Multivariate PLS Modeling of Apicomplexan FabD-Ligand Interaction Space for Mapping Target-Specific Chemical Space and Pharmacophore Fingerprints

Biomolecular recognition underlying drug-target interactions is determined by both binding affinity and specificity. Whilst, quantification of binding efficacy is possible, determining specificity remains a challenge, as it requires affinity data for multiple targets with the same ligand dataset. Thus, understanding the interaction space by mapping the target space to model its complementary chemical space through computational techniques are desirable. In this study, active site architecture of FabD drug target in two apicomplexan parasites viz. Plasmodium falciparum (PfFabD) and Toxoplasma gondii (TgFabD) is explored, followed by consensus docking calculations and identification of fifteen best hit compounds, most of which are found to be derivatives of natural products. Subsequently, machine learning techniques were applied on molecular descriptors of six FabD homologs and sixty ligands to induce distinct multivariate partial-least square models. The biological space of FabD mapped by the various chemical entities explain their interaction space in general. It also highlights the selective variations in FabD of apicomplexan parasites with that of the host. Furthermore, chemometric models revealed the principal chemical scaffolds in PfFabD and TgFabD as pyrrolidines and imidazoles, respectively, which render target specificity and improve binding affinity in combination with other functional descriptors conducive for the design and optimization of the leads.

Elliptical slice sampling

Many probabilistic models introduce strong dependencies between variables using a latent multivariate Gaussian distribution or a Gaussian process. We present a new Markov chain Monte Carlo algorithm for performing inference in models with multivariate Gaussian priors. Its key properties are: 1) it has simple, generic code applicable to many models, 2) it has no free parameters, 3) it works well for a variety of Gaussian process based models. These properties make our method ideal for use while model building, removing the need to spend time deriving and tuning updates for more complex algorithms.

Bayesian learning of noisy Markov decision processes

This work addresses the problem of estimating the optimal value function in a Markov Decision Process from observed state-action pairs. We adopt a Bayesian approach to inference, which allows both the model to be estimated and predictions about actions to be made in a unified framework, providing a principled approach to mimicry of a controller on the basis of observed data. A new Markov chain Monte Carlo (MCMC) sampler is devised for simulation from theposterior distribution over the optimal value function. This step includes a parameter expansion step, which is shown to be essential for good convergence properties of the MCMC sampler. As an illustration, the method is applied to learning a human controller.

An approximate likelihood method for estimating static parameters in multi-target tracking models

This paper considers a class of dynamic Spatial Point Processes (PP) that evolves over time in a Markovian fashion. This Markov in time PP is hidden and observed indirectly through another PP via thinning, displacement and noise. This statistical model is important for Multi object Tracking applications and we present an approximate likelihood based method for estimating the model parameters. The work is supported by an extensive numerical study.

Another Look to the Price-Dividend Ratio: A Markov-Switching Approach

This paper analyzes the stationarity of this ratio in the context of a Markov-switching model à la Hamilton (1989) where an asymmetric speed of adjustment is introduced. This particular specification robustly supports a nonlinear reversion process and identifies two relevant episodes: the post-war period from the mid-50’s to the mid-70’s and the so called “90’s boom” period. A three-regime Markov-switching model displays the best regime identification and reveals that only the first part of the 90’s boom (1985-1995) and the post-war period are near-nonstationary states. Interestingly, the last part of the 90’s boom (1996-2000), characterized by a growing price-dividend ratio, is entirely attributed to a regime featuring a highly reverting process.

Markov Switching Risk Premium and the term structure of interest rates. Empirical evidence from US post-war interest rates

This paper considers the basic present value model of interest rates under rational expectations with two additional features. First, following McCallum (1994), the model assumes a policy reaction function where changes in the short-term interest rate are determined by the long-short spread. Second, the short-term interest rate and the risk premium processes are characterized by a Markov regime-switching model. Using US post-war interest rate data, this paper finds evidence that a two-regime switching model fits the data better than the basic model. The estimation results also show the presence of two alternative states displaying quite different features.

