State-of-the-art neural network-based methods for learning summary statistics have delivered promising results for simulation-based likelihood-free parameter inference. Existing approaches for learning summarizing networks are mainly based on deterministic neural networks, and do not take network prediction uncertainty into account. This work proposes a robust integrated approach that learns summary statistics using Bayesian neural networks, and produces a proposal posterior density using categorical distributions. An adaptive sampling scheme selects simulation locations to efficiently and iteratively refine the predictive proposal posterior of the network conditioned on observations. This allows for more efficient and robust convergence on comparatively large prior spaces. The approximated proposal posterior can then either be processed through a correction mechanism, or be used in conjunction with a density estimator to arrive at the true posterior. We demonstrate our approach on benchmark examples.

Identifying the reactions that govern a dynamical biological system is a crucial but challenging task in systems biology. In this work, we present a data-driven method to infer the underlying biochemical reaction system governing a set of observed species concentrations over time. We formulate the problem as a regression over a large, but limited, mass-action constrained reaction space and utilize sparse Bayesian inference via the regularized horseshoe prior to produce robust, interpretable biochemical reaction networks, along with uncertainty estimates of parameters. The resulting systems of chemical reactions and posteriors inform the biologist of potentially several reaction systems that can be further investigated. We demonstrate the method on two examples of recovering the dynamics of an unknown reaction system, to illustrate the benefits of improved accuracy and information obtained.

Approximate Bayesian Computation is widely used in systems biology for inferring parameters in stochastic gene regulatory network models. Its performance hinges critically on the ability to summarize high-dimensional system responses such as time series into a few informative, low-dimensional summary statistics. The quality of those statistics acutely impacts the accuracy of the inference task. Existing methods to select the best subset out of a pool of candidate statistics do not scale well with large pools of several tens to hundreds of candidate statistics. Since high quality statistics are imperative for good performance, this becomes a serious bottleneck when performing inference on complex and high-dimensional problems. This paper proposes a convolutional neural network architecture for automatically learning informative summary statistics of temporal responses. We show that the proposed network can effectively circumvent the statistics selection problem of the preprocessing step for ABC inference. The proposed approach is demonstrated on two benchmark problem and one challenging inference problem learning parameters in a high-dimensional stochastic genetic oscillator. We also study the impact of experimental design on network performance by comparing different data richness and data acquisition strategies.

SUMMARY: We present StochSS Live!, a web-based service for modeling, simulation and analysis of a wide range of mathematical, biological and biochemical systems. Using an epidemiological model of COVID-19, we demonstrate the power of StochSS Live! to enable researchers to quickly develop a deterministic or a discrete stochastic model, infer its parameters and analyze the results. AVAILABILITY AND IMPLEMENTATION: StochSS Live! is freely available at https://live.stochss.org/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SUMMARY: Discrete stochastic models of gene regulatory networks are fundamental tools for in silico study of stochastic gene regulatory networks. Likelihood-free inference and model exploration are critical applications to study a system using such models. However, the massive computational cost of complex, high-dimensional and stochastic modelling currently limits systematic investigation to relatively simple systems. Recently, machine-learning-assisted methods have shown great promise to handle larger, more complex models. To support both ease-of-use of this new class of methods, as well as their further development, we have developed the scalable inference, optimization and parameter exploration (Sciope) toolbox. Sciope is designed to support new algorithms for machine-learning-assisted model exploration and likelihood-free inference. Moreover, it is built ground up to easily leverage distributed and heterogeneous computational resources for convenient parallelism across platforms from workstations to clouds. AVAILABILITY AND IMPLEMENTATION: The Sciope Python3 toolbox is freely available on https://github.com/Sciope/Sciope, and has been tested on Linux, Windows and macOS platforms. SUPPLEMENTARY INFORMATION: Supplementary information is available at Bioinformatics online.

BACKGROUND: Approximate Bayesian Computation (ABC) has become a key tool for calibrating the parameters of discrete stochastic biochemical models. For higher dimensional models and data, its performance is strongly dependent on having a representative set of summary statistics. While regression-based methods have been demonstrated to allow for the automatic construction of effective summary statistics, their reliance on first simulating a large training set creates a significant overhead when applying these methods to discrete stochastic models for which simulation is relatively expensive. In this τ work, we present a method to reduce this computational burden by leveraging approximate simulators of these systems, such as ordinary differential equations and τ-Leaping approximations. RESULTS: We have developed an algorithm to accelerate the construction of regression-based summary statistics for Approximate Bayesian Computation by selectively using the faster approximate algorithms for simulations. By posing the problem as one of ratio estimation, we use state-of-the-art methods in machine learning to show that, in many cases, our algorithm can significantly reduce the number of simulations from the full resolution model at a minimal cost to accuracy and little additional tuning from the user. We demonstrate the usefulness and robustness of our method with four different experiments. CONCLUSIONS: We provide a novel algorithm for accelerating the construction of summary statistics for stochastic biochemical systems. Compared to the standard practice of exclusively training from exact simulator samples, our method is able to dramatically reduce the number of required calls to the stochastic simulator at a minimal loss in accuracy. This can immediately be implemented to increase the overall speed of the ABC workflow for estimating parameters in complex systems.

Top-K queries are an established heuristic in information retrieval. This paper presents an approach for optimal tiered storage allocation under stream processing workloads using this heuristic: those requiring the analysis of only the top-K ranked most relevant documents from a fixed-length stream, stream window, or batch job. Documents are ranked for relevance on a user-specified interestingness function, the top-K stored for further processing. This scenario bears similarity to the classic Secretary Hiring Problem (SHP), and the expected rate of document writes and document lifetime can be modelled as a function of document index. We present parameter-based algorithms for storage tier placement, minimizing document storage and transport costs. We derive expressions for optimal parameter values in terms of tier storage and transport costs a priori, without needing to monitor the application. This contrasts with (often complex) existing work on tiered storage optimization, which is either tightly coupled to specific use cases, or requires active monitoring of application IO load - ill-suited to long-running or one-off operations common in the scientific computing domain. We motivate and evaluate our model with a trace-driven simulation of human-in-the-loop bio-chemical model exploration, and two cloud storage case studies.

MOTIVATION: Discrete stochastic models of gene regulatory network models are indispensable tools for biological inquiry since they allow the modeler to predict how molecular interactions give rise to nonlinear system output. Model exploration with the objective of generating qualitative hypotheses about the workings of a pathway is usually the first step in the modeling process. It involves simulating the gene network model under a very large range of conditions, due to the large uncertainty in interactions and kinetic parameters. This makes model exploration highly computational demanding. Furthermore, with no prior information about the model behavior, labor-intensive manual inspection of very large amounts of simulation results becomes necessary. This limits systematic computational exploration to simplistic models. RESULTS: We have developed an interactive, smart workflow for model exploration based on semi-supervised learning and human-in-the-loop labeling of data. The workflow lets a modeler rapidly discover ranges of interesting behaviors predicted by the model. Utilizing that similar simulation output is in proximity of each other in a feature space, the modeler can focus on informing the system about what behaviors are more interesting than others by labeling, rather than analyzing simulation results with custom scripts and workflows. This results in a large reduction in time-consuming manual work by the modeler early in a modeling project, which can substantially reduce the time needed to go from an initial model to testable predictions and downstream analysis. AVAILABILITY AND IMPLEMENTATION: A python-package is available at https://github.com/Wrede/mio.git. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.