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Sensitivity analysis of discrete stochastic systems.

Sensitivity analysis quantifies the dependence of system behavior on the parameters that affect the process dynamics. Classical sensitivity analysis, however, does not directly apply to discrete stochastic dynamical systems, which have recently gained popularity because of its relevance in the simulation of biological processes. In this work, sensitivity analysis for discrete stochastic processes is developed based on density function (distribution) sensitivity, using an analog of the classical sensitivity and the Fisher Information Matrix. There exist many circumstances, such as in systems with multistability, in which the stochastic effects become nontrivial and classical sensitivity analysis on the deterministic representation of a system cannot adequately capture the true system behavior. The proposed analysis is applied to a bistable chemical system--the Schlögl model, and to a synthetic genetic toggle-switch model. Comparisons between the stochastic and deterministic analyses show the significance of explicit consideration of the probabilistic nature in the sensitivity analysis for this class of processes.

Algorithms↗

Unifying evolutionary dynamics: from individual stochastic processes to macroscopic models.

A distinctive signature of living systems is Darwinian evolution, that is, a propensity to generate as well as self-select individual diversity. To capture this essential feature of life while describing the dynamics of populations, mathematical models must be rooted in the microscopic, stochastic description of discrete individuals characterized by one or several adaptive traits and interacting with each other. The simplest models assume asexual reproduction and haploid genetics: an offspring usually inherits the trait values of her progenitor, except when a mutation causes the offspring to take a mutation step to new trait values; selection follows from ecological interactions among individuals. Here we present a rigorous construction of the microscopic population process that captures the probabilistic dynamics over continuous time of birth, mutation, and death, as influenced by the trait values of each individual, and interactions between individuals. A by-product of this formal construction is a general algorithm for efficient numerical simulation of the individual-level model. Once the microscopic process is in place, we derive different macroscopic models of adaptive evolution. These models differ in the renormalization they assume, i.e. in the limits taken, in specific orders, on population size, mutation rate, mutation step, while rescaling time accordingly. The macroscopic models also differ in their mathematical nature: deterministic, in the form of ordinary, integro-, or partial differential equations, or probabilistic, like stochastic partial differential equations or superprocesses. These models include extensions of Kimura's equation (and of its approximation for small mutation effects) to frequency- and density-dependent selection. A novel class of macroscopic models obtains when assuming that individual birth and death occur on a short timescale compared with the timescale of typical population growth. On a timescale of very rare mutations, we establish rigorously the models of "trait substitution sequences" and their approximation known as the "canonical equation of adaptive dynamics". We extend these models to account for mutation bias and random drift between multiple evolutionary attractors. The renormalization approach used in this study also opens promising avenues to study and predict patterns of life-history allometries, thereby bridging individual physiology, genetic variation, and ecological interactions in a common evolutionary framework.

Algorithms↗

A dynamic conditional random field model for foreground and shadow segmentation.

This paper proposes a dynamic conditional random field (DCRF) model for foreground object and moving shadow segmentation in indoor video scenes. Given an image sequence, temporal dependencies of consecutive segmentation fields and spatial dependencies within each segmentation field are unified by a dynamic probabilistic framework based on the conditional random field (CRF). An efficient approximate filtering algorithm is derived for the DCRF model to recursively estimate the segmentation field from the history of observed images. The foreground and shadow segmentation method integrates both intensity and gradient features. Moreover, models of background, shadow, and gradient information are updated adaptively for nonstationary background processes. Experimental results show that the proposed approach can accurately detect moving objects and their cast shadows even in monocular grayscale video sequences.

Algorithms↗

Graphical-Model-based Morphometric Analysis.

We propose a novel method for voxel-based morphometry (VBM), which we call Graphical-Model-based Morphometric Analysis (GAMMA), to identify morphological abnormalities automatically, and to find complex probabilistic associations among voxels in magnetic-resonance images and clinical variables. GAMMA is a fully automatic, nonparametric morphometric-analysis algorithm, with high sensitivity and specificity. It uses a Bayesian network to represent the associations among voxels and the function variable, and uses a contextual-clustering method based on a Markov random field to find clusters in which all voxels have similar associations with the function variable. We use loopy belief propagation to infer the unobserved label field and belief map. As opposed to voxel-based morphometric methods based on general linear models, GAMMA is capable of identifying nonlinear associations among the function variable and voxels. Compared with our previous approach, a Bayesian morphometry algorithm, GAMMA has greater sensitivity, specificity, and computational efficiency.

Algorithms↗

Optimization of the kernel functions in a probabilistic neural network analyzing the local pattern distribution.

