TY - JOUR
T1 - Making the Case for Absorbed Radiation Response Biodosimetry-Utility of a High-Throughput Biodosimetry System
AU - Hoffmeyer, Michaela R.
AU - Gillis, Kristin
AU - Park, Jin G.
AU - Murugan, Vel
AU - Labaer, Joshua
N1 - Funding Information:
This work was supported by the Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, U.S. Department of Health and Human Services under Contract Nos. HHS01201000008C and HHS0100201600037C. We are indebted to Dr. Judith L. Bader of the Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, for providing review and commentary on the materials discussed in this article. We also acknowledge Dr. Simon Authier of Citoxlab and Dr. Melanie Doyle-Eisele of LBERI for providing NHP radiation exposure lethality data, and Garrett Dalton of MRIGlobal for providing graphic design support.
Publisher Copyright:
© 2021 by Radiation Research Society. All rights of reproduction in any form reserved.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - There is an unmet need to provide medical personnel with a Food and Drug Administration (FDA)-approved biodosimetry method for quantifying individualized absorbed dose response to inform treatment decisions for a very large patient population potentially exposed to ionizing radiation in the event of a nuclear incident. Validation of biodosimetry devices requires comparison of absorbed dose estimates to delivered dose as an indication of accuracy; however, comparison to delivered dose does not account for biological variability or an individual's radiosensitivity. As there is no FDA-cleared gene-expression-based biodosimetry method for determining biological response to radiation, results from accuracy comparisons to delivered dose yield relatively wide tolerance intervals or uncertainty. The Arizona State University Biodesign Institute is developing a high-throughput, automated real-time polymerase chain reaction (RT-PCR)-based biodosimetry system that provides absorbed dose estimates for patients exposed to 0-10 Gy from blood collected 1-7 days postirradiation. While the absorbed dose estimates result from a calibration against the actual exposed dose, the reported dose estimate is a measure of response to absorbed dose based on the exposure models used in developing the system. A central concern with biodosimetry test evaluation is how variability in the dose estimate results could affect medical decision-making, and if the biodosimetry test system performance is quantitatively sufficient to inform effective treatment. A risk:benefit analysis of the expected system performance in the proposed intended use environment was performed to address the potential medical utility of this biodosimetry system. Uncertainty analysis is based on biomarker variability in non-human primate (NHP) models. Monte Carlo simulation was employed to test multiple groups of biomarkers and their potential variation in response to determine uncertainty associated with dose estimate results. Dose estimate uncertainty ranges from ±1.2-1.7 Gy depending on the exposure dose over a range of 2-10 Gy. The risk:benefit of individualized absorbed dose estimates within the context of medical interventions after a nuclear incident is considered and the application of the biodosimetry system is evaluated in this framework. NHP dose-response relationships, as measured by clinical outcome end points, show expected biological and radiosensitivity responses in the primate populations tested and corroborate the biological variability observed in the reported absorbed dose estimate. Performance is examined in relationship to current clinical management and treatment recommendations, with evaluation of potential patient risk in over-A nd underestimating absorbed dose.
AB - There is an unmet need to provide medical personnel with a Food and Drug Administration (FDA)-approved biodosimetry method for quantifying individualized absorbed dose response to inform treatment decisions for a very large patient population potentially exposed to ionizing radiation in the event of a nuclear incident. Validation of biodosimetry devices requires comparison of absorbed dose estimates to delivered dose as an indication of accuracy; however, comparison to delivered dose does not account for biological variability or an individual's radiosensitivity. As there is no FDA-cleared gene-expression-based biodosimetry method for determining biological response to radiation, results from accuracy comparisons to delivered dose yield relatively wide tolerance intervals or uncertainty. The Arizona State University Biodesign Institute is developing a high-throughput, automated real-time polymerase chain reaction (RT-PCR)-based biodosimetry system that provides absorbed dose estimates for patients exposed to 0-10 Gy from blood collected 1-7 days postirradiation. While the absorbed dose estimates result from a calibration against the actual exposed dose, the reported dose estimate is a measure of response to absorbed dose based on the exposure models used in developing the system. A central concern with biodosimetry test evaluation is how variability in the dose estimate results could affect medical decision-making, and if the biodosimetry test system performance is quantitatively sufficient to inform effective treatment. A risk:benefit analysis of the expected system performance in the proposed intended use environment was performed to address the potential medical utility of this biodosimetry system. Uncertainty analysis is based on biomarker variability in non-human primate (NHP) models. Monte Carlo simulation was employed to test multiple groups of biomarkers and their potential variation in response to determine uncertainty associated with dose estimate results. Dose estimate uncertainty ranges from ±1.2-1.7 Gy depending on the exposure dose over a range of 2-10 Gy. The risk:benefit of individualized absorbed dose estimates within the context of medical interventions after a nuclear incident is considered and the application of the biodosimetry system is evaluated in this framework. NHP dose-response relationships, as measured by clinical outcome end points, show expected biological and radiosensitivity responses in the primate populations tested and corroborate the biological variability observed in the reported absorbed dose estimate. Performance is examined in relationship to current clinical management and treatment recommendations, with evaluation of potential patient risk in over-A nd underestimating absorbed dose.
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U2 - 10.1667/RADE-20-00029.1
DO - 10.1667/RADE-20-00029.1
M3 - Article
C2 - 33667298
AN - SCOPUS:85118653243
SN - 0033-7587
VL - 196
SP - 535
EP - 546
JO - Radiation Research
JF - Radiation Research
IS - 5
ER -