STEPS: Modeling and Simulating Complex Reaction-Diffusion Systems with Python

We describe how the use of the Python language improved the user interface of the program STEPS. STEPS is a simulation platform for modeling and stochastic simulation of coupled reaction-diffusion systems with complex 3-dimensional boundary conditions. Setting up such models is a complicated process that consists of many phases. Initial versions of STEPS relied on a static input format that did not cleanly separate these phases, limiting modelers in how they could control the simulation and becoming increasingly complex as new features and new simulation algorithms were added. We solved all of these problems by tightly integrating STEPS with Python, using SWIG to expose our existing simulation code

Decoupling Environment-Dependent and Independent Genetic Robustness across Bacterial Species

The evolutionary origins of genetic robustness are still under debate: it may arise as a consequence of requirements imposed by varying environmental conditions, due to intrinsic factors such as metabolic requirements, or directly due to an adaptive selection in favor of genes that allow a species to endure genetic perturbations. Stratifying the individual effects of each origin requires one to study the pertaining evolutionary forces across many species under diverse conditions. Here we conduct the first large-scale computational study charting the level of robustness of metabolic networks of hundreds of bacterial species across many simulated growth environments. We provide evidence that variations among species in their level of robustness reflect ecological adaptations. We decouple metabolic robustness into two components and quantify the extents of each: the first, environmental-dependent, is responsible for at least 20% of the non-essential reactions and its extent is associated with the species' lifestyle (specialized/generalist); the second, environmental-independent, is associated (correlation = ∼0.6) with the intrinsic metabolic capacities of a species—higher robustness is observed in fast growers or in organisms with an extensive production of secondary metabolites. Finally, we identify reactions that are uniquely susceptible to perturbations in human pathogens, potentially serving as novel drug-targets

A Computationally Stable Approach to Gaussian Process Interpolation of Deterministic Computer Simulation Data

For many expensive deterministic computer simulators, the outputs do not have replication error and the desired metamodel (or statistical emulator) is an interpolator of the observed data. Realizations of Gaussian spatial processes (GP) are commonly used to model such simulator outputs. Fitting a GP model to $n$ data points requires the computation of the inverse and determinant of $n \times n$ correlation matrices, $R$, that are sometimes computationally unstable due to near-singularity of $R$. This happens if any pair of design points are very close together in the input space. The popular approach to overcome near-singularity is to introduce a small nugget (or jitter) parameter in the model that is estimated along with other model parameters. The inclusion of a nugget in the model often causes unnecessary over-smoothing of the data. In this paper, we propose a lower bound on the nugget that minimizes the over-smoothing and an iterative regularization approach to construct a predictor that further improves the interpolation accuracy. We also show that the proposed predictor converges to the GP interpolator.Comment: 26 pages, 12 figure

An innovative approach for testing bioinformatics programs using metamorphic testing

Background: Recent advances in experimental and computational technologies have fueled the development of many sophisticated bioinformatics programs. The correctness of such programs is crucial as incorrectly computed results may lead to wrong biological conclusion or misguide downstream experimentation. Common software testing procedures involve executing the target program with a set of test inputs and then verifying the correctness of the test outputs. However, due to the complexity of many bioinformatics programs, it is often difficult to verify the correctness of the test outputs. Therefore our ability to perform systematic software testing is greatly hindered

Automated, Systematic and Parallel Approaches to Software Testing in Bioinformatics

Software quality assurance becomes especially critical if bioinformatics tools are to be used in a translational medical setting, such as analysis and interpretation of biological data. We must ensure that only validated algorithms are used, and that they are implemented correctly in the analysis pipeline – and not disrupted by hardware or software failure. In this thesis, I review common quality assurance practice and guidelines for bioinformatics software testing. Furthermore, I present a novel cloud-based framework to enable automated testing of genetic sequence alignment programs. This framework performs testing based on gold standard simulation data sets, and metamorphic testing. I demonstrate the effectiveness of this cloudbased framework using two widely used sequence alignment programs, BWA and Bowtie, and some fault-seeded ‘mutant’ versions of BWA and Bowtie. This preliminary study demonstrates that this type of cloud-based software testing framework is an effective and promising way to implement quality assurance in bioinformatics software that is used in genomic medicine

SBML Level 3: an extensible format for the exchange and reuse of biological models

Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reaction-based models and packages that extend the core with features suited to other model types including constraint-based models, reaction-diffusion models, logical network models, and rule-based models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single-cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution

Comparing simulation results of SBML capable simulators

Motivation: Simulations are an essential tool when analyzing biochemical networks. Researchers and developers seeking to refine simulation tools or develop new ones would benefit greatly from being able to compare their simulation results