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
Project Amount: Refer to main center abstract for funding details.
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Human Health , Health , Safer Chemicals

Objective:

The data gathered in Projects 1 and 2 will include numerous screening measurements in population-based designs utilizing human and mouse iPSC-derived cardiomyocytes, building upon recent advances to maximize the informativeness of cardiomyocyte organotypic culture models. Much of this progress has been developed for drug screening, but the high-throughput organotypic nature of the data makes the cardiomyocyte models ideal for chemical toxicity screening, as well. The screening methods have been critically dependent on appropriate bioinformatics/biostatistics 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 genotyped cells from multiple individuals are now opening new horizons for adding the dimension of population variability. Such analysis will produce meaningful quantification of the degree of genetic variability among the most and least susceptible subjects, including humans. In addition, recent advances to incorporate dosimetry with high-throughput methods have the potential to greatly sharpen estimates of “risk” derived from such in vitro experiments. Finally, parallel advances in mouse models with highly varying genetic backgrounds can elucidate whether variation in these models is related to variation in human models, and to follow up with targeted in vivo validation.

Approach:

Each of the recent methodological in vitro screening advances has produced accompanying challenges in data analysis, and the four Objectives in Project 3 are designed to harness these data in a coherent pipeline. Specifically, we will (i) perform in vitro-toin vivo extrapolation modeling using these high-throughput screening data to provide a more informative risk characterization of chemicals; (ii) conduct dose-response modeling to establish robust and appropriate points of departure, (iii) perform annotation-informed association and population variation analyses, (iv) perform ranking and prioritization analysis of screening outcomes from Projects 1 and 2, using rigorous statistical approaches designed to provide flexible weighting schemes and to incorporate uncertainty.

Expected Results:

This Project will develop a coordinated analysis and decision-support pipeline based on complex data from an organotypic culture model, resulting in standard approaches and tools that can be used in future cardiotoxicity screening and inform human health assessments.

Publications and Presentations:

Publications have been submitted on this subproject: View all 5 publications for this subprojectView all 55 publications for this center

Journal Articles:

Journal Articles have been submitted on this subproject: View all 4 journal articles for this subprojectView all 13 journal articles for this center

Supplemental Keywords:

concentration-response, adverse outcome pathways, IVIVE, extrapolation

Progress and Final Reports:

2015 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-response and Population Variability Assessment of Cardiotoxicity in a Human Induced Pluripotent Stem Cell (iPSC)-derived in vitro Culture Model
R835802C002 Linking in vitro-to-in vivoToxicity Testing Using Genetically-matched Organoids and Mice from a Novel Genetic Reference Population
R835802C003 A Pipeline for in vitro-to-in vivo Extrapolation, Population Modeling, & Prioritization