title: Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study.
abstract: Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown.
  
  
  
  We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk.
  
  
  
  Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10-0·89; p=0·0296) but not stricturing complication (1·13, 0·51-2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12-2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%.
  
  
  
  Our findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy.
  
  
  
  Crohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center.
authors.affiliation: Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, GA, USA; Children's Healthcare of Atlanta, Atlanta, GA, USA. Electronic address: skugath@emory.edu.
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Walters
authors.affiliation: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Kim
authors.affiliation: Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Urko M
authors.initials: UM
authors.lastname: Marigorta
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biostatistics, Harvard T H Chan School of Public Health, Boston, MA, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Schirmer
authors.affiliation: Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Kajari
authors.initials: K
authors.lastname: Mondal
authors.affiliation: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Griffiths
authors.affiliation: Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Noe
authors.affiliation: Department of Pediatric Gastroenterology, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Wallace V
authors.initials: WV
authors.lastname: Crandall
authors.affiliation: Department of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Snapper
authors.affiliation: Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Shervin
authors.initials: S
authors.lastname: Rabizadeh
authors.affiliation: Department of Pediatrics, Goryeb Children's Hospital, Morristown, NJ, USA.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Rosh
authors.affiliation: Department of Pediatrics, Hasbro Children's Hospital, Providence, RI, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Shapiro
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Guthery
authors.affiliation: Department of Pediatrics, Children's Hospital of Eastern Ontario IBD Centre and University of Ottawa, ON, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Mack
authors.affiliation: Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Kellermayer
authors.affiliation: Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kappelman
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Steiner
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Dedrick E
authors.initials: DE
authors.lastname: Moulton
authors.affiliation: Department of Gastroenterology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Keljo
authors.affiliation: Children's Healthcare of Atlanta, Atlanta, GA, USA; Children's Center for Digestive Health Care, Atlanta, GA, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Cohen
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Oliva-Hemker
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Melvin B
authors.initials: MB
authors.lastname: Heyman
authors.affiliation: Department of Pediatrics, Dalhousie University, Halifax, NS, Canada.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Otley
authors.affiliation: Department of Digestive Diseases and Nutrition Center, University at Buffalo, Buffalo, NY, USA.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Baker
authors.affiliation: Department of Pediatrics, Nemours Children's Specialty Care, Jacksonville, FL, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Evans
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Kirschner
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Ashish S
authors.initials: AS
authors.lastname: Patel
authors.affiliation: Department of Pediatrics, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ziring
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Trapnell
authors.affiliation: Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Sylvester
authors.affiliation: Department of Pediatric Gastroenterology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Stephens
authors.affiliation: Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Baldassano
authors.affiliation: Department of Pediatrics, Northwell Health, New York, NY, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Markowitz
authors.affiliation: Department of Pediatrics, Mount Sinai Hospital, New York, NY, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Cho
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Computational and Integrative Biology, Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biostatistics, Harvard T H Chan School of Public Health, Boston, MA, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Huttenhower
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.affiliation: Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Gibson
authors.affiliation: Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Hyams
authors.affiliation: Department of Pediatrics, Mount Sinai Hospital, New York, NY, USA.
authors.forename: Marla C
authors.initials: MC
authors.lastname: Dubinsky
mesh_terms: D000068879:Adalimumab / Q000627:therapeutic use; D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D002648:Child; D015331:Cohort Studies; D003424:Crohn Disease / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy / Q000382:microbiology; D018450:Disease Progression; D005260:Female; D000069196:Gastrointestinal Microbiome; D006801:Humans; D000069285:Infliximab / Q000627:therapeutic use; D007415:Intestinal Obstruction / Q000209:etiology; D008297:Male; D011379:Prognosis; D057216:Propensity Score; D011446:Prospective Studies; D018570:Risk Assessment / Q000379:methods; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab