Regressão Simplex aplicada a delineamentos de mistura e utilização do Algoritmo Boosting

In the composition of this work are present two parts. The first part contains the theory used. The second part contains the two articles. The first article examines two models of the class of generalized linear models for analyzing a mixture experiment, which studied the effect of different diets consist of fat, carbohydrate, and fiber on tumor expression in mammary glands of female rats, given by the ratio mice that had tumor expression in a particular diet. Mixture experiments are characterized by having the effect of collinearity and smaller sample size. In this sense, assuming normality for the answer to be maximized or minimized may be inadequate. Given this fact, the main characteristics of logistic regression and simplex models are addressed. The models were compared by the criteria of selection of models AIC, BIC and ICOMP, simulated envelope charts for residuals of adjusted models, odds ratios graphics and their respective confidence intervals for each mixture component. It was concluded that first article that the simplex regression model showed better quality of fit and narrowest confidence intervals for odds ratio. The second article presents the model Boosted Simplex Regression, the boosting version of the simplex regression model, as an alternative to increase the precision of confidence intervals for the odds ratio for each mixture component. For this, we used the Monte Carlo method for the construction of confidence intervals. Moreover, it is presented in an innovative way the envelope simulated chart for residuals of the adjusted model via boosting algorithm. It was concluded that the Boosted Simplex Regression model was adjusted successfully and confidence intervals for the odds ratio were accurate and lightly more precise than the its maximum likelihood version.

Developmental genetics of red cell indices during puberty: A longitudinal twin study

Red cell number and size increase during puberty, particularly in males. The aim of the present study was to determine whether expression of genes affecting red cell indices varied with age and sex. Haemoglobin, red cell count, and mean cellular volume were measured longitudinally on 578 pairs of twins at twelve, fourteen and sixteen years of age. Data were analysed using a structural equation modeling approach, in which a variety of univariate and longitudinal simplex models were fitted to the data. Significant heritability was demonstrated for all variables across all ages. The genes involved did not differ between the sexes, although there was evidence for sex limitation in the case of haemoglobin at age twelve. Longitudinal analyses indicated that new genes affecting red cell indices were expressed at different stages of puberty. Some of these genes affected the different red cell indices pleiotropically, while others had effects specific to one variable only.

Biometrical Genetics

Biometrical genetics is the science concerned with the inheritance of quantitative traits. In this review we discuss how the analytical methods of biometrical genetics are based upon simple Mendelian principles. We demonstrate how the phenotypic covariance between related individuals provides information on the relative importance of genetic and environmental factors influencing that trait, and how factors such as assortative mating, gene-environment correlation and genotype-environment interaction complicate such interpretations. Twin and adoption studies are discussed as well as their assumptions and limitations. Structural equation modeling (SEM) is introduced and we illustrate how this approach may be applied to genetic problems. In particular, we show how SEM can be used to address complicated issues such as analyzing the causes of correlation between traits or determining the direction of causation (DOC) between variables. (C) 2002 Elsevier Science B.V. All rights reserved.

Do the Genetic or Environmental Determinants of Anxiety and Depression Change with Age? A Longitudinal Study of Australian Twins

Because the determinants of anxiety and depression in late adolescence and early adulthood may differ from those in later life, we investigated the temporal stability and magnitude of genetic and environmental correlates of symptoms of anxiety and depression across the life span. Data were collected from a population-based Australian sample of 4364 complete twin pairs and 777 singletons aged 20 to 96 years who were followed-up over three studies between 1980 and 1996. Each study contained the 14-item self-report DSSI/sAD scale which was used to measure recently experienced symptoms of anxiety and depression. Symptom scores were then divided and assigned to age intervals according to each subject's age at time of participation. We fitted genetic simplex models to take into account the longitudinal nature of the data. For male anxiety and depression, the best fitting simplex models comprised a single genetic innovation at age 20 which was transmitted, and explained genetic variation in anxiety and depression at ages 30, 40, 50 and 60. Most of the lifetime genetic variation in female anxiety and depression could also be explained by innovations at age 20 which were transmitted to all other ages; however, there were also smaller age-dependent genetic innovations at 30 for anxiety and at 40 and 70 for depression. Although the genetic determinants of anxiety and depression appear relatively stable across the life-span for males and females, there is some evidence to support additional mid-life and late age gene action in females for depression. The fact that mid-life onset for anxiety occurs one decade before depression is also consistent with a causal relationship (anxiety leading to depression) between these conditions. These findings have significance for large scale depression prevention projects.

