Linkage disequilibrium assessment via log-linear modeling of SNP haplotype frequencies

Analyses of high-density single-nucleotide polymorphism (SNP) data, such as genetic mapping and linkage disequilibrium (LD) studies, require phase-known haplotypes to allow for the correlation between tightly linked loci. However, current SNP genotyping technology cannot determine phase, which must be inferred statistically. In this paper, we present a new Bayesian Markov chain Monte Carlo (MCMC) algorithm for population haplotype frequency estimation, particulary in the context of LD assessment. The novel feature of the method is the incorporation of a log-linear prior model for population haplotype frequencies. We present simulations to suggest that 1) the log-linear prior model is more appropriate than the standard coalescent process in the presence of recombination (>0.02cM between adjacent loci), and 2) there is substantial inflation in measures of LD obtained by a "two-stage" approach to the analysis by treating the "best" haplotype configuration as correct, without regard to uncertainty in the recombination process. Genet Epidemiol 25:106-114, 2003. (C) 2003 Wiley-Liss, Inc.

Optimal piecewise locally linear modeling

Associative memory networks such as Radial Basis Functions, Neurofuzzy and Fuzzy Logic used for modelling nonlinear processes suffer from the curse of dimensionality (COD), in that as the input dimension increases the parameterization, computation cost, training data requirements, etc. increase exponentially. Here a new algorithm is introduced for the construction of a Delaunay input space partitioned optimal piecewise locally linear models to overcome the COD as well as generate locally linear models directly amenable to linear control and estimation algorithms. The training of the model is configured as a new mixture of experts network with a new fast decision rule derived using convex set theory. A very fast simulated reannealing (VFSR) algorithm is utilized to search a global optimal solution of the Delaunay input space partition. A benchmark non-linear time series is used to demonstrate the new approach.

Within-person analyses of situational interest and boredom: Interactions between task-specific perceptions and achievement goals

Despite the increasing number of studies examining the correlates of interest and boredom, surprisingly little research has focused on within-person fluctuations in these emotions, making it difficult to describe their situational nature. To address this gap in the literature, this study conducted repeated measurements (12 times) on a sample of 158 undergraduate students using a variety of self-report assessments, and examined the within-person relationships between task-specific perceptions (expectancy, utility, and difficulty) and interest and boredom. This study further explored the role of achievement goals in predicting between-person differences in these within-person relationships. Utilizing hierarchical-linear modeling, we found that, on average, a higher perception of both expectancy and utility, as well as a lower perception of difficulty, was associated with higher interest and lower boredom levels within individuals. Moreover, mastery-approach goals weakened the negative within-person relationship between difficulty and interest and the negative within-person relationship between utility and boredom. Mastery-avoidance and performance-avoidance goals strengthened the negative relationship between expectancy and boredom. These results suggest how educators can more effectively instruct students with different types of goals, minimizing boredom and maximizing interest and learning.

Imagery rescripting as a brief stand-alone treatment for depressed patients with intrusive memories

Many depressed patients report intrusive and distressing memories of specific events in their lives. Where present, these memories are believed to act as a maintaining factor. A series of ten patients with major depressive disorder and intrusive memories, many of them reporting severe, chronic, or recurrent episodes of depression, were given an average of 8.1 sessions of imagery rescripting as a stand-alone treatment. Hierarchical linear modelling demonstrated large treatment effects that were well maintained at one year follow-up. Seven patients showed reliable improvement, and six patients clinically significant improvement. These gains were achieved entirely by working through patients' visual imagination and without verbal challenging of negative beliefs. Spontaneous changes in beliefs, rumination, and behaviour were nevertheless observed. (C) 2009 Elsevier Ltd. All rights reserved.

The hemodynamic impulse response to a single neural event

This article investigates the relation between stimulus-evoked neural activity and cerebral hemodynamics. Specifically, the hypothesis is tested that hemodynamic responses can be modeled as a linear convolution of experimentally obtained measures of neural activity with a suitable hemodynamic impulse response function. To obtain a range of neural and hemodynamic responses, rat whisker pad was stimulated using brief (less than or equal to2 seconds) electrical stimuli consisting of single pulses (0.3 millisecond, 1.2 mA) combined both at different frequencies and in a paired-pulse design. Hemodynamic responses were measured using concurrent optical imaging spectroscopy and laser Doppler flowmetry, whereas neural responses were assessed through current source density analysis of multielectrode recordings from a single barrel. General linear modeling was used to deconvolve the hemodynamic impulse response to a single "neural event" from the hemodynamic and neural responses to stimulation. The model provided an excellent fit to the empirical data. The implications of these results for modeling schemes and for physiologic systems coupling neural and hemodynamic activity are discussed.

