Developing and applying heterogeneous phylogenetic models with XRate.
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ABSTRACT:
SUBMITTER: Westesson O
PROVIDER: S-EPMC3367922 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:When the process underlying DNA substitutions varies across evolutionary history, some standard Markov models underlying phylogenetic methods are mathematically inconsistent. The most prominent example is the general time-reversible model (GTR) together with some, but not all, of its submodels. To rectify this deficiency, nonhomogeneous Lie Markov models have been identified as the class of models that are consistent in the face of a changing process of DNA substitutions regardless of taxon sampling. Some well-known models in popular use are within this class, but are either overly simplistic (e.g., the Kimura two-parameter model) or overly complex (the general Markov model). On a diverse set of biological data sets, we test a hierarchy of Lie Markov models spanning the full range of parameter richness. Compared against the benchmark of the ever-popular GTR model, we find that as a whole the Lie Markov models perform well, with the best performing models having 8-10 parameters and the ability to recognize the distinction between purines and pyrimidines.
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Project description:Results of a comprehensive simulation study are reported investigating the effects of sample size, test length, number of attributes and base rate of mastery on item parameter recovery and classification accuracy of four DCMs (i.e., C-RUM, DINA, DINO, and LCDMREDUCED). Effects were evaluated using bias and RMSE computed between true (i.e., generating) parameters and estimated parameters. Effects of simulated factors on attribute assignment were also evaluated using the percentage of classification accuracy. More precise estimates of item parameters were obtained with larger sample size and longer test length. Recovery of item parameters decreased as the number of attributes increased from three to five but base rate of mastery had a varying effect on the item recovery. Item parameter and classification accuracy were higher for DINA and DINO models.
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Project description:How do we understand the complex patterns of neural responses that underlie scene understanding? Studies of the network of brain regions held to be scene-selective-the parahippocampal/lingual region (PPA), the retrosplenial complex (RSC), and the occipital place area (TOS)-have typically focused on single visual dimensions (e.g., size), rather than the high-dimensional feature space in which scenes are likely to be neurally represented. Here we leverage well-specified artificial vision systems to explicate a more complex understanding of how scenes are encoded in this functional network. We correlated similarity matrices within three different scene-spaces arising from: (1) BOLD activity in scene-selective brain regions; (2) behavioral measured judgments of visually-perceived scene similarity; and (3) several different computer vision models. These correlations revealed: (1) models that relied on mid- and high-level scene attributes showed the highest correlations with the patterns of neural activity within the scene-selective network; (2) NEIL and SUN-the models that best accounted for the patterns obtained from PPA and TOS-were different from the GIST model that best accounted for the pattern obtained from RSC; (3) The best performing models outperformed behaviorally-measured judgments of scene similarity in accounting for neural data. One computer vision method-NEIL ("Never-Ending-Image-Learner"), which incorporates visual features learned as statistical regularities across web-scale numbers of scenes-showed significant correlations with neural activity in all three scene-selective regions and was one of the two models best able to account for variance in the PPA and TOS. We suggest that these results are a promising first step in explicating more fine-grained models of neural scene understanding, including developing a clearer picture of the division of labor among the components of the functional scene-selective brain network.
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Project description:BackgroundCertain biological processes, such as the development of cancer and immune activation, can be controlled by rare cellular events that are difficult to capture computationally through simulations of individual cells. Information about such rare events can be gleaned from an attractor analysis, for which a variety of methods exist (in particular for Boolean models). However, explicitly simulating a defined mixed population of cells in a way that tracks even the rarest subpopulations remains an open challenge.ResultsHere we show that when cellular states are described using a Boolean network model, one can exactly simulate the dynamics of non-interacting, highly heterogeneous populations directly, without having to model the various subpopulations. This strategy captures even the rarest outcomes of the model with no sampling error. Our method can incorporate heterogeneity in both cell state and, by augmenting the model, the underlying rules of the network as well (e.g., introducing loss-of-function genetic alterations). We demonstrate our method by using it to simulate a heterogeneous population of Boolean networks modeling the T-cell receptor, spanning ??1020 distinct cellular states and mutational profiles.ConclusionsWe have developed a method for using Boolean models to perform a population-level simulation, in which the population consists of non-interacting individuals existing in different states. This approach can be used even when there are far too many distinct subpopulations to model individually.
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Project description:This Teaching Resource provides lecture notes, slides, and a student assignment for a two-part lecture on mathematical modeling using the Virtual Cell environment. The lectures discuss the steps involved in developing and running simulations using Virtual Cell, with particular focus on spatial partial differential equation models. We discuss how to construct both ordinary differential equation models, in which the cytoplasm is considered a well-mixed cellular compartment, and partial differential equation models, which calculate how chemical species change as a function of both time and location. The Virtual Cell environment is especially well suited for models that explore spatial specificity of cellular reactions. Partial differential equation models in Virtual Cell can give rise to simulations using predefined cellular geometries, which enable direct comparison with imaging data. These models address questions regarding the regulatory capability arising from spatial organization of the cell. Examples are provided of studies that have successfully exploited the Virtual Cell software to address the spatial contribution to signaling.
