Genome-wide association study of cisplatin-induced peripheral neuropathy (CIPN) in testicular cancer survivors.
Bibliographic record
Abstract
4543 Background: CIPN is a potentially permanent side effect of cisplatin chemotherapy. CIPN remains a major clinical challenge due to lack of effective treatment, impact on quality of life and unexplained inter-individual variability. Methods: Testicular cancer patients (n = 847) given cisplatin-based therapy (median dose: 400 mg/m2) were assessed for responses to the validated EORTC QLQ-CIPN20 questionnaire. Associations were evaluated between frequency of sensory neuropathy and cumulative cisplatin dose, smoking history and age. Using the Illumina HumanOmniExpressExome chip and with imputation, 5.1 million SNPs passed quality control (QC) for GWAS inclusion. A gene-based method, PrediXcan, was used to consider associations between the genetically determined component of gene expression and CIPN. Results: Sensory neuropathy was common (57% having any symptom). CIPN sensory items (n = 8) indicated excellent internal consistency (alpha coefficient = 0.88). Using each patient’s mean sensory neuropathy score, we sorted them into 3 ordinal groups according to severity: 43% none, 41% a little, 16% quite a bit/very much. Only age and smoking status, not dose, were significantly related to sensory neuropathy (OR = 1.04 [95% CI 1.03-1.06] and 1.5 [95% CI 1.2-2.0], respectively). The top 2 SNPs (P = 5 x 10-7) from a GWAS of 677 patients that passed QC, were each associated with greater risk of sensory neuropathy (OR = 1.9 [95% CI 1.5-2.4] and 1.9 [95% CI 1.5-2.5]). These SNPs are expression QTLs for LYPD3 (rs12797447), SNX8 and GSTT1 (rs4757366) in lymphoblastoid cell lines. PrediXcan identified lower predicted expression of RPRD1B in whole blood (5453 genes tested) met genome-wide significance for association with increased sensory neuropathy risk (P = 3 x 10-6). Conclusions: Our traditional GWAS identified several SNPs associated with CIPN that were functionally important due to their association with gene expression. Our gene-based test implicated RPRD1B, known to play a role in cell cycle regulation, as associated with CIPN. Future studies will focus on functional validation, analysis of a replication set and meta-analysis with other CIPN studies to identify drug-independent variants.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".