Open Access

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

Athanasios Kondylis

Athanasios Kondylis

PMI R&D, Philip Morris Products S.A.Neuchâtel, Switzerland
Search for this author on
Sciendo|Google Scholar
Kondylis, Athanasios
, 
Ulrike Kogel

Ulrike Kogel

PMI R&D, Philip Morris Products S.A.Neuchâtel, Switzerland
Search for this author on
Sciendo|Google Scholar
Kogel, Ulrike
, 
Jenny Ho

Jenny Ho

Vectura Fertin Pharma Laboratories Pte. Ltd.Singapore
Search for this author on
Sciendo|Google Scholar
Ho, Jenny
, 
EeTsin Wong

EeTsin Wong

Vectura Fertin Pharma Laboratories Pte. Ltd.Singapore
Search for this author on
Sciendo|Google Scholar
Wong, EeTsin
, 
Blaine Phillips

Blaine Phillips

Vectura Fertin Pharma Laboratories Pte. Ltd.Singapore
Search for this author on
Sciendo|Google Scholar
Phillips, Blaine
, 
Julia Hoeng

Julia Hoeng

PMI R&D, Philip Morris Products S.A.Neuchâtel, Switzerland
Search for this author on
Sciendo|Google Scholar
Hoeng, Julia
 and 
Patrick Vanscheeuwijck

Patrick Vanscheeuwijck

PMI R&D, Philip Morris Products S.A.Neuchâtel, Switzerland
Search for this author on
Sciendo|Google Scholar
Vanscheeuwijck, Patrick
  
Jan 30, 2025
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's Cover Image
About this article
Previous Article
Next Article
Cite
Download Cover
Published Online: Jan 30, 2025
Page range: 26 - 33
Received: Jul 05, 2024
Accepted: Nov 08, 2024
DOI: https://doi.org/10.2478/cttr-2025-0003
Keywords
© 2024 Athanasios Kondylis et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

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)_

k cv σR δL* δU*
1 0.2 0.198 0.820 1.219
1 0.3 0.294 0.746 1.341
1 0.4 0.385 0.680 1.470
1 0.5 0.472 0.624 1.604
0.76 0.2 0.198 0.860 1.162
0.76 0.3 0.294 0.800 1.250
0.76 0.4 0.385 0.746 1.340
0.76 0.5 0.472 0.698 1.432

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)_

n α β cv σR δL δU
10 0.05 0.05 0.2 0.198 0.786 1.271
10 0.05 0.05 0.3 0.294 0.700 1.428
10 0.05 0.05 0.4 0.385 0.627 1.596
10 0.05 0.05 0.5 0.472 0.564 1.773
10 0.05 0.1 0.2 0.198 0.805 1.243
10 0.05 0.1 0.3 0.294 0.725 1.380
10 0.05 0.1 0.4 0.385 0.655 1.526
10 0.05 0.1 0.5 0.472 0.596 1.679
Language:
English
Publication timeframe:
4 times per year
Journal Subjects:
General Interest, Life Sciences, Life Sciences, other, Physics, Physics, other
Journal RSS Feed