From www.bloodjournal.org by guest on September 11, 2016. For personal use only. 452
BLOOD, 16 JANUARY 2014 x VOLUME 123, NUMBER 3
CORRESPONDENCE
Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Gregory A. Abel, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215; e-mail: [email protected].
5. Caocci G, La Nasa G, Efficace F. Health-related quality of life and symptom assessment in patients with myelodysplastic syndromes. Exp Rev Hematol. 2009;2:69-80. 6. Bowling A. Measuring Disease. 2nd ed. Oxford, UK: University Press; 2001. 7. Eiser C, Morse R. A review of measures of quality of life for children with chronic illness. Arch Dis Child. 2001;84(3):205-211.
References 1. Malcovati L, Hellstrom-Lindberg ¨ E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943-2964. 2. Methodology Committee of the Patient-Centered Outcomes Research Institute (PCORI). Methodological standards and patient-centeredness in comparative effectiveness research: the PCORI perspective. JAMA. 2012;307(15): 1636-1640. 3. Calvert M, Blazeby J, Altman DG, Revicki DA, Moher D, Brundage MD; CONSORT PRO Group. Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA. 2013;309(8):814-822. 4. Efficace F, Gaidano G, Sprangers M, et al. Preference for involvement in treatment decisions and request for prognostic information in newly-diagnosed patients with higher-risk myelodysplastic syndromes. Ann Oncol. (in press).
8. Abel G, Lee SJ, Stone R, et al. Development of a disease-specific measure of quality of life in myelodysplastic syndromes (MDS): the “QUALMS-1” [abstract]. J Clin Oncol. 2012;30(suppl; abstr 6103):407s. 9. Jobe JB. Cognitive psychology and self-reports: models and methods. Qual Life Res. 2003;12(3):219-227. 10. US Food and Drug Administration. Guidance for Industry. Patient-reported outcome measures: use in medical product development to support labeling claims. U.S. Department of Health and Human Services Food and Drug Administration, December 2009. http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf. Accessed November 29, 2013.
© 2014 by The American Society of Hematology
To the editor: A highly specific blood test for vCJD Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disease originating from exposure to bovine spongiform encephalopathy (BSE). Despite low clinical incidence, the risk of secondary vCJD infection via blood transfusions from subclinical carriers persists. A recent study of appendix samples by the United Kingdom (UK) Health Protection Agency estimates 1 in 2000 silent prion infections in the UK population (95% confidence interval [CI]: 1 in 1248-3546).1 This estimate is in sharp contrast to the small number of recognized clinical cases that may be explained at least in part by the extremely prolonged incubation periods associated with human prion disease and the possibility that the barrier to infection is lower in lymphoreticular tissue than in brain,2 leading to subclinical infection. A sensitive and specific blood-based assay for vCJD infection, though urgently needed, has been elusive because abnormal prion protein (PrP) levels are extremely low in blood and chemically identical normal PrP is in large excess. Previously, we demonstrated a prototype assay that captured and enriched disease-associated PrP from whole blood using stainless steel powder, achieving impressive
analytical (10210 dilution of vCJD-affected brain) and diagnostic (71% of vCJD-infected patient blood samples) sensitivity.3 To explore the assay’s specificity and hence suitability for screening exposed and at-risk populations, we tested 5000 blood samples from the American Red Cross in which, because of minimal BSE exposure, no true positives would be expected (US normals). No samples tested positive (100% specificity; 95% CI: 99.93%100%) (Table 1). The high specificity was reflected in a smaller, healthy UK cohort (UK normals). The assay’s positive likelihood ratio indicates true positives are more than 7000 times as likely as false positives; the negative likelihood ratio indicates true negatives are more than 3 times as likely as false negatives. Finally, we tested a small blind panel of unaffected and vCJD patient samples. Seven of 10 vCJD patient samples tested positive (70% sensitivity), reconfirming but not refining our previous sensitivity estimate. A remaining question is whether the assay can detect sub- or preclinical vCJD-affected individuals. Although it has been suggested that asymptomatic individuals would have particularly low concentrations of abnormal PrP, preclinical blood involvement4
