OP11 Exploring the potential clinical utility of NUDT15 pharmacogenetic testing in clinical practice: a ‘focused reverse phenotyping’ study in the UK IBD Bioresource
Bibliographic record
Abstract
Abstract Background In a previous study we recruited patients with inflammatory bowel disease (IBD) and a history of thiopurine induced myelosuppression (TIM) and identified associated variants in NUDT15. This widely used phenotype-first approach, is limited by ascertainment and recall bias, which impacts understanding of penetrance, expressivity, and variant pathogenicity that are key to clinical implementation. The United Kingdom (UK) National Institute for Health Research (NIHR) IBD Bioresource allows investigators to select large numbers of subjects based on genomic variants of interest, rather than phenotypes, to overcome these biases. Using this ‘focused reverse phenotyping’ approach we sought to investigate the cumulative 6-month risk of myelosuppression in patients with NUDT15 variants. Methods Cases and controls were identified from whole exome sequencing data. Cases included all participants with a loss of function NUDT15 variant (*2, *3, *4, *5, *6 and *9). Control subjects were selected based on wild-type carriage of NUDT15 and TPMT, matched for ethnicity. Our primary outcome measure was time to TIM. Myelosuppression was defined as a white cell count (WCC) <3.5x109/L or a neutrophil count <2.0x109/L that occurred within six months of achieving the maximum thiopurine dose, or in the absence of blood test results, a decision to reduce the dose of or withdraw the thiopurine due to myelosuppression. Severe myelosuppression was defined as a WCC <2.5x109/L or neutrophil count <1.0x109/L and a decision to either reduce the dose of or stop the thiopurine. Results We screened 23,082 patients recruited to the UK NIHR IBD bioresource with whole exome sequence data and identified 451 patients with a loss of function NUDT15 variant. We matched, based on ethnicity, these patients to 916 controls. Overall, 271/21,136 (1.3%) Caucasians and 127/1,089 (11.7%) South Asian carried an NUDT15 variant allele. 239/451 (60%) cases had a history of thiopurine exposure. The median weight-adjusted maximum thiopurine dose amongst cases and controls was 1.78 and 1.79 mg/kg/day, respectively. The time to myelosuppression was shorter in patients with NUDT15 variants as shown in Figure 1. The risk of myelosuppression, severe myelosuppression, and hospitalisation was also higher in patients with NUDT15 variants as shown in table 1. Conclusion In this reverse phenotyping study, the time to myelosuppression was significantly shorter in patients who carried a loss of function NUDT15 variant. The overall risk of myelosuppression was lower than previously observed in phenotype-first studies. Prior to implementation further analysis of the cost-effectiveness of NUDT15 testing is required.
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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 | 0.002 | 0.009 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".