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BackgroundOptimization procedures to identify gene knockouts for targeted biochemical overproduction have been widely in use in modern metabolic engineering. Flux balance analysis (FBA) framework has provided conceptual simplifications for genome-scale dynamic analysis at steady states. Based on FBA, many current optimization methods for targeted bio-productions have been developed under the maximum cell growth assumption. The optimization problem to derive gene knockout strategies recently has been formulated as a bi-level programming problem in OptKnock for maximum targeted bio-productions with maximum growth rates. However, it has been shown that knockout mutants in fact reach the steady states with the minimization of metabolic adjustment (MOMA) from the corresponding wild-type strains instead of having maximal growth rates after genetic or metabolic intervention. In this work, we propose a new bi-level computational framework--MOMAKnock--which can derive robust knockout strategies under the MOMA flux distribution approximation.MethodsIn this new bi-level optimization framework, we aim to maximize the production of targeted chemicals by identifying candidate knockout genes or reactions under phenotypic constraints approximated by the MOMA assumption. Hence, the targeted chemical production is the primary objective of MOMAKnock while the MOMA assumption is formulated as the inner problem of constraining the knockout metabolic flux to be as close as possible to the steady-state phenotypes of wide-type strains. As this new inner problem becomes a quadratic programming problem, a novel adaptive piecewise linearization algorithm is developed in this paper to obtain the exact optimal solution to this new bi-level integer quadratic programming problem for MOMAKnock.ResultsOur new MOMAKnock model and the adaptive piecewise linearization solution algorithm are tested with a small E. coli core metabolic network and a large-scale iAF1260 E. coli metabolic network. The derived knockout strategies are compared with those from OptKnock. Our preliminary experimental results show that MOMAKnock can provide improved targeted productions with more robust knockout strategies.

Solving Generalized LASSO (GL) problems is challenging, particularly when analyzing many features with a complex interacting structure. Recent developments have found effective ways to identify inactive features so that they can be removed or aggregated to reduce the problem size before applying optimization solvers for learning. However, existing methods are mostly devoted to special cases of GL problems with special structures for feature interactions, such as chains or trees. Developing screening rules, particularly, safe screening rules to remove or aggregate features with general interaction structures, calls for a very different screening approach for GL problems. To tackle this challenge, we formulate the GL screening problem as a bound estimation problem in a large linear inequality system when solving them in the dual space. We propose a novel bound propagation algorithm for efficient safe screening for general GL problems, which can be further enhanced by developing novel transformation methods that can effectively decouple interactions among features. The proposed propagation and transformation methods are applicable with dynamic screening that can easily initiate the screening process while existing screening methods require the knowledge of the solution under a desirable regularization parameter. Experiments on both synthetic and real-world data demonstrate the effectiveness of the proposed screening method.

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