Table 1. vCJD infection blood test performance vCJD-negative cohorts
Samples
Positive
Specificity
95% CI
US normals
5000
0
100%
99.9-100%
UK normals
200
0
100%
98.2-100%
vCJD-positive cohorts
Samples
Positive
Sensitivity
95% CI
vCJD spikes
192
192
100%
98.1-100%
vCJD patients
21
17
71.4%
47.8-88.7%
US normals 1 vCJD patients Positive likelihood ratio Negative likelihood ratio 3
Value
95% CI
7047
435-114 146
0.30
0.16-0.56
Whole blood samples were incubated overnight in buffer containing stainless steel powder, as previously described. The powder was heat treated and sequentially incubated with biotinylated anti-PrP antibody, NeutrAvidin-HRP, and chemiluminescent substrate. Samples were scored reactive if the mean signal from 3 replicates exceeded an on-plate negative control cutoff. Repeat-reactive samples were considered positive for vCJD; nonreactive and single-reactive samples were considered negative for vCJD. Anonymous blood samples from unaffected blood donors were obtained from the American Red Cross (US normals) and the National Health Service Blood and Transplant service of England and Wales (UK normals). Positive control samples consisted of 0.1% wt/vol vCJD-infected brain homogenate in whole unaffected human blood (vCJD spikes) and were used to preserve scarce stocks of endogenous vCJD patient samples (vCJD patients). Clopper and Pearson’s “exact” method was used for confidence intervals of proportions. Likelihood ratios and their confidence intervals were calculated using Haldane’s correction and a derived approximation for risk ratios. HRP, horseradish peroxidase.
From www.bloodjournal.org by guest on September 11, 2016. For personal use only. BLOOD, 16 JANUARY 2014 x VOLUME 123, NUMBER 3
and transmission5 have been demonstrated in animal models. Despite some limitations and uncertainties, the prototype vCJD assay has sufficient performance to justify a prevalence study comparing prion-exposed and prion-unexposed populations, which would require 20 000 samples from each cohort (1–b 5 80%, a 5 5%). A blood prevalence study would provide essential information for deciding if routine vCJD screening is needed for blood, tissue, and organ donations and for patients before highrisk surgical procedures. Graham S. Jackson Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Jesse Burk-Rafel Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom University of Michigan Medical School, Ann Arbor, MI Julie A. Edgeworth Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Anita Sicilia Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Sabah Abdilahi Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Justine Korteweg Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Jonathan Mackey Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Claire Thomas Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Guosu Wang Medical Research Council Prion Unit, Department of Neurodegenerative Disease,
CORRESPONDENCE
453
University College London Institute of Neurology, London, United Kingdom Simon Mead Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom National Prion Clinic, National Hospital for Neurology and Neurosurgery, London, United Kingdom John Collinge Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom National Prion Clinic, National Hospital for Neurology and Neurosurgery, London, United Kingdom Acknowledgments: We thank Dr Susan Stramer and the American Red Cross for assistance and provision of samples, Dr Zoe Fox for sample size calculations, Ray Young for the preparation of figures, and Jonathan Wadsworth for critical reading of this letter. This work was supported by the UK Medical Research Council, the UK Department of Health National Institute of Health Research Biomedical Research Centres funding scheme, and the Whitaker International Fellowship (J.B.-R.). Conflict-of-interest disclosure: J.C. is a director and J.C. and G.S.J. are shareholders of D-Gen Limited (London, UK), an academic spin-out company working in the field of prion disease diagnosis, decontamination, and therapeutics. The authors declare no competing financial interests. Contribution: G.S.J. and J.C. conceived the study; J.A.E., A.S., S.A., J.K., J.M., C.T., and G.W. performed assays; S.M. provided clinical expertise and samples; G.S.J. and J.B.-R. analyzed results and made the figures; and G.S.J., J.B.-R., and J.C. wrote the letter and all authors provided input. Correspondence: Graham S. Jackson, Medical Rsearch Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom; e-mail: g.s. [email protected].