Maternal postnatal depression predicts altered offspring biological stress reactivity in adulthood

The offspring of depressed parents have been found to show elevated basal levels of the stress hormone cortisol. Whether heightened cortisol stress reactivity is also present in this group has yet to be clearly demonstrated. We tested whether postnatal maternal depression predicts subsequent increases in offspring biological sensitivity to social stress, as indexed by elevated cortisol reactivity. Participants (mean age 22.4-years) derived from a 22-year prospective longitudinal study of the offspring of mothers who had postnatal depression (PND group; n=38) and a control group (n=38). Salivary cortisol response to a social-evaluative threat (Trier Social Stress Test) was measured. Hierarchical linear modelling indicated that PND group offspring showed greater cortisol reactivity to the stress test than control group participants. Group differences were not explained by offspring depressive or anxiety symptoms, experiences of negative life events, elevated basal cortisol at age 13-years, subsequent exposure to maternal depression, or other key covariates. The findings indicate that the presence of early maternal depression can predict offspring biological sensitivity to social stress in adulthood, with potential implications for broader functioning.

Hierarchical modeling of entangled polymers

We demonstrate that it is possible to link multi-chain molecular dynamics simulations with the tube model using a single chain slip-links model as a bridge. This hierarchical approach allows significant speed up of simulations, permitting us to span the time scales relevant for a comparison with the tube theory. Fitting the mean-square displacement of individual monomers in molecular dynamics simulations with the slip-spring model, we show that it is possible to predict the stress relaxation. Then, we analyze the stress relaxation from slip-spring simulations in the framework of the tube theory. In the absence of constraint release, we establish that the relaxation modulus can be decomposed as the sum of contributions from fast and longitudinal Rouse modes, and tube survival. Finally, we discuss some open questions regarding possible future directions that could be profitable in rendering the tube model quantitative, even for mildly entangled polymers

Statistical modeling suggests that antiandrogens in effluents from wastewater treatment works contribute to widespread sexual disruption in fish living in English rivers.

BACKGROUND: The widespread occurrence of feminized male fish downstream of some wastewater treatment works has led to substantial interest from ecologists and public health professionals. This concern stems from the view that the effects observed have a parallel in humans, and that both phenomena are caused by exposure to mixtures of contaminants that interfere with reproductive development. The evidence for a "wildlife-human connection" is, however, weak: Testicular dysgenesis syndrome, seen in human males, is most easily reproduced in rodent models by exposure to mixtures of antiandrogenic chemicals. In contrast, the accepted explanation for feminization of wild male fish is that it results mainly from exposure to steroidal estrogens originating primarily from human excretion. OBJECTIVES: We sought to further explore the hypothesis that endocrine disruption in fish is multi-causal, resulting from exposure to mixtures of chemicals with both estrogenic and antiandrogenic properties. METHODS: We used hierarchical generalized linear and generalized additive statistical modeling to explore the associations between modeled concentrations and activities of estrogenic and antiandrogenic chemicals in 30 U.K. rivers and feminized responses seen in wild fish living in these rivers. RESULTS: In addition to the estrogenic substances, antiandrogenic activity was prevalent in almost all treated sewage effluents tested. Further, the results of the modeling demonstrated that feminizing effects in wild fish could be best modeled as a function of their predicted exposure to both anti-androgens and estrogens or to antiandrogens alone. CONCLUSION: The results provide a strong argument for a multicausal etiology of widespread feminization of wild fish in U.K. rivers involving contributions from both steroidal estrogens and xeno-estrogens and from other (as yet unknown) contaminants with antiandrogenic properties. These results may add farther credence to the hypothesis that endocrine-disrupting effects seen in wild fish and in humans are caused by similar combinations of endocrine-disrupting chemical cocktails.

Optimal control of a class of discrete–continuous non-linear systems — decomposition and hierarchical structure

A technique is derived for solving a non-linear optimal control problem by iterating on a sequence of simplified problems in linear quadratic form. The technique is designed to achieve the correct solution of the original non-linear optimal control problem in spite of these simplifications. A mixed approach with a discrete performance index and continuous state variable system description is used as the basis of the design, and it is shown how the global problem can be decomposed into local sub-system problems and a co-ordinator within a hierarchical framework. An analysis of the optimality and convergence properties of the algorithm is presented and the effectiveness of the technique is demonstrated using a simulation example with a non-separable performance index.

Modeling small-scale dairy farms in central Mexico using multi-criteria programming

Milk supply from Mexican dairy farms does not meet demand and small-scale farms can contribute toward closing the gap. Two multi-criteria programming techniques, goal programming and compromise programming, were used in a study of small-scale dairy farms in central Mexico. To build the goal and compromise programming models, 4 ordinary linear programming models were also developed, which had objective functions to maximize metabolizable energy for milk production, to maximize margin of income over feed costs, to maximize metabolizable protein for milk production, and to minimize purchased feedstuffs. Neither multicriteria approach was significantly better than the other; however, by applying both models it was possible to perform a more comprehensive analysis of these small-scale dairy systems. The multi-criteria programming models affirm findings from previous work and suggest that a forage strategy based on alfalfa, rye-grass, and corn silage would meet nutrient requirements of the herd. Both models suggested that there is an economic advantage in rescheduling the calving season to the second and third calendar quarters to better synchronize higher demand for nutrients with the period of high forage availability.

