TY - JOUR

T1 - Applying historical data in a nonlinear mixed-effects model can reduce the number of control rats required for calculation of the relative potency of insulin analogues

AU - Nielsen, Emilie Prang

AU - Andersen, Søren

AU - Brand, Christian Lehn

AU - Ditlevsen, Susanne

PY - 2022

Y1 - 2022

N2 - This paper examines how to reduce the number of control animals in preclinical hyperinsulemic glucose clamp studies if we make use of information on historical studies. A dataset consisting of 59 studies in rats to investigate new insulin analogues for diabetics, collected in the years 2000 to 2015, is analysed. A simulation experiment is performed based on a carefully built nonlinear mixed-effects model including historical information, comparing results (for the relative log-potency) with the standard approach ignoring previous studies. We find that by including historical information in the form of the mixed-effects model proposed, we can to remove between 23% and 51% of the control rats in the two studies looked closely upon to get the same level of precision on the relative log-potency as in the standard analysis. How to incorporate the historical information in the form of the mixed-effects model is discussed, where both a mixed-effect meta-analysis approach as well as a Bayesian approach are suggested. The conclusions are similar for the two approaches, and therefore, we conclude that the inclusion of historical information is beneficial in regard to using fewer control rats.

AB - This paper examines how to reduce the number of control animals in preclinical hyperinsulemic glucose clamp studies if we make use of information on historical studies. A dataset consisting of 59 studies in rats to investigate new insulin analogues for diabetics, collected in the years 2000 to 2015, is analysed. A simulation experiment is performed based on a carefully built nonlinear mixed-effects model including historical information, comparing results (for the relative log-potency) with the standard approach ignoring previous studies. We find that by including historical information in the form of the mixed-effects model proposed, we can to remove between 23% and 51% of the control rats in the two studies looked closely upon to get the same level of precision on the relative log-potency as in the standard analysis. How to incorporate the historical information in the form of the mixed-effects model is discussed, where both a mixed-effect meta-analysis approach as well as a Bayesian approach are suggested. The conclusions are similar for the two approaches, and therefore, we conclude that the inclusion of historical information is beneficial in regard to using fewer control rats.

U2 - 10.1371/journal.pone.0257750

DO - 10.1371/journal.pone.0257750

M3 - Journal article

C2 - 35709155

VL - 17

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 6

M1 - e0257750

ER -