The hematopoietic system has a highly regulated and complex structure in which cells are organized to successfully create and maintain new blood cells. Feedback regulation is crucial to tightly control this system, but the specific mechanisms by which control is exerted are not completely understood. In this work, we aim to uncover the underlying mechanisms in hematopoiesis by conducting perturbation experiments, where animal subjects are exposed to an external agent in order to observe the system response and evolution. Developing a proper experimental design for these studies is an extremely challenging task. To address this issue, we have developed a novel Bayesian framework for optimal design of perturbation experiments. We model the numbers of hematopoietic stem and progenitor cells in mice that are exposed to a low dose of radiation. We use a differential equations model that accounts for feedback and feedforward regulation. A significant obstacle is that the experimental data are not longitudinal, rather each data point corresponds to a different animal. This model is embedded in a hierarchical framework with latent variables that capture unobserved cellular population levels. We select the optimum design based on the amount of information gain, measured by the Kullback-Leibler divergence between the probability distributions before and after observing the data. We evaluate our approach using synthetic and experimental data. We show that a proper design can lead to better estimates of model parameters even with relatively few subjects. Additionally, we demonstrate that the model parameters show a wide range of sensitivities to design options. Our method should allow scientists to find the optimal design by focusing on their specific parameters of interest and provide insight to hematopoiesis. Our approach can be extended to more complex models where latent components are used.
Download