Untangling the effects of cellular composition on coexpression analysis
Bibliographic record
Abstract
Coexpression analysis is widely used for inferring regulatory networks, predicting gene function, and interpretation of transcriptome profiling studies, based on methods such as clustering. The majority of such studies use data collected from bulk tissue, where the effects of cellular composition present a potential confound. However, the impact of composition on coexpression analysis has not been studied in detail. Here, we examine this issue for the case of human RNA analysis. Focusing on brain tissue, we found that, for most genes, differences in expression levels across cell types account for a large fraction of the variance of their measured RNA levels (median R 2 = 0.68). We then show that genes that have similar expression patterns across cell types will have correlated RNA levels in bulk tissue, due to the effect of variation in cellular composition. We demonstrate that much of the coexpression and the formation of coexpression clusters can be attributed to this effect for both brain and blood transcriptomes. For brain, we further show how this composition-induced coexpression masks underlying intra-cell-type coexpression observed in single-cell data. An attempt to correct for composition yielded mixed results. Our conclusion is that the dominant coexpression signal in brain, blood, and, likely, other complex tissues can be attributed to cellular compositional effects, rather than intra-cell-type regulatory relationships. These results have implications for the relevance and interpretation of coexpression analysis.
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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 | 0.006 | 0.017 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.003 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| 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".