Statistical Models In Toxicology And Biochemistry
毒理学和生物化学的统计模型
基本信息
- 批准号:7593903
- 负责人:
- 金额:$ 116.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:9,10-anthraquinoneAcetaminophenAddressAffectAlgorithmsAnthraquinonesAreaBiochemical PathwayBiochemistryBiologicalBlood PressureBrainCaenorhabditis elegansCardiovascular DiseasesCardiovascular PhysiologyCell LineCell SurvivalCessation of lifeChemicalsChlorpyrifosChronicClassificationCollaborationsCommunitiesComputing MethodologiesConditionCreatinineDNA Microarray ChipDNA Microarray formatDataData AnalysesData SetDatabasesDevelopmentDiseaseDisease PathwayDorsalDoseEnvironmental Risk FactorEnzymesEvaluationExcretory functionExperimental DesignsFutureGene ExpressionGene ProteinsGenesGeneticGenetic PolymorphismGenomicsGroupingGrowthHealthHumanIncidenceInstitutesIodineJointsLaboratory ResearchLasersLocationLondonMalignant NeoplasmsMeasurementMeasuresMedical ResearchMetabolicMetabolismMethodologyMethodsModelingMolecularMusNational Health and Nutrition Examination SurveyNational Toxicology ProgramNatureNon-Insulin-Dependent Diabetes MellitusNorth CarolinaNumbersParentsPathway interactionsPatientsPeer ReviewPerchloratesPhenotypePolymerase Chain ReactionPopulationProcessProteinsPulse PressureRNARateRattusRegulator GenesResearchResearch DesignRisk AssessmentRisk EstimateRisk FactorsRunningSamplingSeriesShapesSignal PathwaySignal TransductionSimulateStagingStatistical ModelsStatistically SignificantStochastic ProcessesSuggestionSystemTelencephalonTestingTetrachlorodibenzodioxinThyroid HormonesTissuesToxic effectToxicogenomicsToxicokineticsToxicologyToxinTransgenic MiceUniversitiesWomanWorkabsorptionbasecarcinogenesiscomputer based statistical methodsdesignfeedinggenetic manipulationhigh throughput screeningimprovedin uteromenmethod developmentmodel developmentmolecular scalenanoscaleneurogenesisnovelpharmacokinetic modelresearch studyresponsesoundurinary
项目摘要
We developed a quantitative, statistically sound methodology for the analysis of suspected gene regulatory networks using gene expression data sets. The method is based on Bayesian networks and provides a means to directly quantify gene-expression networks and test hypotheses regarding the linkages between genes in this network. The method is currently being applied to a number of data sets including data on early brain development and acetaminophen toxicity.
Data on the molecular scale obtained under different sampling conditions are becoming increasingly available from systems like DNA microarrays. These data can be related to each other in a number of ways such as through their gene products (proteins, enzymes) being involved in the same metabolic andor signaling pathways, through their common linkage to certain diseases, or simply because their parent genes have similar chromosomal locations. In the interpretation of these data, a key question is how to intelligently propose ideas and experiments for further studies based not only on the changing molecular measures, but on their biologically-relevant pathways. We use two biologically-inspired hypotheses that would help identify pathways that would be more relevant to a certain disease condition or the presence of a toxin. First, pathways where the gene products of the perturbed genes are close together in the inherent flow of materialinformation of these pathways are worth considering for further analysis. And second there are certain gene products at the beginning of the biochemical pathway, like the receptorsgrowth factors that are more important than others in being responsible for turning on a pathway. Using these hypotheses, we are developing a novel pathwaygene set enrichment algorithm. We demonstrate its efficacy using different sets of simulated data and also with microarray data obtained from patients with Type 2 diabetes, when compared with the methods currently used.
We are also developing methodology to test the hypothesis of being able to predict genetic response under certain conditions using a database of gene expression responses to carefully chosen genetic perturbations.
In PBPK modeling, the effects of model mis-specification with respect to compound transport into tissues has been investigated with focus on experimental design, coverage by joint confidence regions of the true values of estimated parameters, and the alpha levels of likelihood ratio tests, AIC and BIC tests for model selection.
We have a focused effort on environmental components that may effect brain development. Our initial project is a collaboration between our lab and Fthe National Institute of Medical Research in London, and involves the analysis of genomic data during telencephalon neurogenesis in the mouse. Several experimental and computational analyses were added to the initial submission of this research, based on reviewers suggestions. Building from this project of genetic manipulation during neurogenesis, we have undertaken a project in which AhR transgenic mice were exposed to TCDD in utero, and dorsal and ventral telencephalon were dissected via laser capture. Currently, RNA is being isolated for microarray hybridization.
We have also initiated a collaboration with NIA on expanding the utility a database of polymorphisms associated with particular phenotypes in human populations. We are using this dataset, along with gene-environmental factor data from the chemical toxicogenomics database, to discover relationships between genes, pathways, diseases, and environmental factors.
