Despite medical advances, the emergence and re-emergence of infectious diseases continue to pose a public health threat. Low-dimensional epidemiological models predict that epidemic transitions are preceded by the phenomenon of critical slowing down (CSD). This has raised the possibility of anticipating disease (re-)emergence using CSD-based early-warning signals (EWS), which are statistical moments estimated from time series data. For EWS to be useful at detecting future (re-)emergence, CSD needs to be a generic (model-independent) feature of epidemiological dynamics irrespective of system complexity. Currently, it is unclear whether the predictions of CSD-derived from simple, low-dimensional systems-pertain to real systems, which are high-dimensional. To assess the generality of CSD, we carried out a simulation study of a hierarchy of models, with increasing structural complexity and dimensionality, for a measles-like infectious disease. Our five models included: i) a nonseasonal homogeneous Susceptible-Exposed-Infectious-Recovered (SEIR) model, ii) a homogeneous SEIR model with seasonality in transmission, iii) an age-structured SEIR model, iv) a multiplex network-based model (Mplex) and v) an agent-based simulator (FRED). All models were parameterised to have a herd-immunity immunization threshold of around 90% coverage, and underwent a linear decrease in vaccine uptake, from 92% to 70% over 15 years. We found evidence of CSD prior to disease re-emergence in all models. We also evaluated the performance of seven EWS: the autocorrelation, coefficient of variation, index of dispersion, kurtosis, mean, skewness, variance. Performance was scored using the Area Under the ROC Curve (AUC) statistic. The best performing EWS were the mean and variance, with AUC > 0.75 one year before the estimated transition time. These two, along with the autocorrelation and index of dispersion, are promising candidate EWS for detecting disease emergence.

Large-scale simulations are increasingly used to evaluate potential public health interventions in epidemics such as the H1N1 pandemic of 2009. Due to variations in both disease scenarios and in interventions, it is typical to run thousands of simulations as part of a given study. This paper addresses the challenge of visualizing the results from a large number of simulation runs. We describe a new tool called FRED Navigator that allows a user to interactively visualize results from the FRED agent-based modeling system.

BACKGROUND: Single nucleotide polymorphisms (SNP) constitute more than 90% of the genetic variation, and hence can account for most trait differences among individuals in a given species. Polymorphism detection software PolyBayes and PolyPhred give high false positive SNP predictions even with stringent parameter values. We developed a machine learning (ML) method to augment PolyBayes to improve its prediction accuracy. ML methods have also been successfully applied to other bioinformatics problems in predicting genes, promoters, transcription factor binding sites and protein structures. RESULTS: The ML program C4.5 was applied to a set of features in order to build a SNP classifier from training data based on human expert decisions (True/False). The training data were 27,275 candidate SNP generated by sequencing 1973 STS (sequence tag sites) (12 Mb) in both directions from 6 diverse homozygous soybean cultivars and PolyBayes analysis. Test data of 18,390 candidate SNP were generated similarly from 1359 additional STS (8 Mb). SNP from both sets were classified by experts. After training the ML classifier, it agreed with the experts on 97.3% of test data compared with 7.8% agreement between PolyBayes and experts. The PolyBayes positive predictive values (PPV) (i.e., fraction of candidate SNP being real) were 7.8% for all predictions and 16.7% for those with 100% posterior probability of being real. Using ML improved the PPV to 84.8%, a 5- to 10-fold increase. While both ML and PolyBayes produced a similar number of true positives, the ML program generated only 249 false positives as compared to 16,955 for PolyBayes. The complexity of the soybean genome may have contributed to high false SNP predictions by PolyBayes and hence results may differ for other genomes. CONCLUSION: A machine learning (ML) method was developed as a supplementary feature to the polymorphism detection software for improving prediction accuracies. The results from this study indicate that a trained ML classifier can significantly reduce human intervention and in this case achieved a 5-10 fold enhanced productivity. The optimized feature set and ML framework can also be applied to all polymorphism discovery software. ML support software is written in Perl and can be easily integrated into an existing SNP discovery pipeline.