References 1. Gill ON, Spencer Y, Richard-Loendt A, et al. Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey. BMJ. 2013;347:f5675. 2. Beringue ´ V, Herzog L, Jaumain E, et al. Facilitated cross-species transmission of prions in extraneural tissue. Science. 2012;335(6067):472-475. 3. Edgeworth JA, Farmer M, Sicilia A, et al. Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay. Lancet. 2011;377(9764): 487-493. 4. Saa´ P, Castilla J, Soto C. Presymptomatic detection of prions in blood. Science. 2006;313(5783):92-94. 5. Andreoletti ´ O, Litaise C, Simmons H, et al. Highly efficient prion transmission by blood transfusion. PLoS Pathog. 2012;8(6):e1002782.
© 2014 by The American Society of Hematology
To the editor: Application of CIBMTR risk score to NIH chronic GVHD at individual centers A new risk score to predict mortality in patients with chronic graftversus-host disease (GVHD) was recently reported by Arora et al by analyzing a large amount of data between 1995 and 2004 from the
Center for International Blood and Marrow Transplant Registry (CIBMTR).1 The risk score consists of 10 variables defined at transplantation or at onset of chronic GVHD that are objective and
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 123: 452-453 doi:10.1182/blood-2013-11-539239
A highly specific blood test for vCJD Graham S. Jackson, Jesse Burk-Rafel, Julie A. Edgeworth, Anita Sicilia, Sabah Abdilahi, Justine Korteweg, Jonathan Mackey, Claire Thomas, Guosu Wang, Simon Mead and John Collinge
Updated information and services can be found at: http://www.bloodjournal.org/content/123/3/452.full.html Articles on similar topics can be found in the following Blood collections Transfusion Medicine (270 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
BLOOD, 16 JANUARY 2014 x VOLUME 123, NUMBER 3
CORRESPONDENCE
Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Gregory A. Abel, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215; e-mail: [email protected].
5. Caocci G, La Nasa G, Efficace F. Health-related quality of life and symptom assessment in patients with myelodysplastic syndromes. Exp Rev Hematol. 2009;2:69-80. 6. Bowling A. Measuring Disease. 2nd ed. Oxford, UK: University Press; 2001. 7. Eiser C, Morse R. A review of measures of quality of life for children with chronic illness. Arch Dis Child. 2001;84(3):205-211.
References 1. Malcovati L, Hellstrom-Lindberg ¨ E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943-2964. 2. Methodology Committee of the Patient-Centered Outcomes Research Institute (PCORI). Methodological standards and patient-centeredness in comparative effectiveness research: the PCORI perspective. JAMA. 2012;307(15): 1636-1640. 3. Calvert M, Blazeby J, Altman DG, Revicki DA, Moher D, Brundage MD; CONSORT PRO Group. Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA. 2013;309(8):814-822. 4. Efficace F, Gaidano G, Sprangers M, et al. Preference for involvement in treatment decisions and request for prognostic information in newly-diagnosed patients with higher-risk myelodysplastic syndromes. Ann Oncol. (in press).
8. Abel G, Lee SJ, Stone R, et al. Development of a disease-specific measure of quality of life in myelodysplastic syndromes (MDS): the “QUALMS-1” [abstract]. J Clin Oncol. 2012;30(suppl; abstr 6103):407s. 9. Jobe JB. Cognitive psychology and self-reports: models and methods. Qual Life Res. 2003;12(3):219-227. 10. US Food and Drug Administration. Guidance for Industry. Patient-reported outcome measures: use in medical product development to support labeling claims. U.S. Department of Health and Human Services Food and Drug Administration, December 2009. http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf. Accessed November 29, 2013.