Genetic time-series analysis identifies a major QTL for in vivo alcohol metabolism not predicted by in vitro studies of structural protein polymorphism at the ADH1B or ADH1C loci

After ingestion of a standardized dose of ethanol, alcohol concentrations were assessed, over 3.5 hours from blood (six readings) and breath (10 readings) in a sample of 412 MZ and DZ twins who took part in an Alcohol Challenge Twin Study (ACTS). Nearly all participants were subsequently genotyped on two polymorphic SNPs in the ADH1B and ADH1C loci known to affect in vitro ADH activity. In the DZ pairs, 14 microsatellite markers covering a 20.5 cM region on chromosome 4 that includes the ADH gene family were assessed, Variation in the timed series of autocorrelated blood and breath alcohol readings was studied using a bivariate simplex design. The contribution of a quantitative trait locus (QTL) or QTL's linked to the ADH region was estimated via a mixture of likelihoods weighted by identity-by-descent probabilities. The effects of allelic substitution at the ADH1B and ADH1C loci were estimated in the means part of the model simultaneously with the effects sex and age. There was a major contribution to variance in alcohol metabolism due to a QTL which accounted for about 64% of the additive genetic covariation common to both blood and breath alcohol readings at the first time point. No effects of the ADH1B*47His or ADH1C*349Ile alleles on in vivo metabolism were observed, although these have been shown to have major effects in vitro. This implies that there is a major determinant of variation for in vivo alcohol metabolism in the ADH region that is not accounted for by these polymorphisms. Earlier analyses of these data suggested that alcohol metabolism is related to drinking behavior and imply that this QTL may be protective against alcohol dependence.

OPUS: interactive software for solving linear programming models using the simplex algorithm

Includes bibliography

Immunization with DNA vaccines encoding glycoprotein D or glycoprotein B, alone or in combination, induces protective immunity in animal models of herpes simplex virus-2 disease.

DNA vaccines expressing herpes simplex virus type 2 (HSV-2) full-length glycoprotein D (gD), or a truncated form of HSV-2 glycoprotein B (gB) were evaluated for protective efficacy in two experimental models of HSV-2 infection. Intramuscular (i.m.) injection of mice showed that each construction induced neutralizing serum antibodies and protected the mice from lethal HSV-2 infection. Dose-titration studies showed that low doses (< or = 1 microgram) of either DNA construction induced protective immunity, and that a single immunization with the gD construction was effective. The two DNAs were then tested in a low-dosage combination in guinea pigs. Immune sera from DNA-injected animals had antibodies to both gD and gB, and virus neutralizing activity. When challenged by vaginal infection with HSV-2, the DNA-immunized animals were significantly protected from primary genital disease.

A hybrid Particle Swarm Optimization - Simplex algorithm (PSOS) for structural damage identification

This study proposes a new PSOS-model based damage identification procedure using frequency domain data. The formulation of the objective function for the minimization problem is based on the Frequency Response Functions (FRFs) of the system. A novel strategy for the control of the Particle Swarm Optimization (PSO) parameters based on the Nelder-Mead algorithm (Simplex method) is presented; consequently, the convergence of the PSOS becomes independent of the heuristic constants and its stability and confidence are enhanced. The formulated hybrid method performs better in different benchmark functions than the Simulated Annealing (SA) and the basic PSO (PSO(b)). Two damage identification problems, taking into consideration the effects of noisy and incomplete data, were studied: first, a 10-bar truss and second, a cracked free-free beam, both modeled with finite elements. In these cases, the damage location and extent were successfully determined. Finally, a non-linear oscillator (Duffing oscillator) was identified by PSOS providing good results. (C) 2009 Elsevier Ltd. All rights reserved

Experimental design on the simplex

Optimum experimental designs depend on the design criterion, the model andthe design region. The talk will consider the design of experiments for regressionmodels in which there is a single response with the explanatory variables lying ina simplex. One example is experiments on various compositions of glass such asthose considered by Martin, Bursnall, and Stillman (2001).Because of the highly symmetric nature of the simplex, the class of models thatare of interest, typically Scheff´e polynomials (Scheff´e 1958) are rather differentfrom those of standard regression analysis. The optimum designs are also ratherdifferent, inheriting a high degree of symmetry from the models.In the talk I will hope to discuss a variety of modes for such experiments. ThenI will discuss constrained mixture experiments, when not all the simplex is availablefor experimentation. Other important aspects include mixture experimentswith extra non-mixture factors and the blocking of mixture experiments.Much of the material is in Chapter 16 of Atkinson, Donev, and Tobias (2007).If time and my research allows, I would hope to finish with a few comments ondesign when the responses, rather than the explanatory variables, lie in a simplex.ReferencesAtkinson, A. C., A. N. Donev, and R. D. Tobias (2007). Optimum ExperimentalDesigns, with SAS. Oxford: Oxford University Press.Martin, R. J., M. C. Bursnall, and E. C. Stillman (2001). Further results onoptimal and efficient designs for constrained mixture experiments. In A. C.Atkinson, B. Bogacka, and A. Zhigljavsky (Eds.), Optimal Design 2000,pp. 225–239. Dordrecht: Kluwer.Scheff´e, H. (1958). Experiments with mixtures. Journal of the Royal StatisticalSociety, Ser. B 20, 344–360.1

TLR3 deficiency in patients with herpes simplex encephalitis.

