Searching for Synergies: Matrix Algebraic Approaches for Efficient Pair Screening

Gerlee, Philip,1980Gothenburg University,Göteborgs universitet,Institutionen för matematiska vetenskaper, matematik,Sahlgrenska Cancer Center,Department of Mathematical Sciences, Mathematics,University of Gothenburg,Chalmers tekniska högskola,Chalmers University of Technology (author)

Functionally interacting perturbations, such as synergistic drugs pairs or synthetic lethal gene pairs, are of key interest in both pharmacology and functional genomics. However, to find such pairs by traditional screening methods is both time consuming and costly. We present a novel computational-experimental framework for efficient identification of synergistic target pairs, applicable for screening of systems with sizes on the order of current drug, small RNA or SGA (Synthetic Genetic Array) libraries (>1000 targets). This framework exploits the fact that the response of a drug pair in a given system, or a pair of genes' propensity to interact functionally, can be partly predicted by computational means from (i) a small set of experimentally determined target pairs, and (ii) pre-existing data (e.g. gene ontology, PPI) on the similarities between targets. Predictions are obtained by a novel matrix algebraic technique, based on cyclical projections onto convex sets. We demonstrate the efficiency of the proposed method using drug-drug interaction data from seven cancer cell lines and gene-gene interaction data from yeast SGA screens. Our protocol increases the rate of synergism discovery significantly over traditional screening, by up to 7-fold. Our method is easy to implement and could be applied to accelerate pair screening for both animal and microbial systems.

Schmidt, Linnéa,1985Uppsala universitet,Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,University of Gothenburg,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)linsc345 (author)
Monsefi, NaserGothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,University of Gothenburg (author)
Kling, Teresia,1985Uppsala universitet,Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,University of Gothenburg,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab(Swepub:gu)xdahte (author)
Jörnsten, Rebecka,1971Gothenburg University,Göteborgs universitet,Institutionen för matematiska vetenskaper, matematisk statistik,Department of Mathematical Sciences, Mathematical Statistics,Chalmers tekniska högskola,Chalmers University of Technology,University of Gothenburg(Swepub:cth)jornsten (author)
Nelander, Sven,1974Uppsala universitet,Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,University of Gothenburg,Cancer och vaskulärbiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)svene843 (author)
Göteborgs universitetInstitutionen för matematiska vetenskaper, matematik (creator_code:org_t)

By the author/editor: Gerlee, Philip, ...; Schmidt, Linnéa, ...; Monsefi, Naser; Kling, Teresia, ...; Jörnsten, Rebeck ...; Nelander, Sven, ...

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By the university: University of Gothenburg; Chalmers University of Technology; Uppsala University

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