© 2014 by The American Society of Hematology
To the editor: A highly specific blood test for vCJD Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disease originating from exposure to bovine spongiform encephalopathy (BSE). Despite low clinical incidence, the risk of secondary vCJD infection via blood transfusions from subclinical carriers persists. A recent study of appendix samples by the United Kingdom (UK) Health Protection Agency estimates 1 in 2000 silent prion infections in the UK population (95% confidence interval [CI]: 1 in 1248-3546).1 This estimate is in sharp contrast to the small number of recognized clinical cases that may be explained at least in part by the extremely prolonged incubation periods associated with human prion disease and the possibility that the barrier to infection is lower in lymphoreticular tissue than in brain,2 leading to subclinical infection. A sensitive and specific blood-based assay for vCJD infection, though urgently needed, has been elusive because abnormal prion protein (PrP) levels are extremely low in blood and chemically identical normal PrP is in large excess. Previously, we demonstrated a prototype assay that captured and enriched disease-associated PrP from whole blood using stainless steel powder, achieving impressive
analytical (10210 dilution of vCJD-affected brain) and diagnostic (71% of vCJD-infected patient blood samples) sensitivity.3 To explore the assay’s specificity and hence suitability for screening exposed and at-risk populations, we tested 5000 blood samples from the American Red Cross in which, because of minimal BSE exposure, no true positives would be expected (US normals). No samples tested positive (100% specificity; 95% CI: 99.93%100%) (Table 1). The high specificity was reflected in a smaller, healthy UK cohort (UK normals). The assay’s positive likelihood ratio indicates true positives are more than 7000 times as likely as false positives; the negative likelihood ratio indicates true negatives are more than 3 times as likely as false negatives. Finally, we tested a small blind panel of unaffected and vCJD patient samples. Seven of 10 vCJD patient samples tested positive (70% sensitivity), reconfirming but not refining our previous sensitivity estimate. A remaining question is whether the assay can detect sub- or preclinical vCJD-affected individuals. Although it has been suggested that asymptomatic individuals would have particularly low concentrations of abnormal PrP, preclinical blood involvement4
Table 1. vCJD infection blood test performance vCJD-negative cohorts
Samples
Positive
Specificity
95% CI
US normals
5000
0
100%
99.9-100%
UK normals
200
0
100%
98.2-100%
vCJD-positive cohorts
Samples
Positive
Sensitivity
95% CI
vCJD spikes
192
192
100%
98.1-100%
vCJD patients
21
17
71.4%
47.8-88.7%
US normals 1 vCJD patients Positive likelihood ratio Negative likelihood ratio 3
Value
95% CI
7047
435-114 146
0.30
0.16-0.56
Whole blood samples were incubated overnight in buffer containing stainless steel powder, as previously described. The powder was heat treated and sequentially incubated with biotinylated anti-PrP antibody, NeutrAvidin-HRP, and chemiluminescent substrate. Samples were scored reactive if the mean signal from 3 replicates exceeded an on-plate negative control cutoff. Repeat-reactive samples were considered positive for vCJD; nonreactive and single-reactive samples were considered negative for vCJD. Anonymous blood samples from unaffected blood donors were obtained from the American Red Cross (US normals) and the National Health Service Blood and Transplant service of England and Wales (UK normals). Positive control samples consisted of 0.1% wt/vol vCJD-infected brain homogenate in whole unaffected human blood (vCJD spikes) and were used to preserve scarce stocks of endogenous vCJD patient samples (vCJD patients). Clopper and Pearson’s “exact” method was used for confidence intervals of proportions. Likelihood ratios and their confidence intervals were calculated using Haldane’s correction and a derived approximation for risk ratios. HRP, horseradish peroxidase.
