Extended kalman filter for estimation of parameters in nonlinear state-space models of biochemical networks.

It is system dynamics that determines the function of cells, tissues and organisms. To develop mathematical models and estimate their parameters are an essential issue for studying dynamic behaviors of biological systems which include metabolic networks, genetic regulatory networks and signal transduction pathways, under perturbation of external stimuli. In general, biological dynamic systems are partially observed. Therefore, a natural way to model dynamic biological systems is to employ nonlinear state-space equations. Although statistical methods for parameter estimation of linear models in biological dynamic systems have been developed intensively in the recent years, the estimation of both states and parameters of nonlinear dynamic systems remains a challenging task. In this report, we apply extended Kalman Filter (EKF) to the estimation of both states and parameters of nonlinear state-space models. To evaluate the performance of the EKF for parameter estimation, we apply the EKF to a simulation dataset and two real datasets: JAK-STAT signal transduction pathway and Ras/Raf/MEK/ERK signaling transduction pathways datasets. The preliminary results show that EKF can accurately estimate the parameters and predict states in nonlinear state-space equations for modeling dynamic biochemical networks.

Genetic networks controlling retinal injury.

PURPOSE: The present study defines genomic loci underlying coordinate changes in gene expression following retinal injury. METHODS: A group of acute phase genes expressed in diverse nervous system tissues was defined by combining microarray results from injury studies from rat retina, brain, and spinal cord. Genomic loci regulating the brain expression of acute phase genes were identified using a panel of BXD recombinant inbred (RI) mouse strains. Candidate upstream regulators within a locus were defined using single nucleotide polymorphism databases and promoter motif databases. RESULTS: The acute phase response of rat retina, brain, and spinal cord was dominated by transcription factors. Three genomic loci control transcript expression of acute phase genes in brains of BXD RI mouse strains. One locus was identified on chromosome 12 and was highly correlated with the expression of classic acute phase genes. Within the locus we identified the inhibitor of DNA binding 2 (Id2) as a candidate upstream regulator. Id2 was upregulated as an acute phase transcript in injury models of rat retina, brain, and spinal cord. CONCLUSIONS: We defined a group of transcriptional changes associated with the retinal acute injury response. Using genetic linkage analysis of natural transcript variation, we identified regulatory loci and candidate regulators that control transcript levels of acute phase genes.

Saturday Morning Television Advertisements Aired on English and Spanish Language Networks along the Texas-Mexico Border

Objectives: The aim of this content analysis study is to characterize the TV advertisements aired to an at-risk child population along the Texas-Mexico border. Methods: We characterized the early Saturday morning TV advertisements aired by three broadcast network categories (U.S. English language, U.S. Spanish language, and Mexican Spanish language) in Spring 2010. The number, type (food related vs. non-food related), target audience, and persuasion tactics used were recorded. Advertised foods, based on nutrition content, were categorized as meeting or not meeting current dietary guidelines. Results: Most commercials were non-food related (82.7%, 397 of 480). The majority of the prepared foods (e.g., cereals, snacks, and drinks) advertised did not meet the current U.S. Dietary Guidelines. Additionally, nutrition content information was not available for many of the foods advertised on the Mexican Spanish language broadcast network category. Conclusions: For U.S. children at risk for obesity along the Texas-Mexico border exposure to TV food advertisements may result in the continuation of sedentary behavior as well as an increased consumption of foods of poor nutritional quality. An international regulatory effort to monitor and enforce the reduction of child-oriented food advertising is needed. Editors' Note: This article was submitted in response to the first issue of the Journal of Applied Research on Children: Latino Children.

Functional and motor neuronal analysis of defensive siphon responses in {\it Aplysia californica}

One of the central goals of neuroscience research is to determine how networks of neurons control and modify behavior. One of the most influential model systems for this kind of analysis is the siphon and gill withdrawal reflex of the marine mollusc A. californica. In response to tactile stimulation, the siphon displays 3 different responses: (1) a posterior pointing and leveling (flaring) of the siphon in response to tail stimulation (the siphon T response), (2) constriction and anterior pointing to head stimulation (the siphon H response) and (3) constriction and withdrawal between the animal's parapodia (the siphon S response). The siphon S response is pseudoconditioned by a noxious tail stimulus to resemble the siphon T response. Behavioral and combined behavioral/intracellular studies were conducted to determine the motor neuronal control of these behaviors and to search for mechanisms of siphon response transformation following pseudoconditioning. The present studies have found that the flaring component of pseudoconditioned siphon S responses occurs during mantle pumping (MP) triggered by noxious tail stimulation. Siphon stimulation also triggers MP, as recorded in neurons of the Interneuron II pattern generator which commands MP. The 4 LF$\rm\sb{SB}$ siphon motor neurons (SMNs) were found necessary and sufficient for the siphon T response, while SMNs RD$\rm\sb S$ and LD$\rm\sb{S1}$ were found necessary and sufficient for the siphon H response. Following pseudoconditioning, there is an increase in the number of evoked spikes to the test stimulus for the LF$\rm\sb{SB}$ cells and a decreased number for RD$\rm\sb S.$ Siphon flaring occurring during the pseudoconditioned response correlates with increased LF$\rm\sb{SB}$ activity during triggered MP cycles. This suggests that psuedoconditioning is in part due to reconfiguration of the motor outputs of the Interneuron II network. These results suggest that these defensive responses are controlled and patterned by a well-defined, finite set of motor neurons and interneurons (Interneuron II) that are dedicated to specific behavioral functions, but also have parallel distributed properties. ^

