title: Blood DNA methylation biomarkers predict clinical reactivity in food-sensitized infants.
abstract: BACKGROUND
  The diagnosis of food allergy (FA) can be challenging because approximately half of food-sensitized patients are asymptomatic. Current diagnostic tests are excellent makers of sensitization but poor predictors of clinical reactivity. Thus oral food challenges (OFCs) are required to determine a patient's risk of reactivity.
  
  
  OBJECTIVE
  We sought to discover genomic biomarkers of clinical FA with utility for predicting food challenge outcomes.
  
  
  METHODS
  Genome-wide DNA methylation (DNAm) profiling was performed on blood mononuclear cells from volunteers who had undergone objective OFCs, concurrent skin prick tests, and specific IgE tests. Fifty-eight food-sensitized patients (aged 11-15 months) were assessed, half of whom were clinically reactive. Thirteen nonallergic control subjects were also assessed. Reproducibility was assessed in an additional 48 samples by using methylation data from an independent population of patients with clinical FA.
  
  
  RESULTS
  Using a supervised learning approach, we discovered a DNAm signature of 96 CpG sites that predict clinical outcomes. Diagnostic scores were derived from these 96 methylation sites, and cutoffs were determined in a sensitivity analysis. Methylation biomarkers outperformed allergen-specific IgE and skin prick tests for predicting OFC outcomes. FA status was correctly predicted in the replication cohort with an accuracy of 79.2%.
  
  
  CONCLUSIONS
  DNAm biomarkers with clinical utility for predicting food challenge outcomes are readily detectable in blood. The development of this technology in detailed follow-up studies will yield highly innovative diagnostic assays.
authors: Centre for Food and Allergy Research, Murdoch Childrens Research Institute, Parkville, Australia; Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia; University of Melbourne Department of Paediatrics, Melbourne, Australia; In-FLAME, the International Inflammation Network, World Universities Network (WUN), Perth, Australia.
authors: David
authors: D
authors: Martino
authors: Centre for Food and Allergy Research, Murdoch Childrens Research Institute, Parkville, Australia; Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia.
authors: Thanh
authors: T
authors: Dang
authors: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia.
authors: Alexandra
authors: A
authors: Sexton-Oates
authors: Centre for Food and Allergy Research, Murdoch Childrens Research Institute, Parkville, Australia; School of Paediatrics and Child Health, University of Western Australia, Perth, Australia; In-FLAME, the International Inflammation Network, World Universities Network (WUN), Perth, Australia.
authors: Susan
authors: S
authors: Prescott
authors: Centre for Food and Allergy Research, Murdoch Childrens Research Institute, Parkville, Australia; Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia; University of Melbourne Department of Paediatrics, Melbourne, Australia; Department of Allergy and Immunology, Royal Children's Hospital, Parkville, Australia.
authors: Mimi L K
authors: ML
authors: Tang
authors: Centre for Food and Allergy Research, Murdoch Childrens Research Institute, Parkville, Australia; School of Population and Global Health, University of Melbourne, Melbourne, Australia.
authors: Shyamali
authors: S
authors: Dharmage
authors: Centre for Food and Allergy Research, Murdoch Childrens Research Institute, Parkville, Australia; School of Population and Global Health, University of Melbourne, Melbourne, Australia.
authors: Lyle
authors: L
authors: Gurrin
authors: Centre for Food and Allergy Research, Murdoch Childrens Research Institute, Parkville, Australia; School of Population and Global Health, University of Melbourne, Melbourne, Australia.
authors: Jennifer
authors: J
authors: Koplin
authors: Centre for Food and Allergy Research, Murdoch Childrens Research Institute, Parkville, Australia; Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia; University of Melbourne Department of Paediatrics, Melbourne, Australia.
authors: Anne-Louise
authors: AL
authors: Ponsonby
authors: Centre for Food and Allergy Research, Murdoch Childrens Research Institute, Parkville, Australia; Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia; University of Melbourne Department of Paediatrics, Melbourne, Australia; In-FLAME, the International Inflammation Network, World Universities Network (WUN), Perth, Australia; Institute of Inflammation and Repair, University of Manchester, Manchester, United Kingdom. Electronic address: Katie.Allen@rch.org.au.
authors: Katrina J
authors: KJ
authors: Allen
authors: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia; University of Melbourne Department of Paediatrics, Melbourne, Australia.
authors: Richard
authors: R
authors: Saffery
mesh_terms: D015415:Biomarkers; D019295:Computational Biology; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005512:Food Hypersensitivity / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology*; D020869:Gene Expression Profiling; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007223:Infant; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008954:Models, Biological; D058977:Molecular Sequence Annotation; D011379:Prognosis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; D007073:Immunoglobulin E
keywords: DNA methylation profiling; Food allergy; Infinium; allergy epigenetics; biomarkers; epigenetic epidemiology; epigenetics; methylation profiling; shrunken centroids