Some Toll and Toll-like receptors (TLRs) provide immunity to experimental infections in animal models, but their contribution to host defense in natural ecosystems is unknown. We report a dominant-negative TLR3 allele in otherwise healthy children with herpes simplex virus 1 (HSV-1) encephalitis. TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1, which spreads from the epithelium to the CNS via cranial nerves. TLR3 is also expressed in epithelial and dendritic cells, which apparently use TLR3-independent pathways to prevent further dissemination of HSV-1 and to provide resistance to other pathogens in TLR3-deficient patients. Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS, which suggests that neurotropic viruses have contributed to the evolutionary maintenance of TLR3.

Viral and cellular modulation of virus-induced apoptosis in experimental infection models

The aim of this study was to investigate herpes simplex virus type 1 (HSV-1)- and measles virus (MV)-induced cell death. HSV-1 with deletion in genes encoding infected cell protein (ICP)4 and protein kinase Us3 (d120) induced apoptosis and cathepsin activation in epithelial (HEp-2) and monocytic (U937) cells. Inhibition of cathepsin activity decreased the amount of d120-induced apoptosis indicating that d120-induced apoptosis could be cathepsin-mediated. Also, HSV-1 infection increased caspase activation suggesting that d120-induced apoptosis is probably caspase-mediated. Cystatin treatment decreased the activity of cathepsins and the replication of HSV-1 indicating that cathepsins contribute to HSV-1 infection. Interestingly, d120 induced also necroptosis in monocytic cells. This is the first report on necroptosis in HSV-1- infected cells. MV induced apoptosis in uninfected bystander T lymphocytes, probably via interaction of MV-infected monocytes with uninfected lymphocytes. The expression of death receptor Fas was clearly increased on the surface of lymphocytes. The number of apoptotic cells and the activation of cathepsins and caspases were increased in MVinfected U937 cells suggesting that MV-induced apoptosis could be cathepsin- and caspase-mediated. Cystatin treatment inhibited cathepsin activities but not MV-induced apoptosis. Besides HSV-1-induced apoptosis, innate immune responses were studied in HSV-1-infection. HSV-1 viruses with either ICP4 and Us3, or Us3 deletion only, increased the expression of Toll-like receptor (TLR)3 and stimulated its downstream pathways leading to increased expression of type I interferon gene and to functional interferons. These findings suggest that besides controlling apoptosis, HSV-1 ICP4 and Us3 genes are involved in the control of TLR3 response in infected cell.

A new distribution on the simplex containing the Dirichlet family

The Dirichlet family owes its privileged status within simplex distributions to easyness of interpretation and good mathematical properties. In particular, we recall fundamental properties for the analysis of compositional data such as closure under amalgamation and subcomposition. From a probabilistic point of view, it is characterised (uniquely) by a variety of independence relationships which makes it indisputably the reference model for expressing the non trivial idea of substantial independence for compositions. Indeed, its well known inadequacy as a general model for compositional data stems from such an independence structure together with the poorness of its parametrisation. In this paper a new class of distributions (called Flexible Dirichlet) capable of handling various dependence structures and containing the Dirichlet as a special case is presented. The new model exhibits a considerably richer parametrisation which, for example, allows to model the means and (part of) the variance-covariance matrix separately. Moreover, such a model preserves some good mathematical properties of the Dirichlet, i.e. closure under amalgamation and subcomposition with new parameters simply related to the parent composition parameters. Furthermore, the joint and conditional distributions of subcompositions and relative totals can be expressed as simple mixtures of two Flexible Dirichlet distributions. The basis generating the Flexible Dirichlet, though keeping compositional invariance, shows a dependence structure which allows various forms of partitional dependence to be contemplated by the model (e.g. non-neutrality, subcompositional dependence and subcompositional non-invariance), independence cases being identified by suitable parameter configurations. In particular, within this model substantial independence among subsets of components of the composition naturally occurs when the subsets have a Dirichlet distribution

