title: Three-tiered risk stratification model to predict progression in Barrett's esophagus using epigenetic and clinical features.
abstract: BACKGROUND
  Barrett's esophagus predisposes to esophageal adenocarcinoma. However, the value of endoscopic surveillance in Barrett's esophagus has been debated because of the low incidence of esophageal adenocarcinoma in Barrett's esophagus. Moreover, high inter-observer and sampling-dependent variation in the histologic staging of dysplasia make clinical risk assessment problematic. In this study, we developed a 3-tiered risk stratification strategy, based on systematically selected epigenetic and clinical parameters, to improve Barrett's esophagus surveillance efficiency.
  
  
  RESULTS
  We defined high-grade dysplasia as endpoint of progression, and Barrett's esophagus progressor patients as Barrett's esophagus patients with either no dysplasia or low-grade dysplasia who later developed high-grade dysplasia or esophageal adenocarcinoma. We analyzed 4 epigenetic and 3 clinical parameters in 118 Barrett's esophagus tissues obtained from 35 progressor and 27 non-progressor Barrett's esophagus patients from Baltimore Veterans Affairs Maryland Health Care Systems and Mayo Clinic. Based on 2-year and 4-year prediction models using linear discriminant analysis (area under the receiver-operator characteristic (ROC) curve: 0.8386 and 0.7910, respectively), Barrett's esophagus specimens were stratified into high-risk (HR), intermediate-risk (IR), or low-risk (LR) groups. This 3-tiered stratification method retained both the high specificity of the 2-year model and the high sensitivity of the 4-year model. Progression-free survivals differed significantly among the 3 risk groups, with p = 0.0022 (HR vs. IR) and p<0.0001 (HR or IR vs. LR). Incremental value analyses demonstrated that the number of methylated genes contributed most influentially to prediction accuracy.
  
  
  CONCLUSIONS
  This 3-tiered risk stratification strategy has the potential to exert a profound impact on Barrett's esophagus surveillance accuracy and efficiency.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. fsato@pharm.kyoto-u.ac.jp
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Sato
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jin
authors.forename: Karsten
authors.initials: K
authors.lastname: Schulmann
authors.forename: Jean
authors.initials: J
authors.lastname: Wang
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Greenwald
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ito
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Kan
authors.forename: James P
authors.initials: JP
authors.lastname: Hamilton
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Bogdan
authors.initials: B
authors.lastname: Paun
authors.forename: Stefan
authors.initials: S
authors.lastname: David
authors.forename: Alexandru
authors.initials: A
authors.lastname: Olaru
authors.forename: Yulan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Mori
authors.forename: John M
authors.initials: JM
authors.lastname: Abraham
authors.forename: Harris G
authors.initials: HG
authors.lastname: Yfantis
authors.forename: Tsung-Teh
authors.initials: TT
authors.lastname: Wu
authors.forename: Mary B
authors.initials: MB
authors.lastname: Fredericksen
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wang
authors.forename: Marcia
authors.initials: M
authors.lastname: Canto
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Romero
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
mesh_terms: D001471:Barrett Esophagus / Q000175:diagnosis* / Q000473:pathology*; D002454:Cell Differentiation; D018450:Disease Progression; D018572:Disease-Free Survival; D004724:Endoscopy / Q000379:methods; D044127:Epigenesis, Genetic; D004938:Esophageal Neoplasms / Q000175:diagnosis; D006801:Humans; D008745:Methylation; D011230:Precancerous Conditions; D012372:ROC Curve; D015203:Reproducibility of Results; D012306:Risk; D018570:Risk Assessment / Q000379:methods; D016896:Treatment Outcome