title: TissueCypher(™): A systems biology approach to anatomic pathology.
abstract: BACKGROUND
  Current histologic methods for diagnosis are limited by intra- and inter-observer variability. Immunohistochemistry (IHC) methods are frequently used to assess biomarkers to aid diagnoses, however, IHC staining is variable and nonlinear and the manual interpretation is subjective. Furthermore, the biomarkers assessed clinically are typically biomarkers of epithelial cell processes. Tumors and premalignant tissues are not composed only of epithelial cells but are interacting systems of multiple cell types, including various stromal cell types that are involved in cancer development. The complex network of the tissue system highlights the need for a systems biology approach to anatomic pathology, in which quantification of system processes is combined with informatics tools to produce actionable scores to aid clinical decision-making.
  
  
  OBJECTIVE
  Here, we describe a quantitative, multiplexed biomarker imaging approach termed TissueCypher™ that applies systems biology to anatomic pathology. Applications of TissueCypher™ in understanding the tissue system of Barrett's esophagus (BE) and the potential use as an adjunctive tool in the diagnosis of BE are described.
  
  
  METHODS
  The TissueCypher™ Image Analysis Platform was used to assess 14 epithelial and stromal biomarkers with known diagnostic significance in BE in a set of BE biopsies with nondysplastic BE with reactive atypia (RA, n = 22) and Barrett's with high-grade dysplasia (HGD, n = 17). Biomarker and morphology features were extracted and evaluated in the confirmed BE HGD cases versus the nondysplastic BE cases with RA.
  
  
  RESULTS
  Multiple image analysis features derived from epithelial and stromal biomarkers, including immune biomarkers and morphology, showed significant differences between HGD and RA.
  
  
  CONCLUSIONS
  The assessment of epithelial cell abnormalities combined with an assessment of cellular changes in the lamina propria may serve as an adjunct to conventional pathology in the assessment of BE.
authors.affiliation: Department of Pathology and Laboratory Medicine, Geisinger Medical Center, Danville, PA 17822, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Prichard
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
authors.forename: Jon M
authors.initials: JM
authors.lastname: Davison
authors.affiliation: Cernostics, Inc., 235 William Pitt Way, Pittsburgh, PA 15238, USA.
authors.forename: Bruce B
authors.initials: BB
authors.lastname: Campbell
authors.affiliation: Cernostics, Inc., 235 William Pitt Way, Pittsburgh, PA 15238, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Repa
authors.affiliation: Cernostics, Inc., 235 William Pitt Way, Pittsburgh, PA 15238, USA.
authors.forename: Lia M
authors.initials: LM
authors.lastname: Reese
authors.affiliation: Cernostics, Inc., 235 William Pitt Way, Pittsburgh, PA 15238, USA.
authors.forename: Xuan M
authors.initials: XM
authors.lastname: Nguyen
authors.affiliation: Department of Pathology and Laboratory Medicine, Geisinger Medical Center, Danville, PA 17822, USA.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Foxwell
authors.affiliation: Department of Computational and Systems Biology, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: D Lansing
authors.initials: DL
authors.lastname: Taylor
authors.affiliation: Cernostics, Inc., 235 William Pitt Way, Pittsburgh, PA 15238, USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Critchley-Thorne
keywords: Barrett's esophagus; TissueCypher™; biomarkers; computer vision; digital pathology; high-grade dysplasia; multiplexed immunofluorescence; quantitative image analysis; reactive atypia; stromal cells