title: Association of RNA Biosignatures With Bacterial Infections in Febrile Infants Aged 60 Days or Younger.
abstract: OBJECTIVE
  Young febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. Analysis of host expression patterns ("RNA biosignatures") in response to infections may provide an alternative diagnostic approach.
  
  
  OBJECTIVE
  To assess whether RNA biosignatures can distinguish febrile infants aged 60 days or younger with and without serious bacterial infections.
  
  
  METHODS
  Prospective observational study involving a convenience sample of febrile infants 60 days or younger evaluated for fever (temperature >38° C) in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type.
  
  
  METHODS
  RNA biosignatures compared with cultures for discriminating febrile infants with and without bacterial infections and infants with bacteremia from those without bacterial infections.
  
  
  METHODS
  Bacterial infection confirmed by culture. Performance of RNA biosignatures was compared with routine laboratory screening tests and Yale Observation Scale (YOS) scores.
  
  
  RESULTS
  Of 1883 febrile infants (median age, 37 days; 55.7% boys), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections-including 32 with bacteremia and 15 with urinary tract infections-and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set with 87% (95% CI, 73%-95%) sensitivity and 89% (95% CI, 81%-93%) specificity. Ten classifier genes distinguished infants with bacteremia from those without bacterial infections in the test set with 94% (95% CI, 70%-100%) sensitivity and 95% (95% CI, 88%-98%) specificity. The incremental C statistic for the RNA biosignatures over the YOS score was 0.37 (95% CI, 0.30-0.43).
  
