title: Predicting in vivo anti-hepatofibrotic drug efficacy based on in vitro high-content analysis.
abstract: OBJECTIVE
  Many anti-fibrotic drugs with high in vitro efficacies fail to produce significant effects in vivo. The aim of this work is to use a statistical approach to design a numerical predictor that correlates better with in vivo outcomes.
  
  
  METHODS
  High-content analysis (HCA) was performed with 49 drugs on hepatic stellate cells (HSCs) LX-2 stained with 10 fibrotic markers. ~0.3 billion feature values from all cells in >150,000 images were quantified to reflect the drug effects. A systematic literature search on the in vivo effects of all 49 drugs on hepatofibrotic rats yields 28 papers with histological scores. The in vivo and in vitro datasets were used to compute a single efficacy predictor (E(predict)).
  
  
  RESULTS
  We used in vivo data from one context (CCl(4) rats with drug treatments) to optimize the computation of E(predict). This optimized relationship was independently validated using in vivo data from two different contexts (treatment of DMN rats and prevention of CCl(4) induction). A linear in vitro-in vivo correlation was consistently observed in all the three contexts. We used E(predict) values to cluster drugs according to efficacy; and found that high-efficacy drugs tended to target proliferation, apoptosis and contractility of HSCs.
  
  
  CONCLUSIONS
  The E(predict) statistic, based on a prioritized combination of in vitro features, provides a better correlation between in vitro and in vivo drug response than any of the traditional in vitro markers considered.
authors.affiliation: Computation and Systems Biology Program, Singapore-MIT Alliance, National University of Singapore, Singapore, Singapore.
authors.forename: Baixue
authors.initials: B
authors.lastname: Zheng
authors.forename: Looling
authors.initials: L
authors.lastname: Tan
authors.forename: Xuejun
authors.initials: X
authors.lastname: Mo
authors.forename: Weimiao
authors.initials: W
authors.lastname: Yu
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Lisa
authors.initials: L
authors.lastname: Tucker-Kellogg
authors.forename: Roy E
authors.initials: RE
authors.lastname: Welsch
authors.forename: Peter T C
authors.initials: PT
authors.lastname: So
authors.forename: Hanry
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats
chemical_list: D015415:Biomarkers; D002251:Carbon Tetrachloride
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