Dipl. Phys. Bernhard Steiert
Parameter selection for nonlinear modeling using L1 regularization
A major goal in systems biology is to reveal potential drug targets for cancer therapy. A common property of cancer cells is the alteration of signaling pathways triggering cell-fate decisions resulting in uncontrolled proliferation and tumor growth. However, addressing cancer-specific alterations experimentally by investigating each node in the signaling network one after the other is difficult or even not possible at all. Here, we combine quantitative time-resolved data from different cell lines with non-linear modeling under L1 regularization, which is capable of detecting cell-type specific parameters. To adapt the least-squares numerical optimization routine to L1 regularization, sub-gradient strategies as well as truncation of proposed optimization steps were implemented. Likelihood-ratio tests were used to determine the optimal penalization strength resulting in a sparse solution in terms of a minimal number of cell-type specific parameters that is in agreement with the data. The uniqueness of the solution is investigated using the profile likelihood. Based on the minimal set of cell-type specific parameters experiments were designed for improving identifiability and to validate the model. The approach constitutes a general method to infer an overarching model with a minimum number of individual parameters for the particular models.