Casey P Shannon1, Zsuzsanna Hollander2, Darlene L Y Dai2, Virginia Chen2, Sara Assadian2, Karen K Lam3, Janet E McManus2, Marek Zarzycki4, YoungWoong Kim5, Ji-Young V Kim6, Robert Balshaw7, Olof Gidlöf8, Jenny Öhman8, J Gustav Smith8, Mustafa Toma9, Andrew Ignaszewski9, Ross A Davies10, Diego Delgado11, Haissam Haddad12, Debra Isaac13, Daniel Kim13, Alice Mui14, Miroslaw Rajda15, Lori West16, Michel White17, Shelley Zieroth18, Scott J Tebbutt4, Paul A Keown5, W Robert McMaster19, Raymond T Ng20, Bruce M McManus21. 1. Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada. Electronic address: casey.shannon@hli.ubc.ca. 2. Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada. 3. Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada; Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada. 4. Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 5. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 6. Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. 7. Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada; Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada. 8. Department of Cardiology, Skåne University Hospital, Lund University, Lund, Sweden. 9. Department of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada. 10. Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada. 11. University Health Network/Mount Sinai Hospital, Toronto, Ontario, Canada. 12. Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. 13. Department of Medicine, University of Alberta, Calgary, Aberta, Canada. 14. Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada. 15. Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. 16. Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada. 17. Institut de Cardiologie de Montréal, Montréal, Québec, Canada. 18. Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. 19. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. 20. Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Department of Computer Science, University of British Columbia, Vancouver, British Columbia, Canada. 21. Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada; Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: bruce.mcmanus@hli.ubc.ca.
Abstract
BACKGROUND: Nine mRNA transcripts associated with acute cellular rejection (ACR) in previous microarray studies were ported to the clinically amenable NanoString nCounter platform. Here we report the diagnostic performance of the resulting blood test to exclude ACR in heart allograft recipients: HEARTBiT. METHODS: Blood samples for transcriptomic profiling were collected during routine post-transplantation monitoring in 8 Canadian transplant centres participating in the Biomarkers in Transplantation initiative, a large (n = 1622) prospective observational study conducted between 2009 and 2014. All adult cardiac transplant patients were invited to participate (median age = 56 [17 to 71]). The reference standard for rejection status was histopathology grading of tissue from endomyocardial biopsy (EMB). All locally graded ISHLT ≥ 2R rejection samples were selected for analysis (n = 36). ISHLT 1R (n = 38) and 0R (n = 86) samples were randomly selected to create a cohort approximately matched for site, age, sex, and days post-transplantation, with a focus on early time points (median days post-transplant = 42 [7 to 506]). RESULTS: ISHLT ≥ 2R rejection was confirmed by EMB in 18 and excluded in 92 samples in the test set. HEARTBiT achieved 47% specificity (95% confidence interval [CI], 36%-57%) given ≥ 90% sensitivity, with a corresponding area under the receiver operating characteristic curve of 0.69 (95% CI, 0.56-0.81). CONCLUSIONS: HEARTBiT's diagnostic performance compares favourably to the only currently approved minimally invasive diagnostic test to rule out ACR, AlloMap (CareDx, Brisbane, CA) and may be used to inform care decisions in the first 2 months post-transplantation, when AlloMap is not approved, and most ACR episodes occur.
BACKGROUND: Nine mRNA transcripts associated with acute cellular rejection (ACR) in previous microarray studies were ported to the clinically amenable NanoString nCounter platform. Here we report the diagnostic performance of the resulting blood test to exclude ACR in heart allograft recipients: HEARTBiT. METHODS: Blood samples for transcriptomic profiling were collected during routine post-transplantation monitoring in 8 Canadian transplant centres participating in the Biomarkers in Transplantation initiative, a large (n = 1622) prospective observational study conducted between 2009 and 2014. All adult cardiac transplant patients were invited to participate (median age = 56 [17 to 71]). The reference standard for rejection status was histopathology grading of tissue from endomyocardial biopsy (EMB). All locally graded ISHLT ≥ 2R rejection samples were selected for analysis (n = 36). ISHLT 1R (n = 38) and 0R (n = 86) samples were randomly selected to create a cohort approximately matched for site, age, sex, and days post-transplantation, with a focus on early time points (median days post-transplant = 42 [7 to 506]). RESULTS: ISHLT ≥ 2R rejection was confirmed by EMB in 18 and excluded in 92 samples in the test set. HEARTBiT achieved 47% specificity (95% confidence interval [CI], 36%-57%) given ≥ 90% sensitivity, with a corresponding area under the receiver operating characteristic curve of 0.69 (95% CI, 0.56-0.81). CONCLUSIONS: HEARTBiT's diagnostic performance compares favourably to the only currently approved minimally invasive diagnostic test to rule out ACR, AlloMap (CareDx, Brisbane, CA) and may be used to inform care decisions in the first 2 months post-transplantation, when AlloMap is not approved, and most ACR episodes occur.