Ancient DNA from Hunter-Gatherer and Farmer Groups from Northern Spain Supports a Random Dispersion Model for the Neolithic Expansion into Europe

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Using experiments and expert judgment to model catchability of Pacific rockfishes in trawl surveys, with application to bocaccio (Sebastes paucispinis) off British Columbia

The time series of abundance indices for many groundfish populations, as determined from trawl surveys, are often imprecise and short, causing stock assessment estimates of abundance to be imprecise. To improve precision, prior probability distributions (priors) have been developed for parameters in stock assessment models by using meta-analysis, expert judgment on catchability, and empirically based modeling. This article presents a synthetic approach for formulating priors for rockfish trawl survey catchability (qgross). A multivariate prior for qgross for different surveys is formulated by using 1) a correction factor for bias in estimating fish density between trawlable and untrawlable areas, 2) expert judgment on trawl net catchability, 3) observations from trawl survey experiments, and 4) data on the fraction of population biomass in each of the areas surveyed. The method is illustrated by using bocaccio (Sebastes paucipinis) in British Columbia. Results indicate that expert judgment can be updated markedly by observing the catch-rate ratio from different trawl gears in the same areas. The marginal priors for qgross are consistent with empirical estimates obtained by fitting a stock assessment model to the survey data under a noninformative prior for qgross. Despite high prior uncertainty (prior coefficients of variation ≥0.8) and high prior correlation between qgross, the prior for qgross still enhances the precision of key stock assessment quantities.

Defining plausible migration rates based on historical tagging data: a Bayesian mark-recapture model applied to English sole (Parophrys vetulus)

A generalized Bayesian population dynamics model was developed for analysis of historical mark-recapture studies. The Bayesian approach builds upon existing maximum likelihood methods and is useful when substantial uncertainties exist in the data or little information is available about auxiliary parameters such as tag loss and reporting rates. Movement rates are obtained through Markov-chain Monte-Carlo (MCMC) simulation, which are suitable for use as input in subsequent stock assessment analysis. The mark-recapture model was applied to English sole (Parophrys vetulus) off the west coast of the United States and Canada and migration rates were estimated to be 2% per month to the north and 4% per month to the south. These posterior parameter distributions and the Bayesian framework for comparing hypotheses can guide fishery scientists in structuring the spatial and temporal complexity of future analyses of this kind. This approach could be easily generalized for application to other species and more data-rich fishery analyses.

Identificação de danos estruturais via método de Monte Carlo com cadeias de Markov

O presente trabalho apresenta um estudo referente à aplicação da abordagem Bayesiana como técnica de solução do problema inverso de identificação de danos estruturais, onde a integridade da estrutura é continuamente descrita por um parâmetro estrutural denominado parâmetro de coesão. A estrutura escolhida para análise é uma viga simplesmente apoiada do tipo Euler-Bernoulli. A identificação de danos é baseada em alterações na resposta impulsiva da estrutura, provocadas pela presença dos mesmos. O problema direto é resolvido através do Método de Elementos Finitos (MEF), que, por sua vez, é parametrizado pelo parâmetro de coesão da estrutura. O problema de identificação de danos é formulado como um problema inverso, cuja solução, do ponto de vista Bayesiano, é uma distribuição de probabilidade a posteriori para cada parâmetro de coesão da estrutura, obtida utilizando-se a metodologia de amostragem de Monte Carlo com Cadeia de Markov. As incertezas inerentes aos dados medidos serão contempladas na função de verossimilhança. Três estratégias de solução são apresentadas. Na Estratégia 1, os parâmetros de coesão da estrutura são amostrados de funções densidade de probabilidade a posteriori que possuem o mesmo desvio padrão. Na Estratégia 2, após uma análise prévia do processo de identificação de danos, determina-se regiões da viga potencialmente danificadas e os parâmetros de coesão associados à essas regiões são amostrados a partir de funções de densidade de probabilidade a posteriori que possuem desvios diferenciados. Na Estratégia 3, após uma análise prévia do processo de identificação de danos, apenas os parâmetros associados às regiões identificadas como potencialmente danificadas são atualizados. Um conjunto de resultados numéricos é apresentado levando-se em consideração diferentes níveis de ruído para as três estratégias de solução apresentadas.