This article proposes a procedure for the automatic determination of the elements of the covariance matrix of the gaussian kernel function of probabilistic neural networks. Two matrices, a rotation matrix and a matrix of variances, can be calculated by analyzing the local environment of each training pattern. The combination of them will form the covariance matrix of each training pattern. This automation has two advantages: First, it will free the neural network designer from indicating the complete covariance matrix, and second, it will result in a network with better generalization ability than the original model. A variation of the famous two-spiral problem and real-world examples from the UCI Machine Learning Repository will show a classification rate not only better than the original probabilistic neural network but also that this model can outperform other well-known classification techniques.

Neural Networks, Computer↗

Downscaling climate change scenarios in an urban land use change model.

The objective of this paper is to describe the process through which climate change scenarios were downscaled in an urban land use model and the results of this experimentation. The land use models (Urban Growth Model [UGM] and the Land Cover Deltatron Model [LCDM]) utilized in the project are part of the SLEUTH program which uses a probabilistic cellular automata protocol. The land use change scenario experiments were developed for the 31-county New York Metropolitan Region (NYMR) of the US Mid-Atlantic Region. The Intergovernmental Panel on Climate Change (IPCC), regional greenhouse gas (GHG) emissions scenarios (Special Report on Emissions Scenarios (SRES) A2 and B2 scenarios) were used to define the narrative scenario conditions of future land use change. The specific research objectives of the land use modeling work involving the SLEUTH program were threefold: (1) Define the projected conversion probabilities and the amount of rural-to-urban land use change for the NYMR as derived by the UGM and LCDM for the years 2020 and 2050, as defined by the pattern of growth for the years 1960-1990; (2) Down-scale the IPCC SRES A2 and B2 scenarios as a narrative that could be translated into alternative growth projections; and, (3) Create two alternative future growth scenarios: A2 scenario which will be associated with more rapid land conversion than found in initial projections, and a B2 scenario which will be associated with a slower level of land conversion. The results of the modeling experiments successfully illustrate the spectrum of possible land use/land cover change scenarios for the years 2020 and 2050. The application of these results into the broader scale climate and health impact study is discussed, as is the general role of land use/land cover change models in climate change studies and associated environmental management strategies.

Cities↗

Bayesian inference and attentional modulation in the visual cortex.

The responses of neurons in cortical areas V2 and V4 can be significantly modulated by attention to particular locations within an input image. We show that such effects emerge naturally when perception is viewed as a probabilistic inference process governed by Bayesian principles and implemented in hierarchical cortical networks. The proposed model can explain a rich variety of attention-related responses in cortical area V4 including multiplicative modulation of tuning curves, restoration of neural responses in the presence of distracting stimuli, and influence of attention on neighboring unattended locations. Our results suggest a new interpretation of attention as a cortical mechanism for reducing perceptual uncertainty by combining top-down task-relevant information with bottom-up sensory inputs in a probabilistic manner.

Animals↗

Verification of the optimal probabilistic basis of aural processing in pitch of complex tones.

Periodicity pitch for complex tones has been quantitatively accounted for by a two-stage process of Fourier-frequency analysis subject to random errors and significant nonlinearities, followed by an harmonic pattern recognizer that makes an optimum probabilistic estimate of the fundamental period of musical and speech sounds. The theory predicts that periodicity pitch is a multimodal probabilistic function of a given stimulus. A clear and empirically supported distinction is made between limitations on the pitch mechanism caused by the stochastic nature of aural frequency representation and by the deterministic resolution bandwidths of aural frequency analysis. This model was developed earlier [J. L. Goldstein, J. Acoust. Soc. Am 54, 1496-1516 (1973)] to account for probabilistic data on pitch errors [A. J. M. Houtsma and J. L. Goldstein, J. Acoust. Soc. Am. 51, 520 (1972)] measured with periodic stimuli comprising two successive harmonics. This paper presents new predictions by the theory that were calculated, with computer simulation where needed, for known probabilistic pitch data from stimuli comprising three to six successive harmonics. Predicted pitch errors increase with increasing errors in estimating the frequencies of stimulus harmonics and decrease as more harmonics are added to the stimulus. Optimum processor theory fully accounts for the multicomponent pitch data on the basis of similar errors in estimating component stimulus frequencies as reported earlier, thus providing further evidence for the optimum probabilistic basis of aural signal processing in pitch of complex tones.

Auditory Cortex↗

Probabilistic approaches to fault detection in networked discrete event systems.

In this paper, we consider distributed systems that can be modeled as finite state machines with known behavior under fault-free conditions, and we study the detection of a general class of faults that manifest themselves as permanent changes in the next-state transition functionality of the system. This scenario could arise in a variety of situations encountered in communication networks, including faults occurred due to design or implementation errors during the execution of communication protocols. In our approach, fault diagnosis is performed by an external observer/diagnoser that functions as a finite state machine and which has access to the input sequence applied to the system but has only limited access to the system state or output. In particular, we assume that the observer/diagnoser is only able to obtain partial information regarding the state of the given system at intermittent time intervals that are determined by certain synchronizing conditions between the system and the observer/diagnoser. By adopting a probabilistic framework, we analyze ways to optimally choose these synchronizing conditions and develop adaptive strategies that achieve a low probability of aliasing, i.e., a low probability that the external observer/diagnoser incorrectly declares the system as fault-free. An application of these ideas in the context of protocol testing/classification is provided as an example.