BACKGROUND: Single nucleotide polymorphisms (SNPs) as defined here are single base sequence changes or short insertion/deletions between or within individuals of a given species. As a result of their abundance and the availability of high throughput analysis technologies SNP markers have begun to replace other traditional markers such as restriction fragment length polymorphisms (RFLPs), amplified fragment length polymorphisms (AFLPs) and simple sequence repeats (SSRs or microsatellite) markers for fine mapping and association studies in several species. For SNP discovery from chromatogram data, several bioinformatics programs have to be combined to generate an analysis pipeline. Results have to be stored in a relational database to facilitate interrogation through queries or to generate data for further analyses such as determination of linkage disequilibrium and identification of common haplotypes. Although these tasks are routinely performed by several groups, an integrated open source SNP discovery pipeline that can be easily adapted by new groups interested in SNP marker development is currently unavailable. RESULTS: We developed SNP-PHAGE (SNP discovery Pipeline with additional features for identification of common haplotypes within a sequence tagged site (Haplotype Analysis) and GenBank (-dbSNP) submissions. This tool was applied for analyzing sequence traces from diverse soybean genotypes to discover over 10,000 SNPs. This package was developed on UNIX/Linux platform, written in Perl and uses a MySQL database. Scripts to generate a user-friendly web interface are also provided with common queries for preliminary data analysis. A machine learning tool developed by this group for increasing the efficiency of SNP discovery is integrated as a part of this package as an optional feature. The SNP-PHAGE package is being made available open source at http://bfgl.anri.barc.usda.gov/ML/snp-phage/. CONCLUSION: SNP-PHAGE provides a bioinformatics solution for high throughput SNP discovery, identification of common haplotypes within an amplicon, and GenBank (dbSNP) submissions. SNP selection and visualization are aided through a user-friendly web interface. This tool is useful for analyzing sequence tagged sites (STSs) of genomic sequences, and this software can serve as a starting point for groups interested in developing SNP markers.

This paper offers a novel approach to coevolution based on the sociological theory of symbolic interactionism. It provides a multi-agent computational model along with experimental results that suggest improved fitness, robustness, and knowledge due to emergent symbol systems. The main contribution of the symbolic-interactionist approach to coevolution is the concept of the emergence of a system in the abstract, where an interface between agents evolves. The interface is an emergent symbol system that focuses selective pressure among agents in ways that have been beneficial to agents as a whole in the past, creating a coevolving system that takes advantage of epistasis rather than having to prevent it. Global fitness thereby emerges from local, selfish interaction. The assignment of roles in this system is endogenous.

UNLABELLED: EST-PAGE provides a bioinformatics solution for expressed sequence tags (EST) data entry, database management, GenBank submission, process control and data retrieval from a unified web interface that can be easily customized and adapted by groups working on diverse EST sequencing projects. AVAILABILITY: The system and source code are available upon request from the authors. SUPPLEMENTARY INFORMATION: http://EST-PAGE.binf.gmu.edu

This paper addresses the problem of inferring topological features of gene regulation networks from data that are likely to be available from current experimental methods, such as DNA microarrays. The proposed method uses neural networks to predict the topology class from histograms of perturbation propagation data. The preliminary results with simulated data are encouraging. The trained neural network is able to classify the network topology as random (exponential) or scale-free with 90% accuracy. Compare to the previous network connectivity inference methods that are often problematic with current noisy data, this method is expected to be more robust because it uses global characteristics of dynamic networks.

