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A Statistical Approach for Comparative Assessment of the Effect of Smoke Exposure in In Vivo Experiments: A Case Study of an OECD 90-Day Inhalation Study Including 3R4F and 1R6F Reference Cigarettes Cover

A Statistical Approach for Comparative Assessment of the Effect of Smoke Exposure in In Vivo Experiments: A Case Study of an OECD 90-Day Inhalation Study Including 3R4F and 1R6F Reference Cigarettes

Contributions to Tobacco & Nicotine Research
Volume 34 (2025): Issue 1 (January 2025)
By: Athanasios Kondylis,  Ulrike Kogel,  Jenny Ho,  EeTsin Wong,  Blaine Phillips,  Julia Hoeng and  Patrick Vanscheeuwijck  
Open Access
|Jan 2025

Figures & Tables

Figure 1.

Illustrated cases of the relative effect of a test item versus a reference item as provided by their geometric mean ratio (black circles) and associated 90% confidence intervals (black bars). The blue boxes show the variability of the reference item. Rows A to I illustrate different scenarios (explained further in the main text) for the value of the mean ratio and confidence interval and how they influence conclusions about the differences and equivalence of the two items.
Illustrated cases of the relative effect of a test item versus a reference item as provided by their geometric mean ratio (black circles) and associated 90% confidence intervals (black bars). The blue boxes show the variability of the reference item. Rows A to I illustrate different scenarios (explained further in the main text) for the value of the mean ratio and confidence interval and how they influence conclusions about the differences and equivalence of the two items.

Figure 2.

Long-term variability estimates (σR) depicted in blue bars for all endpoints across the historical 3R4F data. Variability estimates are expressed in percentages.
Long-term variability estimates (σR) depicted in blue bars for all endpoints across the historical 3R4F data. Variability estimates are expressed in percentages.

Figure 3.

Geometric mean ratio estimates (black circles) and their associated 90% confidence intervals for smoke emissions from the 1R6F reference cigarette over the 3R4F reference cigarette for test atmosphere endpoints. Blue boxes define equivalence ranges for the geometric mean ratio estimate based on the variability of 3R4F estimated using historical data. The standard equivalence limits of 0.8 and 1.25 and the reference value of 1 are shown (black dashed lines). TPM: Total Particulate Matter, CO: Carbon monoxide, GSD: Geometric Standard Deviation and MMAD: Mass Median Aerodynamic Diameter.
Geometric mean ratio estimates (black circles) and their associated 90% confidence intervals for smoke emissions from the 1R6F reference cigarette over the 3R4F reference cigarette for test atmosphere endpoints. Blue boxes define equivalence ranges for the geometric mean ratio estimate based on the variability of 3R4F estimated using historical data. The standard equivalence limits of 0.8 and 1.25 and the reference value of 1 are shown (black dashed lines). TPM: Total Particulate Matter, CO: Carbon monoxide, GSD: Geometric Standard Deviation and MMAD: Mass Median Aerodynamic Diameter.

Figure 4.

Geometric mean ratio estimates (black circles) and their associated 90% confidence intervals for smoke from the 1R6F reference cigarette over the 3R4F reference cigarette for female (left panel) and male (right panel) rats across all endpoints related to (from bottom to top): respiratory physiology, exposure, urinary nicotine metabolites, and clinical chemistry. Blue boxes define equivalence ranges for the geometric mean ratio as estimated based on the variability of 3R4F estimated using historical data. The standard equivalence limits of 0.8 and 1.25 and the reference value of 1 are shown (black dashed lines).
Geometric mean ratio estimates (black circles) and their associated 90% confidence intervals for smoke from the 1R6F reference cigarette over the 3R4F reference cigarette for female (left panel) and male (right panel) rats across all endpoints related to (from bottom to top): respiratory physiology, exposure, urinary nicotine metabolites, and clinical chemistry. Blue boxes define equivalence ranges for the geometric mean ratio as estimated based on the variability of 3R4F estimated using historical data. The standard equivalence limits of 0.8 and 1.25 and the reference value of 1 are shown (black dashed lines).

Lower and upper alternative equivalence range limits (δL* and δU*, respectively) for varying statistical design parameters: constant k and coefficient of variation (cv) with corresponding standard deviation (σR)_

kcvσRδL*δU*
10.20.1980.8201.219
10.30.2940.7461.341
10.40.3850.6801.470
10.50.4720.6241.604
0.760.20.1980.8601.162
0.760.30.2940.8001.250
0.760.40.3850.7461.340
0.760.50.4720.6981.432

Lower and upper equivalence range limits (δL and δU, respectively) for varying statistical design parameters: sample size by group (n), consumer’s risk (α), producer’s risk (β), and coefficient of variation (cv) with corresponding standard deviation (σR)_

nαβcvσRδLδU
100.050.050.20.1980.7861.271
100.050.050.30.2940.7001.428
100.050.050.40.3850.6271.596
100.050.050.50.4720.5641.773
100.050.10.20.1980.8051.243
100.050.10.30.2940.7251.380
100.050.10.40.3850.6551.526
100.050.10.50.4720.5961.679
DOI: https://doi.org/10.2478/cttr-2025-0003 | Journal eISSN: 2719-9509
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Language: English
Page range: 26 - 33
Submitted on: Jul 5, 2024
|
Accepted on: Nov 8, 2024
|
Published on: Jan 30, 2025
Published by: Institut für Tabakforschung GmbH
In partnership with: Paradigm Publishing Services
Publication frequency: 4 issues per year
Keywords:
testing,
reference cigarette smoke,
statistical equivalence,
statistical intervals
Related subjects:
General interest,
Life sciences,
Life sciences, other,
Physics,
Physics, other

© 2025 Athanasios Kondylis, Ulrike Kogel, Jenny Ho, EeTsin Wong, Blaine Phillips, Julia Hoeng, Patrick Vanscheeuwijck, published by Institut für Tabakforschung GmbH
This work is licensed under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License.

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