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Project description:Existing methods for the prediction of immunologically active T-cell epitopes are based on the amino acid sequence or structure of pathogen proteins. Additional information regarding the locations of epitopes may be acquired by considering the evolution of viruses in hosts with different immune backgrounds. In particular, immune-dependent evolutionary patterns at sites within or near T-cell epitopes can be used to enhance epitope identification. We have developed a mutation-selection model of T-cell epitope evolution that allows the human leukocyte antigen (HLA) genotype of the host to influence the evolutionary process. This is one of the first examples of the incorporation of environmental parameters into a phylogenetic model and has many other potential applications where the selection pressures exerted on an organism can be related directly to environmental factors. We combine this novel evolutionary model with a hidden Markov model to identify contiguous amino acid positions that appear to evolve under immune pressure in the presence of specific host immune alleles and that therefore represent potential epitopes. This phylogenetic hidden Markov model provides a rigorous probabilistic framework that can be combined with sequence or structural information to improve epitope prediction. As a demonstration, we apply the model to a data set of HIV-1 protein-coding sequences and host HLA genotypes.
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Project description:The most widely used evolutionary model for phylogenetic trees is the equal-rates Markov (ERM) model. A problem is that the ERM model predicts less imbalance than observed for trees inferred from real data; in fact, the observed imbalance tends to fall between the values predicted by the ERM model and those predicted by the proportional-to-distinguishable-arrangements (PDA) model. Here, a continuous multi-rate (MR) family of evolutionary models is presented which contains entire subfamilies corresponding to both the PDA and ERM models. Furthermore, this MR family covers an entire range from 'completely balanced' to 'completely unbalanced' models. In particular, the MR family contains other known evolutionary models. The MR family is very versatile and virtually free of assumptions on the character of evolution; yet it is highly susceptible to rigorous analyses. In particular, such analyses help to uncover adaptability, quasi-stabilization and prolonged stasis as major possible causes of the imbalance. However, the MR model is functionally simple and requires only three parameters to reproduce the observed imbalance.
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Project description:Background: Low health literacy is associated with poorer health. Research has shown that predictive models of health literacy can be developed; however, key variables may be missing from systems where predictive models might be applied, such as health service data. This paper describes an approach to developing predictive health literacy models using variables common to both "source" health literacy data and "target" systems such as health services. Methods: A multilevel synthetic estimation was undertaken on a national (England) dataset containing health literacy, socio-demographic data and geographical (Lower Super Output Area: LSOA) indicators. Predictive models, using variables commonly present in health service data, were produced. An algorithm was written to pilot the calculations in a Family Physician Clinical System in one inner-city area. The minimum data required were age, sex and ethnicity; other missing data were imputed using model values. Results: There are 32,845 LSOAs in England, with a population aged 16 to 65 years of 34,329,091. The mean proportion of the national population below the health literacy threshold in LSOAs was 61.87% (SD 12.26). The algorithm was run on the 275,706 adult working-age people in Lambeth, South London. The algorithm could be calculated for 228,610 people (82.92%). When compared with people for whom there were sufficient data to calculate the risk score, people with insufficient data were more likely to be older, male, and living in a deprived area, although the strength of these associations was weak. Conclusions: Logistic regression using key socio-demographic data and area of residence can produce predictive models to calculate individual- and area-level risk of low health literacy, but requires high levels of ethnicity recording. While the models produced will be specific to the settings in which they are developed, it is likely that the method can be applied wherever relevant health literacy data are available. Further work is required to assess the feasibility, accuracy and acceptability of the method. If feasible, accurate and acceptable, this method could identify people requiring additional resources and support in areas such as medical practice.
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Project description:BackgroundThe advance of omics technologies has made possible to measure several data modalities on a system of interest. In this work, we illustrate how the Non-Parametric Combination methodology, namely NPC, can be used for simultaneously assessing the association of different molecular quantities with an outcome of interest. We argue that NPC methods have several potential applications in integrating heterogeneous omics technologies, as for example identifying genes whose methylation and transcriptional levels are jointly deregulated, or finding proteins whose abundance shows the same trends of the expression of their encoding genes.ResultsWe implemented the NPC methodology within "omicsNPC", an R function specifically tailored for the characteristics of omics data. We compare omicsNPC against a range of alternative methods on simulated as well as on real data. Comparisons on simulated data point out that omicsNPC produces unbiased / calibrated p-values and performs equally or significantly better than the other methods included in the study; furthermore, the analysis of real data show that omicsNPC (a) exhibits higher statistical power than other methods, (b) it is easily applicable in a number of different scenarios, and (c) its results have improved biological interpretability.ConclusionsThe omicsNPC function competitively behaves in all comparisons conducted in this study. Taking into account that the method (i) requires minimal assumptions, (ii) it can be used on different studies designs and (iii) it captures the dependences among heterogeneous data modalities, omicsNPC provides a flexible and statistically powerful solution for the integrative analysis of different omics data.
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