From www.bloodjournal.org by guest on September 11, 2016. For personal use only. BLOOD, 16 JANUARY 2014 x VOLUME 123, NUMBER 3
and transmission5 have been demonstrated in animal models. Despite some limitations and uncertainties, the prototype vCJD assay has sufficient performance to justify a prevalence study comparing prion-exposed and prion-unexposed populations, which would require 20 000 samples from each cohort (1–b 5 80%, a 5 5%). A blood prevalence study would provide essential information for deciding if routine vCJD screening is needed for blood, tissue, and organ donations and for patients before highrisk surgical procedures. Graham S. Jackson Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Jesse Burk-Rafel Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom University of Michigan Medical School, Ann Arbor, MI Julie A. Edgeworth Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Anita Sicilia Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Sabah Abdilahi Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Justine Korteweg Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Jonathan Mackey Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Claire Thomas Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom Guosu Wang Medical Research Council Prion Unit, Department of Neurodegenerative Disease,
CORRESPONDENCE
453
University College London Institute of Neurology, London, United Kingdom Simon Mead Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom National Prion Clinic, National Hospital for Neurology and Neurosurgery, London, United Kingdom John Collinge Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom National Prion Clinic, National Hospital for Neurology and Neurosurgery, London, United Kingdom Acknowledgments: We thank Dr Susan Stramer and the American Red Cross for assistance and provision of samples, Dr Zoe Fox for sample size calculations, Ray Young for the preparation of figures, and Jonathan Wadsworth for critical reading of this letter. This work was supported by the UK Medical Research Council, the UK Department of Health National Institute of Health Research Biomedical Research Centres funding scheme, and the Whitaker International Fellowship (J.B.-R.). Conflict-of-interest disclosure: J.C. is a director and J.C. and G.S.J. are shareholders of D-Gen Limited (London, UK), an academic spin-out company working in the field of prion disease diagnosis, decontamination, and therapeutics. The authors declare no competing financial interests. Contribution: G.S.J. and J.C. conceived the study; J.A.E., A.S., S.A., J.K., J.M., C.T., and G.W. performed assays; S.M. provided clinical expertise and samples; G.S.J. and J.B.-R. analyzed results and made the figures; and G.S.J., J.B.-R., and J.C. wrote the letter and all authors provided input. Correspondence: Graham S. Jackson, Medical Rsearch Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom; e-mail: g.s. [email protected].
References 1. Gill ON, Spencer Y, Richard-Loendt A, et al. Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey. BMJ. 2013;347:f5675. 2. Beringue ´ V, Herzog L, Jaumain E, et al. Facilitated cross-species transmission of prions in extraneural tissue. Science. 2012;335(6067):472-475. 3. Edgeworth JA, Farmer M, Sicilia A, et al. Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay. Lancet. 2011;377(9764): 487-493. 4. Saa´ P, Castilla J, Soto C. Presymptomatic detection of prions in blood. Science. 2006;313(5783):92-94. 5. Andreoletti ´ O, Litaise C, Simmons H, et al. Highly efficient prion transmission by blood transfusion. PLoS Pathog. 2012;8(6):e1002782.
© 2014 by The American Society of Hematology
To the editor: Application of CIBMTR risk score to NIH chronic GVHD at individual centers A new risk score to predict mortality in patients with chronic graftversus-host disease (GVHD) was recently reported by Arora et al by analyzing a large amount of data between 1995 and 2004 from the
Center for International Blood and Marrow Transplant Registry (CIBMTR).1 The risk score consists of 10 variables defined at transplantation or at onset of chronic GVHD that are objective and
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 123: 452-453 doi:10.1182/blood-2013-11-539239
A highly specific blood test for vCJD Graham S. Jackson, Jesse Burk-Rafel, Julie A. Edgeworth, Anita Sicilia, Sabah Abdilahi, Justine Korteweg, Jonathan Mackey, Claire Thomas, Guosu Wang, Simon Mead and John Collinge
Updated information and services can be found at: http://www.bloodjournal.org/content/123/3/452.full.html Articles on similar topics can be found in the following Blood collections Transfusion Medicine (270 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
