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Original Investigation |

Population Screening for Variant Creutzfeldt-Jakob Disease Using a Novel Blood Test:  Diagnostic Accuracy and Feasibility Study

Graham S. Jackson, PhD1; Jesse Burk-Rafel, MSc1,2; Julie Ann Edgeworth, PhD1; Anita Sicilia, MSc1; Sabah Abdilahi, BSc1; Justine Korteweg, BSc1; Jonathan Mackey, BSc1; Claire Thomas, BSc1; Guosu Wang, BSc1; Jonathan M. Schott, MD3; Catherine Mummery, MB, BS3; Patrick F. Chinnery, MD4; Simon Mead, BM, BCh1,5; John Collinge, FRS1,5
[+] Author Affiliations
1MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England
2currently with University of Michigan Medical School, Ann Arbor
3Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England
4Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, England
5National Prion Clinic, National Hospital for Neurology and Neurosurgery, Queen Square, London, England
JAMA Neurol. 2014;71(4):421-428. doi:10.1001/jamaneurol.2013.6001.
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Importance  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.

Objectives  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.

Design, Setting, and Participants  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).

Main Outcome and Measure  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 and Relevance  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.

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Figure 1.
Example Receiver Operating Characteristic Curve for Our Prototype Variant Creutzfeldt-Jakob Disease Blood Test

Post hoc analysis of test-retest data from a masked panel of 21 samples from patients with variant Creutzfeldt-Jakob disease and 169 UK normal samples from NHS Blood and Transplant. The cutoff threshold was varied by changing the number of standard deviations added to the mean of the on-plate negative controls. A 3-SD cutoff produced maximal specificity with some compromises in sensitivity. The dotted “chance diagonal” indicates the receiver operating characteristic curve for a test unable to discriminate between diseased and healthy persons. Other cutoff methods were validated in this fashion, including approaches based on signal-to-noise ratio and using log-transformed data, but the selected approach (mean +3σ) was superior.

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Figure 2.
Test Value Distribution by Sample Cohort

Ratio relative to cutoff data were pooled by cohort, plotted as a histogram, and fit with a lognormal curve. A, The discriminatory ability of the prototype assay is highlighted by the separation of normal samples obtained from the American Red Cross (USA Normals) (n = 5000) and positive control samples consisting of 0.1% weight to volume ratio variant Creutzfeldt-Jakob disease–infected brain homogenate in normal human blood (vCJD Spikes) (n = 192). B, Patients With vCJD data are sparse (n = 21) and produced somewhat smaller test values compared with positive control vCJD Spikes. Nevertheless, the majority of patient values exceeded the cutoff.

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Figure 3.
Test Value Distribution by Sample Cohort

The distribution of ratio relative to cutoff data (an indicator of test strength, with sample ratios above 1, ie, 100, scored reactive) was plotted as a histogram and fit with a lognormal curve. The x-axis was log-transformed for clarity. A, The discriminatory ability of the prototype assay is highlighted by the separation of normal samples obtained from the American Red Cross (USA Normals) (n = 5000) and positive control samples consisting of 0.1% weight to volume ratio variant Creutzfeldt-Jakob disease–infected brain homogenate in normal human blood (vCJD Spikes) (n = 192). The small number of reactive USA Normals above the 100 cutoff shows the excellent specificity of the assay. B, Patients With vCJD data are limited to 21 samples and produced somewhat smaller test values compared with positive control vCJD Spikes. Nevertheless, the distribution was noticeably higher than the USA Normals and the majority of patient test values exceeded the cutoff.

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