Ruth Misener

Global optimization of mixed-integer quadratically-constrained quadratic programs (MIQCQP) through piecewise-linear and edge-concave relaxations

We propose a deterministic global optimization approach, whose novel contributions are rooted in the edge-concave and piecewise-linear underestimators, to address nonconvex mixed-integer quadratically-constrained quadratic programs (MIQCQP) to

Dynamically generated cutting planes for mixed-integer quadratically constrained quadratic programs and their incorporation into GloMIQO 2

{\epsilon}

A framework for the design, modeling and optimization of biomedical systems

-global optimality. The facets of low-dimensional (n ≤ 3) edge-concave aggregations dominating the termwise relaxation of MIQCQP are introduced at every node of a branch-and-bound tree. Concave multivariable terms and sparsely distributed bilinear terms that do not participate in connected edge-concave aggregations are addressed through piecewise-linear relaxations. Extensive computational studies are presented for point packing problems, standard and generalized pooling problems, and examples from GLOBALLib (Meeraus, Globallib. http://www.gamsworld.org/global/globallib.htm).

A mathematical model of subpopulation kinetics for the deconvolution of leukaemia heterogeneity

This manuscript reviews recent advances in deterministic global optimization for Mixed-Integer Nonlinear Programming (MINLP), as well as Constrained Derivative-Free Optimization (CDFO). This work provides a comprehensive and detailed literature review in terms of significant theoretical contributions, algorithmic developments, software implementations and applications for both MINLP and CDFO. Both research areas have experienced rapid growth, with a common aim to solve a wide range of real-world problems. We show their individual prerequisites, formulations and applicability, but also point out possible points of interaction in problems which contain hybrid characteristics. Finally, an inclusive and complete test suite is provided for both MINLP and CDFO algorithms, which is useful for future benchmarking.

Bayesian Optimization with Dimension Scheduling: Application to Biological Systems

The global mixed-integer quadratic optimizer, GloMIQO, addresses mixed-integer quadratically constrained quadratic programs (MIQCQP) to ε-global optimality. This paper documents the branch-and-cut framework integrated into GloMIQO 2. Cutting planes are derived from reformulation–linearization technique equations, convex multivariable terms, αBB convexifications, and low- and high-dimensional edge-concave aggregations. Cuts are based on both individual equations and collections of nonlinear terms in MIQCQP. Novel contributions of this paper include: development of a corollary to Cramas [Concave extensions for nonlinear 0-1 maximization problems, Math. Program. 61 (1993), pp. 53–60] necessary and sufficient condition for the existence of a cut dominating the termwise relaxation of a bilinear expression; algorithmic descriptions for deriving each class of cut; presentation of a branch-and-cut framework integrating the cuts. Computational results are presented along with comparison of the GloMIQO 2 performance to several state-of-the-art solvers.

Maximizing neotissue growth kinetics in a perfusion bioreactor: An in silico strategy using model reduction and Bayesian optimization

The classical αBB method determines univariate quadratic perturbations that convexify twice continuously differentiable functions. This paper generalizes αBB to additionally consider nondiagonal elements in the perturbation Hessian matrix. These correspond to bilinear terms in the underestimators, where previously all nonlinear terms were separable quadratic terms. An interval extension of Gerschgorin’s circle theorem guarantees convexity of the underestimator. It is shown that underestimation parameters which are optimal, in the sense that the maximal underestimation error is minimized, can be obtained by solving a linear optimization model.Theoretical results are presented regarding the instantiation of the nondiagonal underestimator that minimizes the maximum error. Two special cases are analyzed to convey an intuitive understanding of that optimally-selected convexifier. Illustrative examples that convey the practical advantage of these new αBB underestimators are presented.

Robust Superstructure Optimisation of a Bioreactor that Produces Red Blood Cells

Abstract We present an overview of the key building blocks of a design framework for modeling and optimization of biomedical systems with main focus on leukemia, that we have been developing in the Biological Systems Engineering Laboratory and the Centre for Process Systems Engineering at Imperial College. The framework features the following areas: (i) a three-dimensional, biomimetic, in vitro platform for culturing both healthy and diseased blood; (ii) a novel, hollow fiber bioreactor that upgrades this in vitro platform to enable expansion and continuous harvesting of healthy and diseased blood; (iii) a global optimization-based approach for the design and operation of the aforementioned bioreactor; (iv) a pharmacokinetic / pharmacodynamic model representing patient response to Acute Myeloid Leukemia treatment; (v) an experimental framework for cell cycle modeling and quantitative analysis of environmental stress. This manuscript recapitulates the progress made in the different areas as well as the way in which these areas are connected, finally leading to a hybrid in vitro/in silico platform which allows the optimization of the ex vivo expansion of healthy and diseased blood.

Stem cell biomanufacturing under uncertainty: A case study in optimizing red blood cell production

Acute myeloid leukaemia is characterized by marked inter- and intra-patient heterogeneity, the identification of which is critical for the design of personalized treatments. Heterogeneity of leukaemic cells is determined by mutations which ultimately affect the cell cycle. We have developed and validated a biologically relevant, mathematical model of the cell cycle based on unique cell-cycle signatures, defined by duration of cell-cycle phases and cyclin profiles as determined by flow cytometry, for three leukaemia cell lines. The model was discretized for the different phases in their respective progress variables (cyclins and DNA), resulting in a set of time-dependent ordinary differential equations. Cell-cycle phase distribution and cyclin concentration profiles were validated against population chase experiments. Heterogeneity was simulated in culture by combining the three cell lines in a blinded experimental set-up. Based on individual kinetics, the model was capable of identifying and quantifying cellular heterogeneity. When supplying the initial conditions only, the model predicted future cell population dynamics and estimated the previous heterogeneous composition of cells. Identification of heterogeneous leukaemia clones at diagnosis and post-treatment using such a mathematical platform has the potential to predict multiple future outcomes in response to induction and consolidation chemotherapy as well as relapse kinetics.