Algorithms↗

Probabilistic inference in human semantic memory.

The idea of viewing human cognition as a rational solution to computational problems posed by the environment has influenced several recent theories of human memory. The first rational models of memory demonstrated that human memory seems to be remarkably well adapted to environmental statistics but made only minimal assumptions about the form of the environmental information represented in memory. Recently, several probabilistic methods for representing the latent semantic structure of language have been developed, drawing on research in computer science, statistics and computational linguistics. These methods provide a means of extending rational models of memory retrieval to linguistic stimuli, and a way to explore the influence of the statistics of language on human memory.

Association Learning↗

A regularized discriminative model for the prediction of protein-peptide interactions.

MOTIVATION: Short well-defined domains known as peptide recognition modules (PRMs) regulate many important protein-protein interactions involved in the formation of macromolecular complexes and biochemical pathways. Since high-throughput experiments like yeast two-hybrid and phage display are expensive and intrinsically noisy, it would be desirable to more specifically target or partially bypass them with complementary in silico approaches. In the present paper, we present a probabilistic discriminative approach to predicting PRM-mediated protein-protein interactions from sequence data. The model is motivated by the discriminative model of Segal and Sharan as an alternative to the generative approach of Reiss and Schwikowski. In our evaluation, we focus on predicting the interaction network. As proposed by Williams, we overcome the problem of susceptibility to over-fitting by adopting a Bayesian a posteriori approach based on a Laplacian prior in parameter space. RESULTS: The proposed method was tested on two datasets of protein-protein interactions involving 28 SH3 domain proteins in Saccharmomyces cerevisiae, where the datasets were obtained with different experimental techniques. The predictions were evaluated with out-of-sample receiver operator characteristic (ROC) curves. In both cases, Laplacian regularization turned out to be crucial for achieving a reasonable generalization performance. The Laplacian-regularized discriminative model outperformed the generative model of Reiss and Schwikowski in terms of the area under the ROC curve on both datasets. The performance was further improved with a hybrid approach, in which our model was initialized with the motifs obtained with the method of Reiss and Schwikowski. AVAILABILITY: Software and supplementary material is available from http://lehrach.com/wolfgang/dmf.

Algorithms↗

Identifying sequence regions undergoing conformational change via predicted continuum secondary structure.

MOTIVATION: Conformational flexibility is essential to the function of many proteins, e.g. catalytic activity. To assist efforts in determining and exploring the functional properties of a protein, it is desirable to automatically identify regions that are prone to undergo conformational changes. It was recently shown that a probabilistic predictor of continuum secondary structure is more accurate than categorical predictors for structurally ambivalent sequence regions, suggesting that such models are suited to characterize protein flexibility. RESULTS: We develop a computational method for identifying regions that are prone to conformational change directly from the amino acid sequence. The method uses the entropy of the probabilistic output of an 8-class continuum secondary structure predictor. Results for 171 unique amino acid sequences with well-characterized variable structure (identified in the 'Macromolecular movements database') indicate that the method is highly sensitive at identifying flexible protein regions, but false positives remain a problem. The method can be used to explore conformational flexibility of proteins (including hypothetical or synthetic ones) whose structure is yet to be determined experimentally. AVAILABILITY: The predictor, sequence data and supplementary studies are available at http://pprowler.itee.uq.edu.au/sspred/ and are free for academic use.

Algorithms↗

Metabonomic characterization of genetic variations in toxicological and metabolic responses using probabilistic neural networks.

Current emphasis on efficient screening of novel therapeutic agents in toxicological studies has resulted in the evaluation of novel analytical technologies, including genomic (transcriptomic) and proteomic approaches. We have shown that high-resolution 1H NMR spectroscopy of biofluids and tissues coupled with appropriate chemometric analysis can also provide complementary data for use in in vivo toxicological screening of drugs. Metabonomics concerns the quantitative analysis of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification [Nicholson, J. K., Lindon, J. C., and Holmes, E. (1999) Xenobiotica 11, 1181-1189]. In this study, we have used 1H NMR spectroscopy to characterize the time-related changes in the urinary metabolite profiles of laboratory rats treated with 13 model toxins and drugs which predominantly target liver or kidney. These 1H NMR spectra were data-reduced and subsequently analyzed using a probabilistic neural network (PNN) approach. The methods encompassed a database of 1310 samples, of which 583 comprised a training set for the neural network, with the remaining 727 (independent cases) employed as a test set for validation. Using these techniques, the 13 classes of toxicity, together with the variations associated with strain, were distinguishable to >90%. Analysis of the 1H NMR spectral data by multilayer perceptron networks and principal components analysis gave a similar but less accurate classification than PNN analysis. This study has highlighted the value of probabilistic neural networks in developing accurate NMR-based metabonomic models for the prediction of xenobiotic-induced toxicity in experimental animals and indicates possible future uses in accelerated drug discovery programs. Furthermore, the sensitivity of this tool to strain differences may prove to be useful in investigating the genetic variation of metabolic responses and for assessing the validity of specific animal models.

