Using a gene expression biomarker to identify DNA damage‐inducing agents in microarray profiles
Bibliographic record
Abstract
High-throughput transcriptomic technologies are increasingly being used to screen environmental chemicals in vitro to provide mechanistic context for regulatory testing. The TGx-DDI biomarker is a 64-gene expression profile generated from testing 28 model chemicals or treatments (13 that cause DNA damage and 15 that do not) in human TK6 cells. While the biomarker is very accurate at predicting DNA damage inducing (DDI) potential using the nearest shrunken centroid method, the broad utility of the biomarker using other computational methods is not fully known. Here, we determined the accuracy of the biomarker used with the Running Fisher test, a nonparametric correlation test. In TK6 cells, the methods could readily differentiate DDI and non-DDI compounds with balanced accuracies of 87-97%, depending on the threshold for determining DDI positives. The methods identified DDI agents in the metabolically competent hepatocyte cell line HepaRG (accuracy = 90%) but not in HepG2 cells or hepatocytes derived from embryonic stem cells (60 and 80%, respectively). DDI was also accurately classified when the gene expression changes were derived using the nCounter technology (accuracy = 89%). In addition, we found: (1) not all genes contributed equally to the correlations; (2) the minimal overlap in genes between the biomarker and the individual comparisons required for significant positive correlation was 10 genes, but usually was much higher; and (3) different sets of genes in the biomarker can by themselves contribute to the significant correlations. Overall, these results demonstrate the utility of the biomarker to accurately classify DDI agents. Environ. Mol. Mutagen. 59:772-784, 2018. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".