The first step in homology analysis is usually the comparison of sequences by similarity search. The explosive growth of genomic databases makes it increasingly important to develop more rapid approaches to the comparison of large sequence databases while using the most sensitive methods available. This paper explores the consequences of this trade-off, comparing the results produced by BLAST and Smith-Waterman on genoinic- scale sequence searches. Stich comparisons are now possible thanks to the development of novel distributed computing platforms. This study uses the Parabon Frontier/sup TM/ Internet computing platform, which enables the effective use of the vast supply of idle computer cycles on the Internet for high-performance computing. We have ported both Smith-Waterman and BLAST to the Frontier platform, enabling the efficient use of these algorithms on large sequence databases. In addition, we present a novel visualization tool along with quantitative metrics for comparing the results of alternative sequence alignment algorithms. Our results compare the sensitivity of Smith-Waterman and BLAST for identifying homologies on proteome databases.

Evolvability refers to the adaptation of a population's genetic operator set over time. In traditional genetic algorithms, the genetic operator set, consisting of mutation operators, crossover operators, and their associated rates, is usually fixed. We explore the effects of allowing these operators and rates to vary under the influence of selection. The paper focuses on the suitability of alternative mutation models in dynamic landscapes. The mutation models include both traditional models in which all members of the population are subject to the same level of mutation and models in which mutation rates are genetically controlled.

The non-linear complexity of evolutionary algorithms (EAs) make them a challenge to understand. The difficulty in performing detailed analyses of an EA is in sorting through the large amount of of data that can be generated in a single run. This paper describes a visualization tool that facilitates navigation through the details of an EA run. The visualization tool organizes and displays EA data at various levels of detail and allows for easy transitions between related pieces of data.

There are two distinct approaches to solving reinforcement learning problems, namely, searching in value function space and searching in policy space. Temporal difference methods and evolutionary algorithms are well-known examples of these approaches. Kaelbling, Littman and Moore recently provided an informative survey of temporal difference methods. This article focuses on the application of evolutionary algorithms to the reinforcement learning problem, emphasizing alternative policy representations, credit assignment methods, and problem-specific genetic operators. Strengths and weaknesses of the evolutionary approach to reinforcement learning are presented, along with a survey of representative applications.

The majority of current genetic algorithms (GAs), while inspired by natural evolutionary systems, are seldom viewed as biologically plausible models. This is not a criticism of GAs, but rather a reflection of choices made regarding the level of abstraction at which biological mechanisms are modeled, and a reflection of the more engineering-oriented goals of the evolutionary computation community. Understanding better and reducing this gap between GAs and genetics has been a central issue in an interdisciplinary project whose goal is to build GA-based computational models of viral evolution. The result is a system called Virtual Virus (VIV). VIV incorporates a number of more biologically plausible mechanisms, including a more flexible genotype-to-phenotype mapping. In VIV the genes are independent of position, and genomes can vary in length and may contain noncoding regions, as well as duplicative or competing genes. Initial computational studies with VIV have already revealed several emergent phenomena of both biological and computational interest. In the absence of any penalty based on genome length, VIV develops individuals with long genomes and also performs more poorly (from a problem-solving viewpoint) than when a length penalty is used. With a fixed linear length penalty, genome length tends to increase dramatically in the early phases of evolution and then decrease to a level based on the mutation rate. The plateau genome length (i.e., the average length of individuals in the final population) generally increases in response to an increase in the base mutation rate. When VIV converges, there tend to be many copies of good alternative genes within the individuals. We observed many instances of switching between active and inactive genes during the entire evolutionary process. These observations support the conclusion that noncoding regions serve as scratch space in which VIV can explore alternative gene values. These results represent a positive step in understanding how GAs might exploit more of the power and flexibility of biological evolution while simultaneously providing better tools for understanding evolving biological systems.

No abstract available.

The task of optimizing a complex system presents at least two levels of problems for the system designer. First, a class of optimization algorithms must be chosen that is suitable for application to the system. Second, various parameters of the optimization algorithm need to be tuned for efficiency. A class of adaptive search procedures called genetic algorithms (GA) has been used to optimize a wide variety of complex systems. GA's are applied to the second level task of identifying efficient GA's for a set of numerical optimization problems. The results are validated on an image registration problem. GA's are shown to be effective for both levels of the systems optimization problem.