Massively parallel variant characterization identifies <i>NUDT15</i> alleles associated with thiopurine toxicity
Why this work is in the frame
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Bibliographic record
Abstract
Significance Pharmacogenetics is a prototype of genomics-guided precision medicine. While there is a rapid expansion of novel pharmacogenetic variants discovered by genome sequencing, the lack of variant interpretation in a scalable fashion is a formidable barrier in this field. NUDT15 polymorphism is a major genetic cause for hematopoietic toxicity during thiopurine therapy. Motivated by the need to understand NUDT15 variant effects for clinical actions, we developed a massively parallel assay to preemptively characterize 91.8% of all possible missense variants in NUDT15 . Our function-based variant classification accurately predicted thiopurine toxicity risk alleles in patients. These results vastly improved the ability to implement genotype-guided thiopurine therapy and illustrated the value and potential of a high-throughput variant effect screen in general.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 it