New mathematical modeling approach for predicting microbial inactivation by high hydrostatic pressure

A new primary model based on a thermodynamically consistent first-order kinetic approach was constructed to describe non-log-linear inactivation kinetics of pressure-treated bacteria. The model assumes a first-order process in which the specific inactivation rate changes inversely with the square root of time. The model gave reasonable fits to experimental data over six to seven orders of magnitude. It was also tested on 138 published data sets and provided good fits in about 70% of cases in which the shape of the curve followed the typical convex upward form. In the remainder of published examples, curves contained additional shoulder regions or extended tail regions. Curves with shoulders could be accommodated by including an additional time delay parameter and curves with tails shoulders could be accommodated by omitting points in the tail beyond the point at which survival levels remained more or less constant. The model parameters varied regularly with pressure, which may reflect a genuine mechanistic basis for the model. This property also allowed the calculation of (a) parameters analogous to the decimal reduction time D and z, the temperature increase needed to change the D value by a factor of 10, in thermal processing, and hence the processing conditions needed to attain a desired level of inactivation; and (b) the apparent thermodynamic volumes of activation associated with the lethal events. The hypothesis that inactivation rates changed as a function of the square root of time would be consistent with a diffusion-limited process.

Sparse modeling using orthogonal forward regression with PRESS statistic and regularization

The paper introduces an efficient construction algorithm for obtaining sparse linear-in-the-weights regression models based on an approach of directly optimizing model generalization capability. This is achieved by utilizing the delete-1 cross validation concept and the associated leave-one-out test error also known as the predicted residual sums of squares (PRESS) statistic, without resorting to any other validation data set for model evaluation in the model construction process. Computational efficiency is ensured using an orthogonal forward regression, but the algorithm incrementally minimizes the PRESS statistic instead of the usual sum of the squared training errors. A local regularization method can naturally be incorporated into the model selection procedure to further enforce model sparsity. The proposed algorithm is fully automatic, and the user is not required to specify any criterion to terminate the model construction procedure. Comparisons with some of the existing state-of-art modeling methods are given, and several examples are included to demonstrate the ability of the proposed algorithm to effectively construct sparse models that generalize well.

Modeling the effects of node heterogeneity on the performance of grid applications

The performance benefit when using grid systems comes from different strategies, among which partitioning the applications into parallel tasks is the most important. However, in most cases the enhancement coming from partitioning is smoothed by the effects of synchronization overheads, mainly due to the high variability in the execution times of the different tasks, which, in turn, is accentuated by the large heterogeneity of grid nodes. In this paper we design hierarchical, queuing network performance models able to accurately analyze grid architectures and applications. Thanks to the model results, we introduce a new allocation policy based on a combination between task partitioning and task replication. The models are used to study two real applications and to evaluate the performance benefits obtained with allocation policies based on task replication.

Comparing tube models for predicting the linear rheology of branched polymer melts

The hierarchical and "bob" (or branch-on-branch) models are tube-based computational models recently developed for predicting the linear rheology of general mixtures of polydisperse branched polymers. These two models are based on a similar tube-theory framework but differ in their numerical implementation and details of relaxation mechanisms. We present a detailed overview of the similarities and differences of these models and examine the effects of these differences on the predictions of the linear viscoelastic properties of a set of representative branched polymer samples in order to give a general picture of the performance of these models. Our analysis confirms that the hierarchical and bob models quantitatively predict the linear rheology of a wide range of branched polymer melts but also indicate that there is still no unique solution to cover all types of branched polymers without case-by-case adjustment of parameters such as the dilution exponent alpha and the factor p(2) which defines the hopping distance of a branch point relative to the tube diameter. An updated version of the hierarchical model, which shows improved computational efficiency and refined relaxation mechanisms, is introduced and used in these analyses.

Cumulant-based deconvolution and identification: several new families of linear equations

This paper presents several new families of cumulant-based linear equations with respect to the inverse filter coefficients for deconvolution (equalisation) and identification of nonminimum phase systems. Based on noncausal autoregressive (AR) modeling of the output signals and three theorems, these equations are derived for the cases of 2nd-, 3rd and 4th-order cumulants, respectively, and can be expressed as identical or similar forms. The algorithms constructed from these equations are simpler in form, but can offer more accurate results than the existing methods. Since the inverse filter coefficients are simply the solution of a set of linear equations, their uniqueness can normally be guaranteed. Simulations are presented for the cases of skewed series, unskewed continuous series and unskewed discrete series. The results of these simulations confirm the feasibility and efficiency of the algorithms.