Journal
JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS
Volume 114, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vascn.2022.107154
Keywords
Cardiotoxicity; In vitro; Methods; Population variability; Study design; Toxicodynamics
Categories
Funding
- National Institutes of Health [P42 ES027704, T32 ES026568]
- United States Environmental Protection Agency [STAR RD83580201]
Ask authors/readers for more resources
Population-wide in vitro studies using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are effective in assessing cardiotoxicity hazard and population variability. Computational down-sampling analysis can optimize study design and determine the appropriate population size considerations. The study found that a cohort of 5 unique donors is sufficient for accurate estimation of potency and QT prolongation risk, while a cohort of at least 20 donors is needed for estimating inter-individual variability.
Population-wide in vitro studies for characterization of cardiotoxicity hazard, risk, and population variability show that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a powerful and high throughput testing platform for drugs and environmental chemicals alike. However, studies in multiple donor derived hiPSC-CMs, across large libraries of chemicals tested in concentration-response are technically complex, and study design optimization is needed to determine sufficient and fit-for-purpose population size considerations. Therefore, we tested a hypothesis that a computational down-sampling analysis based on the data from hiPSC-CM screening of 136 diverse compounds in a population of 43 non-diseased donors, including multiple replicates of the standard donor hiPSC-CMs, will inform optimal study designs depending on the decision context (hazard, risk and/or inter-individual variability in cardiotoxicity). Through 50 independent random subsamples of 5, 10, or 20 donors, we estimated accuracy and precision for quantifying potency, inter individual variability, and QT prolongation risk; the results were compared to the full 43-donor cohort. We found that for potency and clinical risk of QT prolongation, a cohort of 5 randomly-selected unique donors provides accurate and precise estimates. Larger cohort sizes afforded marginal improvements, and 5 replicates of a single donor performed worse. For estimating inter-individual variability, cohorts of at least 20 donors are needed, with smaller populations on average showing bias towards underestimation in population variance. Collectively, this study shows that a variable-size hiPSC-CM-based population-wide in vitro model can be used in a number of decision scenarios for identifying cardiotoxic hazards of drugs and environmental chemicals in the population context.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available