  
  CONCLUSIONS
  In this preliminary study, RNA biosignatures were defined to distinguish febrile infants aged 60 days or younger with vs without bacterial infections. Further research with larger populations is needed to refine and validate the estimates of test accuracy and to assess the clinical utility of RNA biosignatures in practice.
authors.affiliation: Division of Emergency Medicine, Department of Pediatrics, Children's Hospital of Michigan, Wayne State University, Detroit.
authors.forename: Prashant
authors.initials: P
authors.lastname: Mahajan
authors.affiliation: Departments of Emergency Medicine and Pediatrics, University of California, Davis, School of Medicine, Sacramento.
authors.forename: Nathan
authors.initials: N
authors.lastname: Kuppermann
authors.affiliation: Division of Pediatric Infectious Diseases and Center for Vaccines and Immunity, Nationwide Children's Hospital and The Ohio State University, Columbus.
authors.forename: Asuncion
authors.initials: A
authors.lastname: Mejias
authors.affiliation: Division of Pediatric Infectious Diseases and Center for Vaccines and Immunity, Nationwide Children's Hospital and The Ohio State University, Columbus.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Suarez
authors.affiliation: Benaroya Research Institute, Virginia Mason and Sidra Medical and Research Center, Seattle, Washington, and Doha, Qatar.
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City.
authors.forename: T Charles
authors.initials: TC
authors.lastname: Casper
authors.affiliation: Division of Pediatric Infectious Diseases and Center for Vaccines and Immunity, Nationwide Children's Hospital and The Ohio State University, Columbus.
authors.forename: Bennett
authors.initials: B
authors.lastname: Smith
authors.affiliation: Division of Emergency Medicine, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania7Now at Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Alpern
authors.affiliation: Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Anders
authors.affiliation: Division of Emergency Medicine, Department of Pediatrics, Children's National Medical Center, George Washington School of Medicine and Health Sciences, Washington, DC.
authors.forename: Shireen M
authors.initials: SM
authors.lastname: Atabaki
authors.affiliation: Division of Pediatric Emergency Medicine, Alfred I. DuPont Hospital for Children, Nemours Children's Health System, Wilmington, Delaware.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Bennett
authors.affiliation: Department of Pediatrics, Jacobi Medical Center, Albert Einstein College of Medicine, New York, New York.
authors.forename: Stephen
authors.initials: S
authors.lastname: Blumberg
authors.affiliation: Section of Emergency Medicine, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Bema
authors.initials: B
authors.lastname: Bonsu
authors.affiliation: Department of Emergency Medicine, Hurley Medical Center and University of Michigan, Flint.
authors.forename: Dominic
authors.initials: D
authors.lastname: Borgialli
authors.affiliation: Departments of Emergency Medicine and Pediatrics, University of Rochester Medical Center, Rochester, New York.
authors.forename: Anne
authors.initials: A
authors.lastname: Brayer
authors.affiliation: Departments of Pediatrics and Emergency Medicine, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee.
authors.forename: Lorin
authors.initials: L
authors.lastname: Browne
authors.affiliation: Section of Emergency Medicine, Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University, Columbus.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Cohen
authors.affiliation: Division of Pediatric Emergency Medicine, Alfred I. DuPont Hospital for Children, Nemours Children's Health System, Wilmington, Delaware.
authors.forename: Ellen F
authors.initials: EF
authors.lastname: Crain
authors.affiliation: Sections of Emergency Medicine and Infectious Diseases, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston.
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Cruz
authors.affiliation: Division of Emergency Medicine, Department of Pediatrics, Columbia University College of Physicians & Surgeons, New York, New York.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dayan
authors.affiliation: Division of Emergency Medicine, Department of Pediatrics, University of Maryland Medical Center, Baltimore.
authors.forename: Rajender
authors.initials: R
authors.lastname: Gattu
authors.affiliation: Department of Pediatrics, Primary Children's Medical Center, University of Utah, Salt Lake City.
authors.forename: Richard
authors.initials: R
authors.lastname: Greenberg
authors.affiliation: Department of Emergency Medicine, Helen DeVos Children's Hospital of Spectrum Health, Grand Rapids, Michigan22Now with the Departments of Emergency Medicine and Pediatrics, Western Michigan University Homer Stryker, MD, School of Medicine, Kalamazoo.
authors.forename: John D
authors.initials: JD
authors.lastname: Hoyle
authors.affiliation: Department of Pediatrics, St Louis Children's Hospital, Washington University, St Louis, Missouri24Now with the Division of Pediatric Emergency Medicine, University of California San Francisco School of Medicine.
authors.forename: David M
authors.initials: DM
authors.lastname: Jaffe
authors.affiliation: Department of Pediatrics, Bellevue Hospital New York University Langone Center, New York.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Levine
authors.affiliation: Department of Pediatrics, Women and Children's Hospital of Buffalo, State University of New York at Buffalo.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Lillis
authors.affiliation: Department of Emergency Medicine and Pediatrics, Hasbro Children's Hospital and Brown University, Providence, Rhode Island.
authors.forename: James G
authors.initials: JG
authors.lastname: Linakis
authors.affiliation: Department of Pediatrics, Bellevue Hospital New York University Langone Center, New York28Now with the Department of Emergency Medicine, Phoenix Children's Hospital, Phoenix, Arizona.
authors.forename: Jared
authors.initials: J
authors.lastname: Muenzer
authors.affiliation: Department of Pediatrics, Boston Children's Hospital, Harvard University, Boston, Massachusetts.
authors.forename: Lise E
authors.initials: LE
authors.lastname: Nigrovic
authors.affiliation: Division of Emergency Medicine, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Powell
authors.affiliation: Departments of Emergency Medicine and Pediatrics, University of Michigan, Ann Arbor.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Rogers
authors.affiliation: Department of Pediatrics, Children's Hospital Colorado, University of Colorado-Denver, Aurora.
authors.forename: Genie
authors.initials: G
authors.lastname: Roosevelt
authors.affiliation: Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ruddy
authors.affiliation: Department of Pediatrics, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee35Now with Children's Hospital of Colorado, University of Colorado School of Medicine, Aurora.
authors.forename: Mary
authors.initials: M
authors.lastname: Saunders
authors.affiliation: Department of Pediatrics, Bellevue Hospital, New York University Langone Medical Center, New York.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Tunik
authors.affiliation: Department of Emergency Medicine, University of California, Davis School of Medicine, Sacramento.
authors.forename: Leah
authors.initials: L
authors.lastname: Tzimenatos
authors.affiliation: Division of Pediatric Emergency Medicine, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Melissa
authors.initials: M
authors.lastname: Vitale
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Dean
authors.affiliation: Division of Pediatric Infectious Diseases and Center for Vaccines and Immunity, Nationwide Children's Hospital and The Ohio State University, Columbus.
authors.forename: Octavio
authors.initials: O
authors.lastname: Ramilo
mesh_terms: D016470:Bacteremia / Q000097:blood; D001424:Bacterial Infections / Q000097:blood / Q000150:complications / Q000175:diagnosis*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003955:Diagnostic Tests, Routine; D004636:Emergency Service, Hospital; D005260:Female; D005334:Fever / Q000097:blood / Q000382:microbiology*; D005819:Genetic Markers; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D016920:Meningitis, Bacterial / Q000097:blood / Q000150:complications / Q000175:diagnosis; D046228:Microarray Analysis / Q000379:methods; D011446:Prospective Studies; D012313:RNA / Q000097:blood* / Q000235:genetics; D018709:Statistics, Nonparametric; D014552:Urinary Tract Infections / Q000097:blood / Q000150:complications / Q000175:diagnosis
chemical_list: D015415:Biomarkers; D005819:Genetic Markers; D012313:RNA