Animals↗

A probabilistic rule-based expert system.

This paper explores a medical expert system combining techniques of Bayesian network modelling with ideas of weighted inference rules. The weights of the individual rules can be estimated objectively from a training set of actual cases; and they can be used in a Monte Carlo stimulation to estimate objectively conditional probabilities of diagnosis given particular combinations of symptoms. The paper describes and evaluates a medical expert system built according to this design. The diagnostic accuracy of the program was found to be similar to that obtained through the usual application of Bayes theorem with the assumption of conditional independence of symptoms given disease, even though the Bayesian classifier has more than 70 times as many numerical parameters. The method may be promising in cases where small training sets do not permit accurate estimation of large numbers of parameters.

Abdominal Pain↗

TigrScan and GlimmerHMM: two open source ab initio eukaryotic gene-finders.

UNLABELLED: We describe two new Generalized Hidden Markov Model implementations for ab initio eukaryotic gene prediction. The C/C++ source code for both is available as open source and is highly reusable due to their modular and extensible architectures. Unlike most of the currently available gene-finders, the programs are re-trainable by the end user. They are also re-configurable and include several types of probabilistic submodels which can be independently combined, such as Maximal Dependence Decomposition trees and interpolated Markov models. Both programs have been used at TIGR for the annotation of the Aspergillus fumigatus and Toxoplasma gondii genomes. AVAILABILITY: Source code and documentation are available under the open source Artistic License from http://www.tigr.org/software/pirate

Algorithms↗

On an interacting particle system modeling an epidemic.

We consider an interacting particle system on Zd to model an epidemic. Each site of Zd can be in either one of three states: empty, healthy or infected. Healthy and infected individuals give birth at different rates to healthy individuals on empty sites. Healthy individuals get infected by infected individuals. Infected and healthy individuals die at different rates. We prove that in dimension 1 and with nearest-neighbor interactions the epidemic may persist forever if and only if the rate at which infected individuals give birth to healthy individuals is high enough. This is in sharp contrast with models analysed by Andjel and Schinazi (1994) and Sato et al. (1994) where infected individuals do not give birth. We also show that some results in the latter reference can be obtained easily and rigorously using probabilistic coupling to the contact process.

Disease Outbreaks↗

On parameter estimation of chaotic systems via symbolic time-series analysis.

Symbolic time-series analysis is used for estimating the parameters of chaotic systems. It is assumed that a "target model" (i.e., a discrete- or continuous-time description of the data-generating mechanism) is available, but with unknown parameters. A time series, i.e., a noisy, finite sequence of a measured (output) variable, is given. The proposed method first prescribes to symbolize the time series, i.e., to transform it into a sequence of symbols, from which the statistics of symbols are readily derived. Then, a symbolic model (in the form of a Markov chain) is derived from the data. It allows one to predict, in a probabilistic fashion, the time evolution of the symbol sequence. The unknown parameters are derived by matching either the statistics of symbols, or the symbolic prediction derived from data, with those generated by the (parametrized) target model. Three examples of application (the Henon map, a population model, and the Duffing system) prove that satisfactory results can be obtained even with short time series.

Algorithms↗

Duplication models for biological networks.

Are biological networks different from other large complex networks? Both large biological and nonbiological networks exhibit power-law graphs (number of nodes with degree k, N(k) approximately k(-beta)), yet the exponents, beta, fall into different ranges. This may be because duplication of the information in the genome is a dominant evolutionary force in shaping biological networks (like gene regulatory networks and protein-protein interaction networks) and is fundamentally different from the mechanisms thought to dominate the growth of most nonbiological networks (such as the Internet). The preferential choice models used for nonbiological networks like web graphs can only produce power-law graphs with exponents greater than 2. We use combinatorial probabilistic methods to examine the evolution of graphs by node duplication processes and derive exact analytical relationships between the exponent of the power law and the parameters of the model. Both full duplication of nodes (with all their connections) as well as partial duplication (with only some connections) are analyzed. We demonstrate that partial duplication can produce power-law graphs with exponents less than 2, consistent with current data on biological networks. The power-law exponent for large graphs depends only on the growth process, not on the starting graph.

Internet↗