Functional data analysis approaches for genotype-phenotype association studies from next-generation sequencing

Next-generation DNA sequencing platforms can effectively detect the entire spectrum of genomic variation and is emerging to be a major tool for systematic exploration of the universe of variants and interactions in the entire genome. However, the data produced by next-generation sequencing technologies will suffer from three basic problems: sequence errors, assembly errors, and missing data. Current statistical methods for genetic analysis are well suited for detecting the association of common variants, but are less suitable to rare variants. This raises great challenge for sequence-based genetic studies of complex diseases.^ This research dissertation utilized genome continuum model as a general principle, and stochastic calculus and functional data analysis as tools for developing novel and powerful statistical methods for next generation of association studies of both qualitative and quantitative traits in the context of sequencing data, which finally lead to shifting the paradigm of association analysis from the current locus-by-locus analysis to collectively analyzing genome regions.^ In this project, the functional principal component (FPC) methods coupled with high-dimensional data reduction techniques will be used to develop novel and powerful methods for testing the associations of the entire spectrum of genetic variation within a segment of genome or a gene regardless of whether the variants are common or rare.^ The classical quantitative genetics suffer from high type I error rates and low power for rare variants. To overcome these limitations for resequencing data, this project used functional linear models with scalar response to develop statistics for identifying quantitative trait loci (QTLs) for both common and rare variants. To illustrate their applications, the functional linear models were applied to five quantitative traits in Framingham heart studies. ^ This project proposed a novel concept of gene-gene co-association in which a gene or a genomic region is taken as a unit of association analysis and used stochastic calculus to develop a unified framework for testing the association of multiple genes or genomic regions for both common and rare alleles. The proposed methods were applied to gene-gene co-association analysis of psoriasis in two independent GWAS datasets which led to discovery of networks significantly associated with psoriasis.^

Social support, health status and health services utilization among the noninstitutionalized elderly: An analysis of the Supplement on Aging to the 1984 national health interview survey

The association between Social Support, Health Status, and Health Services Utilization of the elderly, was explored based on the analysis of data from the Supplement on Aging to the National Health Interview Survey, 1984 (N = 11,497) using a modified framework of Aday and Andersen's Expanded Behavioral Model. The results suggested that Social Support as operationalized in this study was an independent determinant of the use of health services. The quantity of social activities and the use of community services were the two most consistent determinants across different types of health services use.^ The effects of social support on the use of health services were broken down into three components to facilitate explanations of the mechanisms through which social support operated. The Predisposing and Enabling component of Social Support had independent, although not uniform, effects on the use of health services. Only slight substitute effects of social support were detected. These included the substitution of the use of senior centers for longer stay in the hospital and the substitution of help with IADL problems for the use of formal home care services.^ The effect of financial support on the use of health services was found to be different for middle and low income populations. This differential effect was also found for the presence of intimate networks, the frequencies of interaction with children and the perceived availability of support among urban/rural, male/female and white/non-white subgroups.^ The study also suggested that the selection of appropriate Health Status measures should be based on the type of Health Services Utilization in which a researcher is interested. The level of physical function limitation and role activity limitation were the two most consistent predictors of the volume of physician visits, number of hospital days, and average length of stay in the hospital during the past year.^ Some alternative hypotheses were also raised and evaluated, when possible. The impacts of the complex sample design, the reliability and validity of the measures and other limitations of this analysis were also discussed. Finally, a revised framework was proposed and discussed based on the analysis. Some policy implications and suggestions for future study were also presented. ^

A comparative state policy analysis of the adoption of birth defects surveillance legislation

Birth defects are the leading cause of infant mortality in the United States and are a major cause of lifetime disability. However, efforts to understand their causes have been hampered by a lack of population-specific data. During 1990–2004, 22 state legislatures responded to this need by proposing birth defects surveillance legislation (BDSL). The contrast between these states and those that did not pass BDSL provides an opportunity to better understand conditions associated with US public health policy diffusion. ^ This study identifies key state-specific determinants that predict: (1) the introduction of birth defects surveillance legislation (BDSL) onto states' formal legislative agenda, and (2) the successful adoption of these laws. Secondary aims were to interpret these findings in a theoretically sound framework and to incorporate evidence from three analytical approaches. ^ The study begins with a comparative case study of Texas and Oregon (states with divergent BDSL outcomes), including a review of historical documentation and content analysis of key informant interviews. After selecting and operationalizing explanatory variables suggested by the case study, Qualitative Comparative Analysis (QCA) was applied to publically available data to describe important patterns of variation among 37 states. Results from logistic regression were compared to determine whether the two methods produced consistent findings. ^ Themes emerging from the comparative case study included differing budgetary conditions and the significance of relationships within policy issue networks. However, the QCA and statistical analysis pointed to the importance of political parties and contrasting societal contexts. Notably, state policies that allow greater access to citizen-driven ballot initiatives were consistently associated with lower likelihood of introducing BDSL. ^ Methodologically, these results indicate that a case study approach, while important for eliciting valuable context-specific detail, may fail to detect the influence of overarching, systemic variables, such as party competition. However, QCA and statistical analyses were limited by a lack of existing data to operationalize policy issue networks, and thus may have downplayed the impact of personal interactions. ^ This study contributes to the field of health policy studies in three ways. First, it emphasizes the importance of collegial and consistent relationships among policy issue network members. Second, it calls attention to political party systems in predicting policy outcomes. Finally, a novel approach to interpreting state data in a theoretically significant manner (QCA) has been demonstrated.^