Parallelized Latent Dirichlet Allocation Provides a Novel Interpretability of Mutation Signatures in Cancer Genomes
Bibliographic record
Abstract
Mutation signatures are defined as the distribution of specific mutations such as activity of AID/APOBEC family proteins. Previous studies have reported numerous signatures, using matrix factorization methods for mutation catalogs. Different mutation signatures are active in different tumor types; hence, signature activity varies greatly among tumor types and becomes sparse. Because of this, many previous methods require dividing mutation catalogs for each tumor type. Here, we propose parallelized latent Dirichlet allocation (PLDA), a novel Bayesian model to simultaneously predict mutation signatures with all mutation catalogs. PLDA is an extended model of latent Dirichlet allocation (LDA), which is one of the methods used for signature prediction. It has parallelized hyperparameters of Dirichlet distributions for LDA, and they represent the sparsity of signature activities for each tumor type, thus facilitating simultaneous analyses. First, we conducted a simulation experiment to compare PLDA with previous methods (including SigProfiler and SignatureAnalyzer) using artificial data and confirmed that PLDA could predict signature structures as accurately as previous methods without searching for the optimal hyperparameters. Next, we applied PLDA to PCAWG (Pan-Cancer Analysis of Whole Genomes) mutation catalogs and obtained a signature set different from the one predicted by SigProfiler. Further, we have shown that the mutation spectrum represented by the predicted signature with PLDA provides a novel interpretability through post-analyses.
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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 | 0.004 | 0.011 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".