title: Synergistic drug combinations from electronic health records and gene expression.
abstract: OBJECTIVE
  Using electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding.
  
  
  METHODS
  We applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis.
  
  
  RESULTS
  From EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence.
  
  
  CONCLUSIONS
  This is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing.
authors.affiliation: Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, CA, USA.
authors.forename: Yen S
authors.initials: YS
authors.lastname: Low
authors.affiliation: twoXAR, Inc., Palo Alto, CA, USA.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Daugherty
authors.affiliation: twoXAR, Inc., Palo Alto, CA, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Schroeder
authors.affiliation: Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, CA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Chen
authors.affiliation: Clinical Informatics, Stanford University.
authors.forename: Tina
authors.initials: T
authors.lastname: Seto
authors.affiliation: Clinical Informatics, Stanford University.
authors.forename: Susan
authors.initials: S
authors.lastname: Weber
authors.affiliation: Department of Statistics, Stanford University.
authors.forename: Michael
authors.initials: M
authors.lastname: Lim
authors.affiliation: Department of Statistics, Stanford University.|Department of Health Research and Policy, Stanford University.
authors.forename: Trevor
authors.initials: T
authors.lastname: Hastie
authors.affiliation: Quantitative Sciences Unit, Stanford University.
authors.forename: Maya
authors.initials: M
authors.lastname: Mathur
authors.affiliation: Quantitative Sciences Unit, Stanford University.
authors.forename: Manisha
authors.initials: M
authors.lastname: Desai
authors.affiliation: twoXAR, Inc., Palo Alto, CA, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Farrington
authors.affiliation: twoXAR, Inc., Palo Alto, CA, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Radin
authors.affiliation: twoXAR, Inc., Palo Alto, CA, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Sirota
authors.affiliation: Palo Alto Medical Foundation Research Institute, Palo Alto, CA, USA.
authors.forename: Pragati
authors.initials: P
authors.lastname: Kenkare
authors.affiliation: Palo Alto Medical Foundation Research Institute, Palo Alto, CA, USA.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Thompson
authors.affiliation: Palo Alto Medical Foundation Research Institute, Palo Alto, CA, USA.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Yu
authors.affiliation: Department of Health Research and Policy, Stanford University.|Cancer Prevention Institute of California, Fremont, CA, USA.
authors.forename: Scarlett L
authors.initials: SL
authors.lastname: Gomez
authors.affiliation: Division of Oncology, Department of Medicine, Stanford University.
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.affiliation: Department of Health Research and Policy, Stanford University.|Division of Oncology, Department of Medicine, Stanford University.
authors.forename: Allison W
authors.initials: AW
authors.lastname: Kurian
authors.affiliation: Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, CA, USA.
authors.forename: Nigam H
authors.initials: NH
authors.lastname: Shah
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D058492:Drug Repositioning; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D057286:Electronic Health Records; D005260:Female; D015870:Gene Expression; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged
keywords: breast cancer; combination therapies; drug discovery; drug interactions; drug repurposing; electronic health records