone a statistical methodology to test for their presence in empirical data.
  
  
  RESULTS
  Starting from a taxonomy of a broad range of forms of interplay between constituents of a combined manipulation, we propose a sound statistical hypothesis testing framework to test for the presence of each particular form of interplay. We illustrate the framework with analyses of public gene expression data on the combined treatment of dendritic cells with curdlan and GM-CSF and show that these lead to valuable insights into the mode of action of the constituent treatments and their combination.
  
  
  METHODS
  R code implementing the statistical testing procedure for microarray gene expression data is available as supplementary material. The data are available from the Gene Expression Omnibus with accession number GSE32986.
authors.affiliation: Research Group of Quantitative Psychology and Individual Differences, Faculty of Psychology and Educational Sciences, KU Leuven, Belgium; Methodology and Statistics, Tilburg University, Tilburg, The Netherlands.
authors.forename: Katrijn
authors.initials: K
authors.lastname: Van Deun
authors.affiliation: KU Leuven-University of Leuven, Department of Development and Regeneration @ Kulak, Kortrijk, Belgium.
authors.forename: Lieven
authors.initials: L
authors.lastname: Thorrez
authors.affiliation: GlaxoSmithKline Vaccines, Rixensart, Belgium.
authors.forename: Robert A
authors.initials: RA
authors.lastname: van den Berg
authors.affiliation: Biosystems data analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Age K
authors.initials: AK
authors.lastname: Smilde
authors.affiliation: Research Group of Quantitative Psychology and Individual Differences, Faculty of Psychology and Educational Sciences, KU Leuven, Belgium.
authors.forename: Iven
authors.initials: I
authors.lastname: Van Mechelen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003198:Computer Simulation; D030541:Databases, Genetic; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D004359:Drug Therapy, Combination; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D051379:Mice; D015233:Models, Statistical; D020411:Oligonucleotide Array Sequence Analysis; D010363:Pattern Recognition, Automated / Q000379:methods*; D047071:beta-Glucans / Q000494:pharmacology*
chemical_list: D047071:beta-Glucans; C038459:curdlan; D016178:Granulocyte-Macrophage Colony-Stimulating Factor