Robust and Adaptive Two-stage Designs in Nonlinear Mixed Effect Models

Fayette, Lucie; Leroux, Romain; Mentré, France; Seurat, Jérémy

doi:10.1208/s12248-023-00810-9

Cited by 1 publication

(1 citation statement)

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“…In our real application, data from the two experiments were fitted separately, the first one being only used to design the second experiment. One potential alternative would have been to pool the data from multiple experiments to improve parameter precision of estimation, as in model-based adaptive designs [22, 9]. Nonetheless, we leveraged the first experiment to establish a prior for accurately estimated parameters and not for those with significant uncertainty - modulated in part by the impact of noise on inference.…”

Section: Discussionmentioning

confidence: 99%

Design, optimization, and inference of biphasic decay of infectious virus particles

Seurat,

Gerbino,

Meyer

et al. 2024

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The loss of virus particles is typically considered to arise from a first-order kinetic process. Signals of deviations from this exponential decay are often de-prioritized. Here, we propose methods to evaluate if a design is adequate to evaluate evidence for multiphasic virus particle decay and to optimize the sampling times of decay experiments, accounting for uncertainties in viral kinetics. First, we evaluate 1500 synthetic scenarios of biphasic decays, with varying decay rates and initial proportions of subpopulations. Robust inference of multiphasic decay is more likely when the faster decaying subpopulation predominates insofar as early samples are taken to resolve the faster decay rate. Overall, we find that design optimization leads to a better precision of estimation while reducing the number of samples. It helps to estimate adequately the fastest decay in 54% of situations vs. 41% using a non-optimized design. We then apply these methods to infer multiple decay rates associated with the decay of PhiD9, an evolved isolate derived from phage Phi21. A pilot experiment confirmed that PhiD9 decay is multiphasic, but was unable to resolve the rate or proportion of the fast decay subpopulation(s). We then applied optimal design methods to propose new PhiD9 sampling times. Using this strategy, we were able to robustly estimate both decay rates and their respective subpopulations. Notably, we conclude that the vast majority (94%) of the population decays at a rate 16-fold higher than a slow decaying population. Altogether, these results provide methods to quantitatively estimate heterogeneity in viral decay.

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Section: Discussionmentioning

confidence: 99%