Sex-influenced mortality in a large Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) cohort caused by RYR2 p.R420W
Bibliographic record
Abstract
Background: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an arrhythmia syndrome causing sudden cardiac death (SCD). We have ascertained three multiplex, multigenerational families with CPVT due to RYR2 (p.R420W) disrupting calcium channel regulation. The effect of RYR2 p.R420W on survival is described. Methods: Cases of sudden death were ascertained from clinical and genetics chart reviews following informed research consent from individuals or their next of kin (Study ID 00-176). Individuals were considered well-ascertained if disease status of ≥ 50% of their sibship was known (n=60). Affected individuals included mutation positive, obligate carriers (OC), and/or documented SCD <50 years (n=32). Unaffected status was defined as mutation negative (n=23). Remaining individuals were designated unknown (n=5). Unaffected and Unknown groups were combined. Time to death was compared using Kaplan-Meier time-to-event analysis and multivariate Cox regression. Survival was compared to families with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) due to TMEM43 p.S358L. Results: Affected status with RYR2 p.R420W was significantly associated with mortality (RR=4, 95% CI: 1.1-14.5), with 24% mortality in the affected group by age 30. Affected males died earlier than females (RR=6, 95% CI: 1.7-20.4). Median survival in males with RYR2 p.R420W was 50 years (95% CI: 5.5-94.5), compared to TMEM43 44 years (95% CI: 42.0-46.8). Median survival in females with RYR2 was 76 years (95% CI: 37.7-115.2), compared to TMEM43 73 years (95% CI: 69.6-76.1). Conclusions: The RYR2 p.R420W mutation significantly affects mortality. There is a clear sex-influence. Median survival is comparable to another highly lethal mutation TMEM43 p.S358L causing ARVC.
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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 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".