9 A Pair Ranking (PRank) Method for Assessing Assay …
169
9.4.4 Gene Sets Related to Adverse Outcome Pathways
(AOPs)
To investigate whether the assay transferability is AOP-specific, the gene sets related
to different AOP were extracted from the Comparative Toxicogenomics Database
(CTD) [40]. CTD aims to provide a comprehensive resource for better understanding
the interrelationship among genes, chemicals, and diseases and advancing the public
health. In this chapter, we used the gene-pathway association table in CTD, which
was downloaded from http://ctdbase.org/downloads/. Only the pathways with more
than 200 genes were kept for further analysis.
9.4.5 Code Availability
The source code of PRank, the processed microarray data, and the annotation data
used in this chapter can be downloaded from GitHub at the link https://github.com/
iguana128/Frontier-source-codes.
9.5 Case Studies
9.5.1 In Vitro to in Vivo Extrapolation (IVIVE) in TGx
Efforts have been made to develop in vitro systems tailored to address toxicologically
relevant mechanisms and enhance risk assessment. Also, drug failures either in preclinical or clinical development often require pharmaceutical companies to go back
into lead optimization and select new molecules without unwanted properties. In
this context, ICH-M3 (http://www.ich.org/products/guidelines/safety/safety-single/
article/guidance-on-nonclinical-safety-studies-for-the-conduct-of-human-clinicaltrials-and-marketing-author.html) highlights, “additional nonclinical studies to
provide mechanistic understanding can be useful.” In this field, in vitro to in vivo
extrapolation (IVIVE) has emerged as one of the powerful twenty-first-century
methodologies for risk assessment and safety evaluation. IVIVE is defined as, “The
qualitative or quantitative transposition of experimental results or observations made
in vitro to predict phenomena in vivo, on full living organisms.” A comprehensive
assessment of IVIVE potential in TGx assay systems is of great importance for
promoting the 3Rs principle and improving risk assessment power.
The proposed PRank method was employed to investigate the IVIVE potential
based on the Open TG-GATEs data sets. Figure 9.4a illustrates the concordances
among three TGx assays including rat in vitro, human in vitro, and rat in vivo repeated
dosing. The highest PRank score 0.77 was obtained between two in vitro assay
systems, highlighting the testing systems was dominated by the divergence among
169
9.4.4 Gene Sets Related to Adverse Outcome Pathways
(AOPs)
To investigate whether the assay transferability is AOP-specific, the gene sets related
to different AOP were extracted from the Comparative Toxicogenomics Database
(CTD) [40]. CTD aims to provide a comprehensive resource for better understanding
the interrelationship among genes, chemicals, and diseases and advancing the public
health. In this chapter, we used the gene-pathway association table in CTD, which
was downloaded from http://ctdbase.org/downloads/. Only the pathways with more
than 200 genes were kept for further analysis.
9.4.5 Code Availability
The source code of PRank, the processed microarray data, and the annotation data
used in this chapter can be downloaded from GitHub at the link https://github.com/
iguana128/Frontier-source-codes.
9.5 Case Studies
9.5.1 In Vitro to in Vivo Extrapolation (IVIVE) in TGx
Efforts have been made to develop in vitro systems tailored to address toxicologically
relevant mechanisms and enhance risk assessment. Also, drug failures either in preclinical or clinical development often require pharmaceutical companies to go back
into lead optimization and select new molecules without unwanted properties. In
this context, ICH-M3 (http://www.ich.org/products/guidelines/safety/safety-single/
article/guidance-on-nonclinical-safety-studies-for-the-conduct-of-human-clinicaltrials-and-marketing-author.html) highlights, “additional nonclinical studies to
provide mechanistic understanding can be useful.” In this field, in vitro to in vivo
extrapolation (IVIVE) has emerged as one of the powerful twenty-first-century
methodologies for risk assessment and safety evaluation. IVIVE is defined as, “The
qualitative or quantitative transposition of experimental results or observations made
in vitro to predict phenomena in vivo, on full living organisms.” A comprehensive
assessment of IVIVE potential in TGx assay systems is of great importance for
promoting the 3Rs principle and improving risk assessment power.
The proposed PRank method was employed to investigate the IVIVE potential
based on the Open TG-GATEs data sets. Figure 9.4a illustrates the concordances
among three TGx assays including rat in vitro, human in vitro, and rat in vivo repeated
dosing. The highest PRank score 0.77 was obtained between two in vitro assay
systems, highlighting the testing systems was dominated by the divergence among