2015 Progress Report: A Pipeline for in vitro-to-in vivo Extrapolation, Population Modeling, & Prioritization

EPA Grant Number: R835802C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R835802
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Organotypic Culture Models For Predictive Toxicology Center
Center Director: Rusyn, Ivan
Title: A Pipeline for in vitro-to-in vivo Extrapolation, Population Modeling, & Prioritization
Investigators: Wright, Fred A. , Reif, David , Wetmore, Barbara , Zhou, Yihui
Institution: North Carolina State University
EPA Project Officer: Klieforth, Barbara I
Project Period: June 1, 2015 through May 31, 2019 (Extended to May 31, 2020)
Project Period Covered by this Report: June 1, 2015 through May 31,2016
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Human Health , Health , Safer Chemicals

Objective:

The activities in Projects 1 and 2 necessitate a targeted, yet comprehensive analytic pipeline for analyzing organotypic culture model data screened for dosimetry, physiological parameters, and genetic profiles, culminating in an informed basis for ranking and prioritization. 

The activity in Project 3 will be to collate, analyze, and synthesize the results from Projects 1 and 2. The data gathered in Projects 1 and 2 includes numerous screening measurements in human iPSC-derived cardiomyocytes and rodent embryonic stem cells, building upon recent advances to maximize the informativeness of beating cardiomyocyte models. The screening methods have been critically dependent on appropriate methods to handle these multiple streams of data, with a focus on concentration-response modeling and multivariate analysis. The comparatively low screening costs and availability of low-cost genotyping now also are able to add the dimension of population variation to the analysis, to produce meaningful quantifications of fold-ranges for the most and least susceptible subsets of human populations. The objectives in Project 3 are designed to harness these data in a coherent pipeline. This Project will develop a coordinated analysis and decision-support pipeline based on complex data from an organotypic culture model systems in humans and mice, resulting in standard approaches and tools that can be used in future cardiotoxicity screening and inform human health assessments. Furthermore, these research goals will be achieved by pursuing the following specific objectives.

Specific Objective 1: To apply and refine methods to use the pharmacokinetic data from Project 1 to perform in vitro-to-in vivo extrapolation and subsequent generation of oral equivalent doses. [This Objective has been moved to Project 1 at Texas A&M University. As detailed in the overall Center Report, Professor Weihsueh Chiu, co-investigator in Project 1, will conduct the modeling work that was originally proposed under Project 3. Dr. Chiu is an expert in pharmacokinetic modeling and is more than qualified to lead the work as proposed.] 

Specific Objective 2: To apply concentration-response modeling to establish robust and appropriate points of departure.

Specific Objective 3: To perform annotation-informed analyses of population variation and association.

Specific Objective 4: To perform ranking and prioritization analyses of the ToxCast chemicals screened.

Progress Summary:

Most of the work in the past year has focused on the activities proposed under Specific Objectives 2, 3, and 4. To date, we have accomplished the following:

  • We have developed an improved pipeline for dose-response analysis, applicable to both physiological parameters and to expression data (e.g., the TempOSeq technology). We have performed comparisons of our routines to existing packages such as tcpl.
  • We have made substantial progress on modifying the ToxPi analysis method to
    • handle multiple dimensions of prioritization,
    • to handle missing data, and
    • to quantify across endpoints with irregular correlation structure.
  • We have made progress on new methods for controlling for stratification in genetic association, which will be used in Objective 3 for a limited number of high-priority SNP variants. 

The progress to date has put us in a position that we can engage in automated and efficient prioritization and ranking of chemicals in the next year. 

Future Activities:

  • We will finalize the dose-response analysis pipeline, with built-in robustness and outlier flagging.
  • We will work closely with Project 1 and 2 personnel to analyze the data from high-content screening and high-throughput transcriptomics.
  • We will implement improved clustering techniques into ToxPi, so that similarity among chemicals can be assessed and visualized simultaneously with standard priority ranking.
  • We will develop a protocol for variability analysis across cell lines, developing chemical prioritization schemes that assess population variability by dissecting technical and population sources. 


Journal Articles on this Report : 4 Displayed | Download in RIS Format

Other subproject views: All 18 publications 10 publications in selected types All 10 journal articles
Other center views: All 192 publications 35 publications in selected types All 35 journal articles
Type Citation Sub Project Document Sources
Journal Article Auerbach S, Filer D, Reif D, Walker V, Holloway AC, Schlezinger J, Srinivasan S, Svoboda D, Judson R, Bucher JR, Thayer KA. Prioritizing environmental chemicals for obesity and diabetes outcomes research: a screening approach using ToxCastTM high-throughput data. Environmental Health Perspectives 2016;124(8):1141-1154. R835802 (2015)
R835802 (2016)
R835802 (2017)
R835802 (2018)
R835802C003 (2015)
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  • Abstract from PubMed
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  • Journal Article Grondin CJ, Davis AP, Wiegers TC, King BL, Wiegers JA, Reif DM, Hoppin JA, Mattingly CJ. Advancing exposure science through chemical data curation and integration in the Comparative Toxicogenomics Database. Environmental Health Perspectives 2016;124(10):1592-1599. R835802 (2015)
    R835802 (2016)
    R835802 (2017)
    R835802 (2018)
    R835802C003 (2015)
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  • Abstract from PubMed
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  • Journal Article Judson R, Houck K, Martin M, Richard AM, Knudsen TB, Shah I, Little S, Wambaugh J, Woodrow Setzer R, Kothya P, Phuong J, Filer D, Smith D, Reif D, Rotroff D, Kleinstreuer N, Sipes N, Xia M, Huang R, Crofton K, Thomas RS. Editor's highlight: Analysis of the effects of cell stress and cytotoxicity on in vitro assay activity across a diverse chemical and assay space. Toxicological Sciences 2016;152(2):323-339. R835802 (2015)
    R835802 (2016)
    R835802 (2017)
    R835802 (2018)
    R835802C003 (2015)
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  • Journal Article Zhang G, Marvel S, Truong L, Tanguay RL, Reif DM. Aggregate entropy scoring for quantifying activity across endpoints with irregular correlation structure. Reproductive Toxicology 2016;62:92-99. R835802 (2015)
    R835802 (2016)
    R835802 (2017)
    R835802 (2018)
    R835802C003 (2015)
    R835168 (Final)
    R835796 (2017)
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  • Supplemental Keywords:

    cardiovascular, stem cells, toxicity pathway, variability, dose-response, ToxCast

    Progress and Final Reports:

    Original Abstract
  • 2016
  • 2017
  • 2018 Progress Report

  • Main Center Abstract and Reports:

    R835802    Organotypic Culture Models For Predictive Toxicology Center

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R835802C001 High-throughput Hazard,Dose-responseandPopulationVariabilityAssessmentof Cardiotoxicity in aHumanInducedPluripotentStem Cell(iPSC)-derivedin vitro Culture Model
    R835802C002 Linking in vitro-to-in vivoToxicity Testing Using Genetically-matchedOrganoids and Mice from a Novel Genetic Reference Population
    R835802C003 A Pipeline for in vitro-to-in vivo Extrapolation, Population Modeling, & Prioritization