Experimental design on the simplex

Optimum experimental designs depend on the design criterion, the model and the design region. The talk will consider the design of experiments for regression models in which there is a single response with the explanatory variables lying in a simplex. One example is experiments on various compositions of glass such as those considered by Martin, Bursnall, and Stillman (2001). Because of the highly symmetric nature of the simplex, the class of models that are of interest, typically Scheff´e polynomials (Scheff´e 1958) are rather different from those of standard regression analysis. The optimum designs are also rather different, inheriting a high degree of symmetry from the models. In the talk I will hope to discuss a variety of modes for such experiments. Then I will discuss constrained mixture experiments, when not all the simplex is available for experimentation. Other important aspects include mixture experiments with extra non-mixture factors and the blocking of mixture experiments. Much of the material is in Chapter 16 of Atkinson, Donev, and Tobias (2007). If time and my research allows, I would hope to finish with a few comments on design when the responses, rather than the explanatory variables, lie in a simplex. References Atkinson, A. C., A. N. Donev, and R. D. Tobias (2007). Optimum Experimental Designs, with SAS. Oxford: Oxford University Press. Martin, R. J., M. C. Bursnall, and E. C. Stillman (2001). Further results on optimal and efficient designs for constrained mixture experiments. In A. C. Atkinson, B. Bogacka, and A. Zhigljavsky (Eds.), Optimal Design 2000, pp. 225–239. Dordrecht: Kluwer. Scheff´e, H. (1958). Experiments with mixtures. Journal of the Royal Statistical Society, Ser. B 20, 344–360. 1

Modelagem matemática: uma abordagem do método gráfico e do método simplex na resolução de problemas de otimização

Pós-graduação em Matemática em Rede Nacional - IBILCE

Molecular basis oh herpes simplex virus entry into the cell and retargeting of the viral tropism for the design of oncolytic herpesviruses

Herpes simplex virus 1 (HSV-1) infects oral epitelial cells, then spreads to the nerve endings and estabilishes latency in sensory ganglia, from where it may, or may not reactivate. Diseases caused by virus reactivation include mild diseases such as muco-cutaneous lesions, and more severe, and even life-threatening encephalitis, or systemic infections affecting diverse organs. Herpes simplex virus represents the most comprehensive example of virus receptor interaction in Herpesviridae family, and the prototype virus encoding multipartite entry genes. In fact, it encodes 11-12 glycoproteins and a number of additional membrane proteins: five of these proteins play key roles in virus entry into subsceptible cells. Thus, glycoprotein B (gB) and glycoprotein C (gC) interact with heparan sulfate proteoglycan to enable initial attachment to cell surfaces. In the next step, in the entry cascade, gD binds a specific surface receptor such as nectin1 or HVEM. The interaction of glycoprotein D with the receptor alters the conformation of gD to enable the activation of gB, glycoprotein H, and glycoprotein L, a trio of glycoproteins that execute the fusion of the viral envelope with the plasma membrane. In this thesis, I described two distinct projects: I. The retargeting of viral tropism for the design of oncolytic Herpesviruses: • capable of infecting cells through the human epitelial growth factor receptor 2 (HER2), overexpressed in highly malignant mammary and ovarian tumors and correlates with a poor prognosis; • detargeted from its natural receptors, HVEM and nectin1. To this end, we inserted a ligand to HER2 in gD. Because HER2 has no natural ligand, the selected ligand was a single chain antibody (scFv) derived from MAb4D5 (monoclonal antibody to HER2), herein designated scHER2. All recombinant viruses were targeted to HER2 receptor, but only two viruses (R-LM113 and R-LM249) were completely detargeted from HVEM and nectin1. To engineer R-LM113, we removed a large portion at the N-terminus of gD (from aa 6 to aa 38) and inserted scHER2 sequence plus 9-aa serine-glycine flexible linker at position 39. On the other hand, to engineer R-LM249, we replaced the Ig-folded core of gD (from aa 61 to aa 218) with scHER2 flanked by Ser-Gly linkers. In summary, these results provide evidence that: i. gD can tolerate an insert almost as big as gD itself; ii. the Ig-like domain of gD can be removed; iii. the large portion at the N-terminus of gD (from aa 6 to aa 38) can be removed without loss of key function; iv. R-LM113 and R-LM249 recombinants are ready to be assayed in animal models of mammary and ovary tumour. This finding and the avaibility of a large number of scFv greatly increase the collection of potential receptors to which HSV can be redirected. II. The production and purification of recombinant truncated form of the heterodimer gHgL. We cloned a stable insect cell line expressing a soluble form of gH in complex with gL under the control of a metalloprotein inducible promoter and purified the heterodimer by means of ONE-STrEP-tag system by IBA. With respect to biological function, the purified heterodimer is capable: • of reacting to antibodies that recognize conformation dependent epitopes and neutralize virion infectivity; • of binding a variety cells at cell surface. No doubt, the availability of biological active purified gHgL heterodimer, in sufficient quantities, will speed up the efforts to solve its crystal structure and makes it feasible to identify more clearly whether gHgL has a cellular partner, and what is the role of this interaction on virus entry.