We have designed and analyzed a series of experiments running beads through the COPAS Biosorter. The analysis shows that measurements on beads was reproducible with consistent machine settings as well as the effect of the machine settings on two classic measurements, EXT and TOF. A pronounced batch effect on bead measuremennts was also uncovered. We also applied a previously developed Markov type population model for growth to 2 experiments exposing C. elegans to chlorpyrifos. The estimated growth rates were used to deduce the nature of the chlorpyrifos effect on growth. Later we extended the model to include death of worms and the curling of worms as it affected TOF measurements.
An algorithm was developed for estimating absolute quantities of initial amplicon in PCR amplifications. This method is an improvement over other analytical approaches because it allows the absolute estimate to be made using a single amplification run.
A rigorous analysis is being conducted comparing the previously developed Tao-Gen algorithm to current alternative Bayesian Network methods with respect to alternative prior distributions. The applications area is primarily uncovering geneprotein signal transduction networks with missing nodes.
Previous studies have shown that perchlorate is significantly positively correlated with TSH and negatively correlated with T4 in women. Since thyroid hormones have an impact on cardiovascular function, it is possible that environmental levels of perchlorate may have an effect on blood pressure. Using the NHANES data from 2001-2002, we explored the statistical relationship between perchlorate and blood pressure in both men and women, and men and women whose urinary iodine levels were <100 ugL . In all 7 groupings of these data: all men, men with urinary iodine <100 ugL, men with urinary iodine8805;100 ugL, all men and women, all women, women with urinary iodine <100 ugL, and women with urinary iodine 8805;100 ugL, perchlorate divided by creatinine to adjust for urinary dilution was not a significant regressor of pulse pressure. Treating perchloratecreatinine as a categorical variable to test for non-linear results also resulted in non-significant coefficients. Using the models from pulse pressure, we also looked at the effects of perchlorate on DBP and SBP separately, but there was no significant effect. From this, it appears environmental levels of perchlorate do not have a statistically significant effect on the pulse pressure of men or women, regardless of their iodine levels. Thyroid hormones and several other known risk factors for cardiovascular disease did show significant results.
We are developing a mathematical and pharmacological framework to describe the absorption, distribution and metabolism of nanoscale materials in mammalian systems. This work is in collaboration with colleagues at the National Toxicology Program, the National Center for Toxicological Research and North Carolina State University.
A physiologically based pharmacokinetic model was developed to represent the absorption, distribution, metabolism, and excretion of anthraquinone in rats. The model results were used in a two-stage model of carcinogenesis applied to results from the chronic feed study of anthraquinone.
Cell viability high throughput screening (HTS) data for 13 cell lines were analyzed to screen 1353 chemicals for dose-response effects. The analysis revealed systematic effects of plate location on the measured cell viability. A dose-response analysis of the data was performed with an algorithm including corrections for the plate location effects. Various statistical tests for identifying significant concentration-response relationships and for addressing replicability were developed.
我们开发了一种定量的,统计上合理的方法,用于使用基因表达数据集分析可疑的基因调控网络。该方法基于贝叶斯网络,提供了一种直接量化基因表达网络和测试关于该网络中基因之间联系的假设的方法。该方法目前正在应用于许多数据集,包括早期大脑发育和对乙酰氨基酚毒性的数据。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christopher J Portier其他文献
A call from 40 public health scientists for an end to the continuing humanitarian and environmental catastrophe in Gaza
- DOI:
10.1186/s12940-024-01097-9 - 发表时间:
2024-06-28 - 期刊:
- 影响因子:5.900
- 作者:
Leslie London;Andrew Watterson;Donna Mergler;Maria Albin;Federico Andrade-Rivas;Agostino Di Ciaula;Pietro Comba;Fernanda Giannasi;Rima R Habib;Alastair Hay;Jane Hoppin;Peter Infante;Mohamed Jeebhay;Karl Kelsey;Rokho Kim;Richard Lemen;Hester Lipscomb;Elsebeth Lynge;Corrado Magnani;Celeste Monforton;Benoit Nemery;Vera Ngowi;Dennis Nowak;Iman Nuwayhid;Christine Oliver;David Ozonoff;Domyung Paek;Varduhi Petrosyan;Christopher J Portier;Beate Ritz;Linda Rosenstock;Kathleen Ruff;Peter Sly;Morando Soffritti;Colin L. Soskolne;William Suk;Benedetto Terracini;Harri Uolevi Vainio;Paolo Vineis;Roberta White - 通讯作者:
Roberta White
Christopher J Portier的其他文献
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{{ truncateString('Christopher J Portier', 18)}}的其他基金
Receptor Interaction For TCDD And Its Structural Analogs
TCDD 及其结构类似物的受体相互作用
- 批准号:
6501230 - 财政年份:
- 资助金额:
$ 116.08万 - 项目类别:
相似国自然基金
SirT1在Acetaminophen诱发的药物性肝损伤中的作用及机制
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- 批准年份:2011
- 资助金额:24.0 万元
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Operating Grants
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