title: Population screening for variant Creutzfeldt-Jakob disease using a novel blood test: diagnostic accuracy and feasibility study.
abstract: OBJECTIVE
  Our study indicates a prototype blood-based variant Creutzfeldt-Jakob disease (vCJD) assay has sufficient sensitivity and specificity to justify a large study comparing vCJD prevalence in the United Kingdom with a bovine spongiform encephalopathy-unexposed population. In a clinical diagnostic capacity, the assay's likelihood ratios dramatically change an individual's pretest disease odds to posttest probabilities and can confirm vCJD infection.
  
  
  OBJECTIVE
  To determine the diagnostic accuracy of a prototype blood test for vCJD and hence its suitability for clinical use and for screening prion-exposed populations.
  
  
  METHODS
  Retrospective, cross-sectional diagnostic study of blood samples from national blood collection and prion disease centers in the United States and United Kingdom. Anonymized samples were representative of the US blood donor population (n = 5000), healthy UK donors (n = 200), patients with nonprion neurodegenerative diseases (n = 352), patients in whom a prion disease diagnosis was likely (n = 105), and patients with confirmed vCJD (n = 10).
  
  
  METHODS
  Presence of vCJD infection determined by a prototype test (now in clinical diagnostic use) that captures, enriches, and detects disease-associated prion protein from whole blood using stainless steel powder.
  
  
  RESULTS
  The assay's specificity among the presumed negative American donor samples was 100% (95% CI, 99.93%-100%) and was confirmed in a healthy UK cohort (100% specificity; 95% CI, 98.2%-100%). Of potentially cross-reactive blood samples from patients with nonprion neurodegenerative diseases, no samples tested positive (100% specificity; 95% CI, 98.9%-100%). Among National Prion Clinic referrals in whom a prion disease diagnosis was likely, 2 patients with sporadic CJD tested positive (98.1% specificity; 95% CI, 93.3%-99.8%). Finally, we reconfirmed but could not refine our previous sensitivity estimate in a small blind panel of samples from unaffected individuals and patients with vCJD (70% sensitivity; 95% CI, 34.8%-93.3%).
  
  
  CONCLUSIONS
  In conjunction with the assay's established high sensitivity (71.4%; 95% CI, 47.8%-88.7%), the extremely high specificity supports using the assay to screen for vCJD infection in prion-exposed populations. Additionally, the lack of cross-reactivity and false positives in a range of nonprion neurodegenerative diseases supports the use of the assay in patient diagnosis.
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England.
authors.forename: Graham S
authors.initials: GS
authors.lastname: Jackson
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England2currently with University of Michigan Medical School, Ann Arbor.
authors.forename: Jesse
authors.initials: J
authors.lastname: Burk-Rafel
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England.
authors.forename: Julie Ann
authors.initials: JA
authors.lastname: Edgeworth
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England.
authors.forename: Anita
authors.initials: A
authors.lastname: Sicilia
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England.
authors.forename: Sabah
authors.initials: S
authors.lastname: Abdilahi
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England.
authors.forename: Justine
authors.initials: J
authors.lastname: Korteweg
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mackey
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England.
authors.forename: Claire
authors.initials: C
authors.lastname: Thomas
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England.
authors.forename: Guosu
authors.initials: G
authors.lastname: Wang
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schott
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mummery
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England5National Prion Clinic, National Hospital for Neurology and Neurosurgery, Queen Square, London, England.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England5National Prion Clinic, National Hospital for Neurology and Neurosurgery, Queen Square, London, England.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000818:Animals; D002417:Cattle; D015331:Cohort Studies; D007562:Creutzfeldt-Jakob Syndrome / Q000097:blood* / Q000175:diagnosis* / Q000453:epidemiology; D003430:Cross-Sectional Studies; D005240:Feasibility Studies; D006403:Hematologic Tests / Q000379:methods* / Q000639:trends; D006801:Humans; D011159:Population Surveillance / Q000379:methods*; D017096:Prion Diseases / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D012189:Retrospective Studies; D006113:United Kingdom / Q000453:epidemiology; D014481:United States / Q000453:epidemiology