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TransOrGAN: An Artificial Intelligence Mapping of Rat Transcriptomic Profiles between Organs, Ages, and Sexes
Ting Li1, Ruth Roberts2,3, Zhichao Liu4
1National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas 72079, United States.
Abstract:
Animal studies are required for the evaluation of candidate drugs to ensure patient and volunteer safety. Toxicogenomics is often applied in these studies to gain understanding of the underlying mechanisms of toxicity, which is usually focused on critical organs such as the liver or kidney in young male rats. There is a strong ethical reason to reduce, refine and replace animal use (the 3Rs), where the mapping of data between organs, sexes and ages could reduce the cost and time of drug development. Herein, we proposed a generative adversarial network (GAN)-based framework entitled TransOrGAN that allowed the molecular mapping of gene expression profiles in different rodent organ systems and across sex and age groups. We carried out a proof-of-concept study based on rat RNA-seq data from 288 samples in 9 different organs of both sexes and 4 developmental stages. First, we demonstrated that TransOrGAN could infer transcriptomic profiles between any 2 of the 9 organs studied, yielding an average cosine similarity of 0.984 between synthetic transcriptomic profiles and their corresponding real profiles. Second, we found that TransOrGAN could infer transcriptomic profiles observed in females from males, with an average cosine similarity of 0.984. Third, we found that TransOrGAN could infer transcriptomic profiles in juvenile, adult, and aged animals from adolescent animals with an average cosine similarity of 0.981, 0.983, and 0.989, respectively. Altogether, TransOrGAN is an innovative approach to infer transcriptomic profiles between ages, sexes, and organ systems, offering the opportunity to reduce animal usage and to provide an integrated assessment of toxicity in the whole organism irrespective of sex or age.
Insights
TransOrGAN, a novel generative adversarial network framework, accurately infers gene expression profiles across organs, sexes, and ages in rodents. This approach reduces animal testing and enhances toxicity assessments in drug development.
Area of Science:
- Computational Biology
- Toxicogenomics
- Bioinformatics
Background:
- Animal studies are crucial for drug safety evaluation, often employing toxicogenomics to understand toxicity mechanisms in specific organs and demographics.
- Ethical considerations (the 3Rs: reduce, refine, replace) necessitate minimizing animal use in research.
- Data mapping across organs, sexes, and ages can significantly reduce drug development costs and timelines.
Purpose of the Study:
- To introduce TransOrGAN, a generative adversarial network (GAN)-based framework for molecular mapping of gene expression profiles.
- To demonstrate the capability of TransOrGAN to infer transcriptomic data across different rodent organ systems, sexes, and age groups.
- To provide a method for reducing animal usage and enabling integrated toxicity assessment.
Main Methods:
- Development of a generative adversarial network (GAN)-based framework named TransOrGAN.
- Utilized rat RNA-seq data from 288 samples across 9 organs, both sexes, and 4 developmental stages for proof-of-concept.
- Validated TransOrGAN's ability to infer transcriptomic profiles between organs, sexes, and age groups.
Main Results:
- TransOrGAN successfully inferred transcriptomic profiles between any two of the nine studied organs with an average cosine similarity of 0.984.
- The framework accurately inferred female transcriptomic profiles from male data (average cosine similarity: 0.984).
- TransOrGAN inferred transcriptomic profiles across different age groups (juvenile, adult, aged) from adolescent data with high accuracy (0.981-0.989).
Conclusions:
- TransOrGAN offers an innovative method for inferring transcriptomic profiles across diverse biological contexts (age, sex, organ systems).
- The framework has the potential to significantly reduce the number of animals required for drug development studies.
- TransOrGAN facilitates a comprehensive, organism-wide assessment of toxicity, independent of sex or age.
