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Gene expression response in target organ and whole blood varies as a function of target organ injury phenotype.

Lobenhofer EK, Auman JT, Blackshear PE, Boorman GA, Bushel PR, Cunningham ML, Fostel JM, Gerrish K, Heinloth AN, Irwin RD, Malarkey DE, Merrick BA, Sieber SO, Tucker CJ, Ward SM, Wilson RE, Hurban P, Tennant RW, Paules RS - Genome Biol. (2008)

Bottom Line: This report details the standardized experimental design and the different data streams that were collected (histopathology, clinical chemistry, hematology and gene expression from the target tissue (liver) and a bio-available tissue (blood)) after treatment with eight known hepatotoxicants (at multiple time points and doses with multiple biological replicates).The results of the study demonstrate the classification of histopathological differences, likely reflecting differences in mechanisms of cell-specific toxicity, using either liver tissue or blood transcriptomic data.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cogenics, Division of Clinical Data, Inc, Morrisville, NC 27560, USA. elobenhofer@cogenics.com

ABSTRACT
This report details the standardized experimental design and the different data streams that were collected (histopathology, clinical chemistry, hematology and gene expression from the target tissue (liver) and a bio-available tissue (blood)) after treatment with eight known hepatotoxicants (at multiple time points and doses with multiple biological replicates). The results of the study demonstrate the classification of histopathological differences, likely reflecting differences in mechanisms of cell-specific toxicity, using either liver tissue or blood transcriptomic data.

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Related in: MedlinePlus

Hierarchical clustering of animals in the high dose/48 hour group using SVM-derived classifiers. Two-way hierarchical clustering using Ward's minimum variance as the heuristic criteria and Euclidean distance as the similarity metric was performed on all of the animals in the high dose/48 hour group using the blood expression values for the 60 transcripts identified as compound classifiers for this dose/time group by a SVM algorithm. The degree of relatedness between each sample is represented by the dendrogram (hierarchical tree) presented in this figure, wherein the height of each branch represents the distance between the two objects being connected.
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Figure 2: Hierarchical clustering of animals in the high dose/48 hour group using SVM-derived classifiers. Two-way hierarchical clustering using Ward's minimum variance as the heuristic criteria and Euclidean distance as the similarity metric was performed on all of the animals in the high dose/48 hour group using the blood expression values for the 60 transcripts identified as compound classifiers for this dose/time group by a SVM algorithm. The degree of relatedness between each sample is represented by the dendrogram (hierarchical tree) presented in this figure, wherein the height of each branch represents the distance between the two objects being connected.

Mentions: Transcript data from blood, however, were also unable to group individual animals in some instances in which the compound manifested different phenotypic responses across the animals of that particular dose/time group. At the high dose/48 hour time point, three of the compounds (diquat, thioacetamide, and galactosamine) demonstrated variability in regards to the extent of hepatocellular necrosis, the amount of inflammatory cell infiltrates and/or indications of hepatocellular repair (mitosis). Consistent with this observation, these are also the three compounds that did not separate perfectly in the dendrogram resulting from the hierarchical clustering of the blood gene expression data for the 60 SVM-identified classifiers for this dose/time group (Figure 2), suggesting that the phenotypic response resulting from exposure to a given compound was having a greater impact on the gene expression profile compared to a unified transcriptional response resulting merely from the exposure to the compound per se. Taken together, these results indicate that the details of the injury resulting from compound application are a more appropriate grouping than are the doses and time points of individual compounds when using gene expression data from the primary site of injury - in this case the liver - or when using gene expression data from a surrogate source such as whole blood.


Gene expression response in target organ and whole blood varies as a function of target organ injury phenotype.

Lobenhofer EK, Auman JT, Blackshear PE, Boorman GA, Bushel PR, Cunningham ML, Fostel JM, Gerrish K, Heinloth AN, Irwin RD, Malarkey DE, Merrick BA, Sieber SO, Tucker CJ, Ward SM, Wilson RE, Hurban P, Tennant RW, Paules RS - Genome Biol. (2008)

Hierarchical clustering of animals in the high dose/48 hour group using SVM-derived classifiers. Two-way hierarchical clustering using Ward's minimum variance as the heuristic criteria and Euclidean distance as the similarity metric was performed on all of the animals in the high dose/48 hour group using the blood expression values for the 60 transcripts identified as compound classifiers for this dose/time group by a SVM algorithm. The degree of relatedness between each sample is represented by the dendrogram (hierarchical tree) presented in this figure, wherein the height of each branch represents the distance between the two objects being connected.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2481421&req=5

Figure 2: Hierarchical clustering of animals in the high dose/48 hour group using SVM-derived classifiers. Two-way hierarchical clustering using Ward's minimum variance as the heuristic criteria and Euclidean distance as the similarity metric was performed on all of the animals in the high dose/48 hour group using the blood expression values for the 60 transcripts identified as compound classifiers for this dose/time group by a SVM algorithm. The degree of relatedness between each sample is represented by the dendrogram (hierarchical tree) presented in this figure, wherein the height of each branch represents the distance between the two objects being connected.
Mentions: Transcript data from blood, however, were also unable to group individual animals in some instances in which the compound manifested different phenotypic responses across the animals of that particular dose/time group. At the high dose/48 hour time point, three of the compounds (diquat, thioacetamide, and galactosamine) demonstrated variability in regards to the extent of hepatocellular necrosis, the amount of inflammatory cell infiltrates and/or indications of hepatocellular repair (mitosis). Consistent with this observation, these are also the three compounds that did not separate perfectly in the dendrogram resulting from the hierarchical clustering of the blood gene expression data for the 60 SVM-identified classifiers for this dose/time group (Figure 2), suggesting that the phenotypic response resulting from exposure to a given compound was having a greater impact on the gene expression profile compared to a unified transcriptional response resulting merely from the exposure to the compound per se. Taken together, these results indicate that the details of the injury resulting from compound application are a more appropriate grouping than are the doses and time points of individual compounds when using gene expression data from the primary site of injury - in this case the liver - or when using gene expression data from a surrogate source such as whole blood.

Bottom Line: This report details the standardized experimental design and the different data streams that were collected (histopathology, clinical chemistry, hematology and gene expression from the target tissue (liver) and a bio-available tissue (blood)) after treatment with eight known hepatotoxicants (at multiple time points and doses with multiple biological replicates).The results of the study demonstrate the classification of histopathological differences, likely reflecting differences in mechanisms of cell-specific toxicity, using either liver tissue or blood transcriptomic data.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cogenics, Division of Clinical Data, Inc, Morrisville, NC 27560, USA. elobenhofer@cogenics.com

ABSTRACT
This report details the standardized experimental design and the different data streams that were collected (histopathology, clinical chemistry, hematology and gene expression from the target tissue (liver) and a bio-available tissue (blood)) after treatment with eight known hepatotoxicants (at multiple time points and doses with multiple biological replicates). The results of the study demonstrate the classification of histopathological differences, likely reflecting differences in mechanisms of cell-specific toxicity, using either liver tissue or blood transcriptomic data.

Show MeSH
Related in: MedlinePlus