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The use of benchmark dose uncertainty measurements for robust comparative potency analyses

Ryan Wheeldon, Stephen D. Dertinger, Steven M. Bryce, Jeffrey C. Bemis, George Johnson Orcid Logo

Environmental and Molecular Mutagenesis, Volume: 62, Issue: 3, Pages: 203 - 215

Swansea University Authors: Ryan Wheeldon, George Johnson Orcid Logo

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DOI (Published version): 10.1002/em.22422

Abstract

The Benchmark Dose (BMD) method is the favored approach for quantitative dose–response analysis where uncertainty measurements are delineated between the upper (BMDU) and lower (BMDL) confidence bounds, or confidence intervals (CIs). Little has been published on the accurate interpretation of uncert...

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Published in: Environmental and Molecular Mutagenesis
ISSN: 0893-6692 1098-2280
Published: Wiley 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa56076
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spelling 2021-05-04T13:32:57.0553625 v2 56076 2021-01-19 The use of benchmark dose uncertainty measurements for robust comparative potency analyses c36eeeb84e2f50ae8990f1aedd18590c Ryan Wheeldon Ryan Wheeldon true false 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 2021-01-19 The Benchmark Dose (BMD) method is the favored approach for quantitative dose–response analysis where uncertainty measurements are delineated between the upper (BMDU) and lower (BMDL) confidence bounds, or confidence intervals (CIs). Little has been published on the accurate interpretation of uncertainty measurements for potency comparative analyses between different test conditions. We highlight this by revisiting a previously published comparative in vitro genotoxicity dataset for human lymphoblastoid TK6 cells that were exposed to each of 10 clastogens in the presence and absence (+/−) of low concentration (0.25%) S9, and scored for p53, γH2AX and Relative Nuclei Count (RNC) responses at two timepoints (Tian et al., 2020). The researchers utilized BMD point estimates in potency comparative analysis between S9 treatment conditions. Here we highlight a shortcoming that the use of BMD point estimates can mischaracterize potency differences between systems. We reanalyzed the dose responses by BMD modeling using PROAST v69.1. We used the resulting BMDL and BMDU metrics to calculate “S9 potency ratio confidence intervals” that compare the relative potency of compounds +/− S9 as more statistically robust metrics for comparative potency measurements compared to BMD point estimate ratios. We performed unsupervised hierarchical clustering that identified four S9‐dependent groupings: high and low‐level potentiation, no effect, and diminution. This work demonstrates the importance of using BMD uncertainty measurements in potency comparative analyses between test conditions. Irrespective of the source of the data, we propose a stepwise approach when performing BMD modeling in comparative potency analyses between test conditions. Journal Article Environmental and Molecular Mutagenesis 62 3 203 215 Wiley 0893-6692 1098-2280 BMD, comparative, DNA damage, potency, uncertainty 11 3 2021 2021-03-11 10.1002/em.22422 COLLEGE NANME COLLEGE CODE Swansea University SU Library paid the OA fee (TA Institutional Deal) TA Deal - Library 2021-05-04T13:32:57.0553625 2021-01-19T11:45:16.3532462 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Ryan Wheeldon 1 Stephen D. Dertinger 2 Steven M. Bryce 3 Jeffrey C. Bemis 4 George Johnson 0000-0001-5643-9942 5 56076__19181__eb84a9f54d9d43ce863726d100a51223.pdf 56076 VOR.em.22422.pdf 2021-01-26T10:57:34.2488564 Output 2706178 application/pdf Version of Record true Distributed under the terms of a Creative Commons Attribution 4.0 License (CC-BY). true eng http://creativecommons.org/licenses/by/4.0/
title The use of benchmark dose uncertainty measurements for robust comparative potency analyses
spellingShingle The use of benchmark dose uncertainty measurements for robust comparative potency analyses
Ryan Wheeldon
George Johnson
title_short The use of benchmark dose uncertainty measurements for robust comparative potency analyses
title_full The use of benchmark dose uncertainty measurements for robust comparative potency analyses
title_fullStr The use of benchmark dose uncertainty measurements for robust comparative potency analyses
title_full_unstemmed The use of benchmark dose uncertainty measurements for robust comparative potency analyses
title_sort The use of benchmark dose uncertainty measurements for robust comparative potency analyses
author_id_str_mv c36eeeb84e2f50ae8990f1aedd18590c
37d0f121db69fd09f364df89e4405e31
author_id_fullname_str_mv c36eeeb84e2f50ae8990f1aedd18590c_***_Ryan Wheeldon
37d0f121db69fd09f364df89e4405e31_***_George Johnson
author Ryan Wheeldon
George Johnson
author2 Ryan Wheeldon
Stephen D. Dertinger
Steven M. Bryce
Jeffrey C. Bemis
George Johnson
format Journal article
container_title Environmental and Molecular Mutagenesis
container_volume 62
container_issue 3
container_start_page 203
publishDate 2021
institution Swansea University
issn 0893-6692
1098-2280
doi_str_mv 10.1002/em.22422
publisher Wiley
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
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description The Benchmark Dose (BMD) method is the favored approach for quantitative dose–response analysis where uncertainty measurements are delineated between the upper (BMDU) and lower (BMDL) confidence bounds, or confidence intervals (CIs). Little has been published on the accurate interpretation of uncertainty measurements for potency comparative analyses between different test conditions. We highlight this by revisiting a previously published comparative in vitro genotoxicity dataset for human lymphoblastoid TK6 cells that were exposed to each of 10 clastogens in the presence and absence (+/−) of low concentration (0.25%) S9, and scored for p53, γH2AX and Relative Nuclei Count (RNC) responses at two timepoints (Tian et al., 2020). The researchers utilized BMD point estimates in potency comparative analysis between S9 treatment conditions. Here we highlight a shortcoming that the use of BMD point estimates can mischaracterize potency differences between systems. We reanalyzed the dose responses by BMD modeling using PROAST v69.1. We used the resulting BMDL and BMDU metrics to calculate “S9 potency ratio confidence intervals” that compare the relative potency of compounds +/− S9 as more statistically robust metrics for comparative potency measurements compared to BMD point estimate ratios. We performed unsupervised hierarchical clustering that identified four S9‐dependent groupings: high and low‐level potentiation, no effect, and diminution. This work demonstrates the importance of using BMD uncertainty measurements in potency comparative analyses between test conditions. Irrespective of the source of the data, we propose a stepwise approach when performing BMD modeling in comparative potency analyses between test conditions.
published_date 2021-03-11T04:10:45Z
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