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@ARTICLE{Abend:1010512,
      author       = {Abend, M. and Amundson, S. A. and Badie, C. and Kriehuber,
                      R. and Lacombe, J. and Lopez-Riego, M. and Lumniczky, K. and
                      Endesfelder, D. and O'Brien, G. and Doucha-Senf, S. and
                      Ghandhi, S. A. and Hargitai, R. and Kis, E. and Lundholm, L.
                      and Oskamp, D. and Ostheim, P. and Schwanke, D. and Shuryak,
                      I. and Siebenwith, C. and Unverricht-Yeboah, M. and Wojcik,
                      A. and Zenhausern, F. and Port, M.},
      title        = {{RENEB} {I}nter-{L}aboratory {C}omparison 2021: {T}he
                      {G}ene {E}xpression {A}ssay},
      journal      = {Radiation research},
      volume       = {199},
      number       = {6},
      issn         = {0033-7587},
      address      = {Great Falls, Va.},
      publisher    = {Radiation Research Society},
      reportid     = {FZJ-2023-03095},
      pages        = {598-615},
      year         = {2023},
      abstract     = {Early and high-throughput individual dose estimates are
                      essential following large-scale radiation exposure events.
                      In the context of the Running the European Network for
                      Biodosimetry and Physical Dosimetry (RENEB) 2021 exercise,
                      gene expression assays were conducted and their
                      corresponding performance for dose-assessment is presented
                      in this publication. Three blinded, coded whole blood
                      samples from healthy donors were exposed to 0, 1.2 and 3.5
                      Gy X-ray doses (240 kVp, 1 Gy/min) using the X-ray source
                      Yxlon. These exposures correspond to clinically relevant
                      groups of unexposed, low dose (no severe acute health
                      effects expected) and high dose exposed individuals
                      (requiring early intensive medical health care). Samples
                      were sent to eight teams for dose estimation and
                      identification of clinically relevant groups. For
                      quantitative reverse transcription polymerase chain reaction
                      (qRT-PCR) and microarray analyses, samples were lysed,
                      stored at 20°C and shipped on wet ice. RNA isolations and
                      assays were run in each laboratory according to locally
                      established protocols. The time-to-result for both rough
                      early and more precise later reports has been documented
                      where possible. Accuracy of dose estimates was calculated as
                      the difference between estimated and reference doses for all
                      doses (summed absolute difference, SAD) and by determining
                      the number of correctly reported dose estimates that were
                      defined as ±0.5 Gy for reference doses <2.5 Gy and ±1.0 Gy
                      for reference doses >3 Gy, as recommended for triage
                      dosimetry. We also examined the allocation of dose estimates
                      to clinically/diagnostically relevant exposure groups.
                      Altogether, 105 dose estimates were reported by the eight
                      teams, and the earliest report times on dose categories and
                      estimates were 5 h and 9 h, respectively. The coefficient of
                      variation for $85\%$ of all 436 qRT-PCR measurements did not
                      exceed $10\%.$ One team reported dose estimates that
                      systematically deviated several-fold from reported dose
                      estimates, and these outliers were excluded from further
                      analysis. Teams employing a combination of several genes
                      generated about two-times lower median SADs (0.8 Gy)
                      compared to dose estimates based on single genes only (1.7
                      Gy). When considering the uncertainty intervals for triage
                      dosimetry, dose estimates of all teams together were
                      correctly reported in $100\%$ of the 0 Gy, $50\%$ of the 1.2
                      Gy and $50\%$ of the 3.5 Gy exposed samples. The order of
                      dose estimates (from lowest to highest) corresponding to
                      three dose categories (unexposed, low dose and highest
                      exposure) were correctly reported by all teams and all
                      chosen genes or gene combinations. Furthermore, if teams
                      reported no exposure or an exposure >3.5 Gy, it was always
                      correctly allocated to the unexposed and the highly exposed
                      group, while low exposed (1.2 Gy) samples sometimes could
                      not be discriminated from highly (3.5 Gy) exposed samples.
                      All teams used FDXR and $78.1\%$ of correct dose estimates
                      used FDXR as one of the predictors. Still, the accuracy of
                      reported dose estimates based on FDXR differed considerably
                      among teams with one team's SAD (0.5 Gy) being comparable to
                      the dose accuracy employing a combination of genes. Using
                      the workflow of this reference team, we performed additional
                      experiments after the exercise on residual RNA and cDNA sent
                      by six teams to the reference team. All samples were
                      processed similarly with the intention to improve the
                      accuracy of dose estimates when employing the same workflow.
                      Re-evaluated dose estimates improved for half of the samples
                      and worsened for the others. In conclusion, this
                      inter-laboratory comparison exercise enabled (1)
                      identification of technical problems and corrections in
                      preparations for future events, (2) confirmed the early and
                      high-throughput capabilities of gene expression, (3)
                      emphasized different biodosimetry approaches using either
                      only FDXR or a gene combination, (4) indicated some
                      improvements in dose estimation with FDXR when employing a
                      similar methodology, which requires further research for the
                      final conclusion and (5) underlined the applicability of
                      gene expression for identification of unexposed and highly
                      exposed samples, supporting medical management in
                      radiological or nuclear scenarios},
      cin          = {S-US},
      ddc          = {530},
      cid          = {I:(DE-Juel1)S-US-20090406},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {37057982},
      UT           = {WOS:001004143500007},
      doi          = {10.1667/RADE-22-00206.1},
      url          = {https://juser.fz-juelich.de/record/1010512},
}