Advancing Disease Modeling in Animal-Based Research in Support of Precision Medicine Proceedings of a Workshop (2018) / Chapter Skim
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6 Assessing Safety and Toxicology
6 Assessing Safety and Toxicology
Pages 69-81
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From page 69... ...
fellow and director and head of WW Animal Research Strategy at GSK, talked about the successes and challenges of testing for patient susceptibilities in preclinical drug safety assessment. There are many modeling platforms used throughout the drug development process, but animal models are used strategically throughout 69
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From page 70... ...
Cancer treatments give us an opportunity to study toxicities and the concordance between animal and human studies, because higher levels of toxicity from cancer drugs are generally tolerated. One study on cardiovascular liabilities associated with cancer drugs found that, while there was an overall low incidence of most events, the intra-patient incidence varied widely, suggesting that individual patients are more susceptible, Berridge said.
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From page 71... ...
However, the system is not designed to identify those rare clinical events associated with individual patient susceptibilities. As precision medicine advances, there may be an expectation that preclinical assessment will identify these individual susceptibilities, and as technological capabilities advance, it may be possible to do so.
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From page 72... ...
Stevens said that focusing on modules of genes can define biological or pathophysiological responses while reducing complexity compared to analysis at individual gene level, thus avoiding the "curse of dimensionality" -- that is, the need for more and more data as the dimensions of the data increase. At the same time, modules retain biological content and help improve data interpretation through network visualization, rather than analysis of individual elements or genes.
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From page 73... ...
Stevens told workshop participants that correlation of individual histological morphologies of injury with changes in WGCNA modules reveals identifiable and interpretable patterns. For example, modular gene changes in a rat model of bile duct ligation demonstrate that the WGCNA module activity parallels the changes in traditional measures of liver injury, such as histological morphology and serum biochemistry.
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From page 74... ...
mouse population is a rationally interbred population with highly randomized polymorphisms that mimics human genetic diversity, said Harrill. These mice were created through a genetic reshuffling of genes from eight founder strains, each with a different genetic profile and different propensities for diseases (see Figure 6-1)
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From page 75... ...
These mice are used • to identify specific polymorphisms associated with xenobiotic toxicity, • to evaluate biomarker performance toward assessing human clini cal adverse outcomes, and • as a tool for population-based estimates of chemical potency for risk assessment. To Identify Specific Polymorphisms Associated with Xenobiotic Toxicity A diverse mouse population can be used to identify specific gene variants that influence susceptibility to drug and chemical toxicity.
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From page 76... ...
INTEGRATING EVIDENCE FROM ANIMAL AND HUMAN STUDIES The Integrated Risk Information System (IRIS) was created in 1985 to enable consistent evaluations of chemical toxicity, said Kristina Thayer, who serves as director of the IRIS Division at the Environmental Protection Agency (EPA)
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From page 77... ...
For example, the bias analysis might look at whether or not the study used randomization; sensitivity analysis might look at the variation in exposure levels; applicability analysis might determine how relevant a specific animal model is to human health; and reporting quality analysis might look at whether the specific form of the chemical was reported. Each of these criteria receives an overall score of good, adequate, poor, or critically deficient.
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From page 78... ...
Human and animal studies are synthesized separately, but their evidence streams are integrated together, a step that also includes mechanistic evidence that can inform the study results. Mechanistic evidence is particularly important when the studies are of lower quality and a determination cannot be made on the studies alone.
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From page 79... ...
FIGURE 6-3: Across study evaluations SOURCE: Thayer, Slide 8 eral findings, the factors that increase or decrease confidence in the findings, a judgment rating about the strength of the evidence, the inference across evidence streams, and a final conclusion about the evidence (see Figure 6-4)
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From page 80... ...
80 FIGURE 6-4 Table to summarize evidence synthesis summarize judgments. FIGURE 6-4: Table to and integration evidence synthesis and SOURCE: Thayer, slide 13.
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From page 81... ...
Animal models in environmental health are assumed to be relevant to human health unless there are data to suggest otherwise. "Exact findings in animals and humans aren't necessarily required.
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