An environmentally based growth model that uses finite difference calculus with maximum likelihood method: its application to the brackish water bivalve Corbicula japonica in Lake Abashiri, Japan

We present a growth analysis model that combines large amounts of environmental data with limited amounts of biological data and apply it to Corbicula japonica. The model uses the maximum-likelihood method with the Akaike information criterion, which provides an objective criterion for model selection. An adequate distribution for describing a single cohort is selected from available probability density functions, which are expressed by location and scale parameters. Daily relative increase rates of the location parameter are expressed by a multivariate logistic function with environmental factors for each day and categorical variables indicating animal ages as independent variables. Daily relative increase rates of the scale parameter are expressed by an equation describing the relationship with the daily relative increase rate of the location parameter. Corbicula japonica grows to a modal shell length of 0.7 mm during the first year in Lake Abashiri. Compared with the attain-able maximum size of about 30 mm, the growth of juveniles is extremely slow because their growth is less susceptible to environmental factors until the second winter. The extremely slow growth in Lake Abashiri could be a geographical genetic variation within C. japonica.

Learning the Structure of Deep Sparse Graphical Models

Deep belief networks are a powerful way to model complex probability distributions. However, learning the structure of a belief network, particularly one with hidden units, is difficult. The Indian buffet process has been used as a nonparametric Bayesian prior on the directed structure of a belief network with a single infinitely wide hidden layer. In this paper, we introduce the cascading Indian buffet process (CIBP), which provides a nonparametric prior on the structure of a layered, directed belief network that is unbounded in both depth and width, yet allows tractable inference. We use the CIBP prior with the nonlinear Gaussian belief network so each unit can additionally vary its behavior between discrete and continuous representations. We provide Markov chain Monte Carlo algorithms for inference in these belief networks and explore the structures learned on several image data sets.

Gaussian Process Regression Networks

We introduce a new regression framework, Gaussian process regression networks (GPRN), which combines the structural properties of Bayesian neural networks with the non-parametric flexibility of Gaussian processes. This model accommodates input dependent signal and noise correlations between multiple response variables, input dependent length-scales and amplitudes, and heavy-tailed predictive distributions. We derive both efficient Markov chain Monte Carlo and variational Bayes inference procedures for this model. We apply GPRN as a multiple output regression and multivariate volatility model, demonstrating substantially improved performance over eight popular multiple output (multi-task) Gaussian process models and three multivariate volatility models on benchmark datasets, including a 1000 dimensional gene expression dataset.

Statistical user simulation with a hidden agenda

Recent work in the area of probabilistic user simulation for training statistical dialogue managers has investigated a new agenda-based user model and presented preliminary experiments with a handcrafted model parameter set. Training the model on dialogue data is an important next step, but non-trivial since the user agenda states are not observable in data and the space of possible states and state transitions is intractably large. This paper presents a summary-space mapping which greatly reduces the number of state transitions and introduces a tree-based method for representing the space of possible agenda state sequences. Treating the user agenda as a hidden variable, the forward/backward algorithm can then be successfully applied to iteratively estimate the model parameters on dialogue data. © 2007 Association for Computational Linguistics.

Partially Observable Markov Decision Processes with continuous observations for dialogue management

This work shows how a dialogue model can be represented as a Partially Observable Markov Decision Process (POMDP) with observations composed of a discrete and continuous component. The continuous component enables the model to directly incorporate a confidence score for automated planning. Using a testbed simulated dialogue management problem, we show how recent optimization techniques are able to find a policy for this continuous POMDP which outperforms a traditional MDP approach. Further, we present a method for automatically improving handcrafted dialogue managers by incorporating POMDP belief state monitoring, including confidence score information. Experiments on the testbed system show significant improvements for several example handcrafted dialogue managers across a range of operating conditions.