Controller design faces a trade-off between robustness and performance, and the reliability of linear controllers has caused many practitioners to focus on the former. However, there is renewed interest in improving system performance to deal with growing energy constraints. This paper describes a learning-based model predictive control (LBMPC) scheme that provides deterministic guarantees on robustness, while statistical identification tools are used to identify richer models of the system in order to improve performance; the benefits of this framework are that it handles state and input constraints, optimizes system performance with respect to a cost function, and can be designed to use a wide variety of parametric or nonparametric statistical tools. The main insight of LBMPC is that safety and performance can be decoupled under reasonable conditions in an optimization framework by maintaining two models of the system. The first is an approximate model with bounds on its uncertainty, and the second model is updated by statistical methods. LBMPC improves performance by choosing inputs that minimize a cost subject to the learned dynamics, and it ensures safety and robustness by checking whether these same inputs keep the approximate model stable when it is subject to uncertainty. Furthermore, we show that if the system is sufficiently excited, then the LBMPC control action probabilistically converges to that of an MPC computed using the true dynamics.

Engineered metabolic pathways often suffer from flux imbalances that can overburden the cell and accumulate intermediate metabolites, resulting in reduced product titers. One way to alleviate such imbalances is to adjust the expression levels of the constituent enzymes using a combinatorial expression library. Typically, this approach requires high-throughput assays, which are unfortunately unavailable for the vast majority of desirable target compounds. To address this, we applied regression modeling to enable expression optimization using only a small number of measurements. We characterized a set of constitutive promoters in Saccharomyces cerevisiae that spanned a wide range of expression and maintained their relative strengths irrespective of the coding sequence. We used a standardized assembly strategy to construct a combinatorial library and express for the first time in yeast the five-enzyme violacein biosynthetic pathway. We trained a regression model on a random sample comprising 3% of the total library, and then used that model to predict genotypes that would preferentially produce each of the products in this highly branched pathway. This generalizable method should prove useful in engineering new pathways for the sustainable production of small molecules.

Intratumoral heterogeneity in cancers arises from genomic instability and epigenomic plasticity and is associated with resistance to cytotoxic and targeted therapies. We show here that cell-state heterogeneity, defined by differentiation-state marker expression, is high in triple-negative and basal-like breast cancer subtypes, and that drug tolerant persister (DTP) cell populations with altered marker expression emerge during treatment with a wide range of pathway-targeted therapeutic compounds. We show that MEK and PI3K/mTOR inhibitor-driven DTP states arise through distinct cell-state transitions rather than by Darwinian selection of preexisting subpopulations, and that these transitions involve dynamic remodeling of open chromatin architecture. Increased activity of many chromatin modifier enzymes, including BRD4, is observed in DTP cells. Co-treatment with the PI3K/mTOR inhibitor BEZ235 and the BET inhibitor JQ1 prevents changes to the open chromatin architecture, inhibits the acquisition of a DTP state, and results in robust cell death in vitro and xenograft regression in vivo.

Inverse optimization refers to the inference of unknown parameters of an optimization problem based on knowledge of its optimal solutions. This paper considers inverse optimization in the setting where measurements of the optimal solutions of a convex optimization problem are corrupted by noise. We first provide a formulation for inverse optimization and prove it to be NP-hard. In contrast to existing methods, we show that the parameter estimates produced by our formulation are statistically consistent. Our approach involves combining a new duality-based reformulation for bilevel programs with a regularization scheme that smooths discontinuities in the formulation. Using epi-convergence theory, we show the regularization parameter can be adjusted to approximate the original inverse optimization problem to arbitrary accuracy, which we use to prove our consistency results. Next, we propose two solution algorithms based on our duality-based formulation. The first is an enumeration algorithm that is applicable to settings where the dimensionality of the parameter space is modest, and the second is a semiparametric approach that combines nonparametric statistics with a modified version of our formulation. These numerical algorithms are shown to maintain the statistical consistency of the underlying formulation. Lastly, using both synthetic and real data, we demonstrate that our approach performs competitively when compared with existing heuristics.

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