Allen Holder

A Spectral Approach to Protein Structure Alignment

A new intrinsic geometry based on a spectral analysis is used to motivate methods for aligning protein folds. The geometry is induced by the fact that a distance matrix can be scaled so that its eigenvalues are positive. We provide a mathematically rigorous development of the intrinsic geometry underlying our spectral approach and use it to motivate two alignment algorithms. The first uses eigenvalues alone and dynamic programming to quickly compute a fold alignment. Family identification results are reported for the Skolnick40 and Proteus300 data sets. The second algorithm extends our spectral method by iterating between our intrinsic geometry and the 3D geometry of a fold to make high-quality alignments. Results and comparisons are reported for several difficult fold alignments. The second algorithms ability to correctly identify fold families in the Skolnick40 and Proteus300 data sets is also established.

Do genome-scale models need exact solvers or clearer standards?

Constraint‐based analysis of genome‐scale models (GEMs) arose shortly after the first genome sequences became available. As numerous reviews of the field show, this approach and methodology has proven to be successful in studying a wide range of biological phenomena (McCloskey et al, 2013; Bordbar et al, 2014). However, efforts to expand the user base are impeded by hurdles in correctly formulating these problems to obtain numerical solutions. In particular, in a study entitled “An exact arithmetic toolbox for a consistent and reproducible structural analysis of metabolic network models” (Chindelevitch et al, 2014), the authors apply an exact solver to 88 genome‐scale constraint‐based models of metabolism. The authors claim that COBRA calculations (Orth et al, 2010) are inconsistent with their results and that many published and actively used (Lee et al, 2007; McCloskey et al, 2013) genome‐scale models do support cellular growth in existing studies only because of numerical errors. They base these broad claims on two observations: (i) three reconstructions (iAF1260, iIT341, and iNJ661) compute feasibly in COBRA, but are infeasible when exact numerical algorithms are used by their software (entitled MONGOOSE); (ii) linear programs generated by MONGOOSE for iIT341 were submitted to the NEOS Server (a Web site that runs linear programs through various solvers) and gave inconsistent results. They further claim that a large percentage of these COBRA models are actually unable to produce biomass flux. Here, we demonstrate that the claims made by Chindelevitch et al (2014) stem from an incorrect parsing of models from files rather than actual problems with numerical error or COBRA computations.

Fast and robust techniques for the euclidean p-median problem with uniform weights

We discuss new solution techniques for the p-median problem, with the goal being to improve the solution time and quality of current techniques. In particular, we hybridize the discrete Lloyd algorithm and the vertex substitution heuristic. We also compare three starting point techniques and present a new solution method that provides consistently good results when appropriately initialized.

Fast protein structure alignment

We address the problem of aligning the 3D structures of two proteins. Our pairwise comparisons are based on a new optimization model that is succinctly expressed in terms of linear transformations and highlights the problems intrinsic geometry. The optimization problem is approximately solved with a new polynomial time algorithm. The worst-case analysis of the algorithm shows that the solution is bounded by a constant depending on the data of the problem.

Uncertain Data Envelopment Analysis

Abstract Data Envelopment Analysis (DEA) is a nonparametric, data driven method to conduct relative performance measurements among a set of decision making units (DMUs). Efficiency scores are computed based on assessing input and output data for each DMU by means of linear programming. Traditionally, these data are assumed to be known precisely. We instead consider the situation in which data is uncertain, and in this case, we demonstrate that efficiency scores increase monotonically with uncertainty. This enables inefficient DMUs to leverage uncertainty to counter their assessment of being inefficient. Using the framework of robust optimization, we propose an uncertain DEA (uDEA) model for which an optimal solution determines (1) the maximum possible efficiency score of a DMU over all permissible uncertainties, and (2) the minimal amount of uncertainty that is required to achieve this efficiency score. We show that the uDEA model is a proper generalization of traditional DEA and provide a first-order algorithm to solve the uDEA model with ellipsoidal uncertainty sets. Finally, we present a case study applying uDEA to the problem of deciding efficiency of radiotherapy treatments.

Dynamic programming used to align protein structures with a spectrum is robust.

Several efficient algorithms to conduct pairwise comparisons among large databases of protein structures have emerged in the recent literature. The central theme is the design of a measure between the Cα atoms of two protein chains, from which dynamic programming is used to compute an alignment. The efficiency and efficacy of these algorithms allows large-scale computational studies that would have been previously impractical. The computational study herein shows that the structural alignment algorithm eigen-decomposition alignment with the spectrum (EIGAs) is robust against both parametric and structural variation.

Recommendations for an Undergraduate Curriculum at the Interface of Operations Research and Computer Science

In March 2007, the INFORMS Computing Society formed the ICS Education Committee, charged with outlining an undergraduate curriculum that would prepare students for graduate study and/or industrial work at the interface of operations research and computer science. The result is a set of essential and recommended skills that undergraduate students should seek to acquire in order to be successful in such endeavors. This article presents the findings of the committee.

A Decomposition of the Pure Parsimony Haplotyping Problem

We partially order a collection of genotypes so that we can represent the NP-Hard problem of inferring the least number of haplotypes in terms of substructures we call g-lattices. This representation allows us to prove that the problem can be solved efficiently if the genotypes partition into chains with certain structure. Even without the specified structure, the decomposition shows how to separate the underlying integer programming model into smaller models.

Robust Analysis of Fluxes in Genome-Scale Metabolic Pathways

Constraint-based optimization, such as flux balance analysis (FBA), has become a standard systems-biology computational method to study cellular metabolisms that are assumed to be in a steady state of optimal growth. The methods are based on optimization while assuming (i) equilibrium of a linear system of ordinary differential equations, and (ii) deterministic data. However, the steady-state assumption is biologically imperfect, and several key stoichiometric coefficients are experimentally inferred from situations of inherent variation. We propose an approach that explicitly acknowledges heterogeneity and conducts a robust analysis of metabolic pathways (RAMP). The basic assumption of steady state is relaxed, and we model the innate heterogeneity of cells probabilistically. Our mathematical study of the stochastic problem shows that FBA is a limiting case of our RAMP method. Moreover, RAMP has the properties that: A) metabolic states are (Lipschitz) continuous with regards to the probabilistic modeling parameters, B) convergent metabolic states are solutions to the deterministic FBA paradigm as the stochastic elements dissipate, and C) RAMP can identify biologically tolerable diversity of a metabolic network in an optimized culture. We benchmark RAMP against traditional FBA on genome-scale metabolic reconstructed models of E. coli, calculating essential genes and comparing with experimental flux data.