Impact of Clinical and Pharmacogenetic Variables on the Risk of Fluoropyrimidine-Related Adverse Events within Ontario
Bibliographic record
Abstract
Severe life-threatening adverse events are a major limitation of fluoropyrimidine chemotherapy, these events are disastrous for patients and costly to the healthcare system. Identifying patients at high risk for developing adverse events would allow for preventive dose reduction, improving patient outcomes and reducing healthcare cost. This thesis uses data pulled from provincial databases to quantify the adverse event burden of fluoropyrimidines in Ontario. We found that 31% of Ontario patients treated with fluoropyrimidine systemic chemotherapy developed a severe adverse event that requires acute medical care. Patients that required acute medical therapy were significantly costlier to the public system averaging an increased cost of $16,754 (CAD). Therefore, there is a substantial potential to reduce cost to the health care system and pay for preventive screening strategies. A known risk factor for fluoropyrimidine adverse events is Dihydropyrimidine dehydrogenase (DPD, gene DPYD) deficiency. We demonstrate that screening for DPD deficiency through targeted genetic testing and genotype-guided dosing reduces the risk of adverse events in genetically deficient patients. Unfortunately, 31% of wildtype patients still experience a severe adverse event, requiring further research into predictors of adverse event risk. Following up on genetic variants, we tested for a recently described intrageneric DPYD deletion through a nested case-control study. We found the deletion associated with toxicity, however the variant was too rare to decide on the overall relevancy to clinical testing at this time. Next, we looked beyond genetics and tested the impact of plasma folate level on adverse event risk. Despite previous literature suggesting an association we found that plasma folate levels were not predictive of fluoropyrimidine adverse event risk. Therefore, there remains a significant number of unexplained fluoropyrimidine-related adverse events. In conclusion, while folate level did not show a predictive value, pharmacogenetic testing was found to be feasible and effective at reducing adverse events. To this end, we worked with Health Quality Ontario to translate these findings, pretreatment DPYD testing is now recommended to be a publicly funded test in Ontario.
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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 | 0.006 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.002 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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 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".