A graphical method for reducing and relating models in systems biology

Motivation: In Systems Biology, an increasing collection of models of various biological processes is currently developed and made available in publicly accessible repositories, such as biomodels.net for instance, through common exchange formats such as SBML. To date, however, there is no general method to relate different models to each other by abstraction or reduction relationships, and this task is left to the modeler for re-using and coupling models. In mathematical biology, model reduction techniques have been studied for a long time, mainly in the case where a model exhibits different time scales, or different spatial phases, which can be analyzed separately. These techniques are however far too restrictive to be applied on a large scale in systems biology, and do not take into account abstractions other than time or phase decompositions. Our purpose here is to propose a general computational method for relating models together, by considering primarily the structure of the interactions and abstracting from their dynamics in a first step

Computational Cancer Biology: An Evolutionary Perspective

ISSN:1553-734XISSN:1553-735

Current advances in systems and integrative biology

Systems biology has gained a tremendous amount of interest in the last few years. This is partly due to the realization that traditional approaches focusing only on a few molecules at a time cannot describe the impact of aberrant or modulated molecular environments across a whole system. Furthermore, a hypothesis-driven study aims to prove or disprove its postulations, whereas a hypothesis-free systems approach can yield an unbiased and novel testable hypothesis as an end-result. This latter approach foregoes assumptions which predict how a biological system should react to an altered microenvironment within a cellular context, across a tissue or impacting on distant organs. Additionally, re-use of existing data by systematic data mining and re-stratification, one of the cornerstones of integrative systems biology, is also gaining attention. While tremendous efforts using a systems methodology have already yielded excellent results, it is apparent that a lack of suitable analytic tools and purpose-built databases poses a major bottleneck in applying a systematic workflow. This review addresses the current approaches used in systems analysis and obstacles often encountered in large-scale data analysis and integration which tend to go unnoticed, but have a direct impact on the final outcome of a systems approach. Its wide applicability, ranging from basic research, disease descriptors, pharmacological studies, to personalized medicine, makes this emerging approach well suited to address biological and medical questions where conventional methods are not ideal

MCMC Methods for Multi-Response Generalized Linear Mixed Models: The MCMCglmm R Package

Generalized linear mixed models provide a flexible framework for modeling a range of data, although with non-Gaussian response variables the likelihood cannot be obtained in closed form. Markov chain Monte Carlo methods solve this problem by sampling from a series of simpler conditional distributions that can be evaluated. The R package MCMCglmm implements such an algorithm for a range of model fitting problems. More than one response variable can be analyzed simultaneously, and these variables are allowed to follow Gaussian, Poisson, multi(bi)nominal, exponential, zero-inflated and censored distributions. A range of variance structures are permitted for the random effects, including interactions with categorical or continuous variables (i.e., random regression), and more complicated variance structures that arise through shared ancestry, either through a pedigree or through a phylogeny. Missing values are permitted in the response variable(s) and data can be known up to some level of measurement error as in meta-analysis. All simu- lation is done in C/ C++ using the CSparse library for sparse linear systems.

Ranking relations using analogies in biological and information networks

Analogical reasoning depends fundamentally on the ability to learn and generalize about relations between objects. We develop an approach to relational learning which, given a set of pairs of objects $\mathbf{S}=\{A^{(1)}:B^{(1)},A^{(2)}:B^{(2)},\ldots,A^{(N)}:B ^{(N)}\}$, measures how well other pairs A:B fit in with the set $\mathbf{S}$. Our work addresses the following question: is the relation between objects A and B analogous to those relations found in $\mathbf{S}$? Such questions are particularly relevant in information retrieval, where an investigator might want to search for analogous pairs of objects that match the query set of interest. There are many ways in which objects can be related, making the task of measuring analogies very challenging. Our approach combines a similarity measure on function spaces with Bayesian analysis to produce a ranking. It requires data containing features of the objects of interest and a link matrix specifying which relationships exist; no further attributes of such relationships are necessary. We illustrate the potential of our method on text analysis and information networks. An application on discovering functional interactions between pairs of proteins is discussed in detail, where we show that our approach can work in practice even if a small set of protein pairs is provided.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS321 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

A Likelihood-Free Inference Framework for Population Genetic Data using Exchangeable Neural Networks

An explosion of high-throughput DNA sequencing in the past decade has led to a surge of interest in population-scale inference with whole-genome data. Recent work in population genetics has centered on designing inference methods for relatively simple model classes, and few scalable general-purpose inference techniques exist for more realistic, complex models. To achieve this, two inferential challenges need to be addressed: (1) population data are exchangeable, calling for methods that efficiently exploit the symmetries of the data, and (2) computing likelihoods is intractable as it requires integrating over a set of correlated, extremely high-dimensional latent variables. These challenges are traditionally tackled by likelihood-free methods that use scientific simulators to generate datasets and reduce them to hand-designed, permutation-invariant summary statistics, often leading to inaccurate inference. In this work, we develop an exchangeable neural network that performs summary statistic-free, likelihood-free inference. Our framework can be applied in a black-box fashion across a variety of simulation-based tasks, both within and outside biology. We demonstrate the power of our approach on the recombination hotspot testing problem, outperforming the state-of-the-art.Comment: 9 pages, 8 figure

The Epitheliome: agent-based modelling of the social behaviour of cells

We have developed a new computational modelling paradigm for predicting the emergent behaviour resulting from the interaction of cells in epithelial tissue. As proof-of-concept, an agent-based model, in which there is a one-to-one correspondence between biological cells and software agents, has been coupled to a simple physical model. Behaviour of the computational model is compared with the growth characteristics of epithelial cells in monolayer culture, using growth media with low and physiological calcium concentrations. Results show a qualitative fit between the growth characteristics produced by the simulation and the in vitro cell models