DNA methylation age acceleration is associated with ALS age of onset and survival
Bibliographic record
Abstract
Amyotrophic lateral sclerosis (ALS) patients, includingC9orf72-carriers and identical twins [1], have highly variable disease characteristics (e.g., duration and age/site of onset) [7], suggesting the influence of epigenetic variations.DNA methylation (DNAm) is a key epigenetic modification and linked to the risk of several neurodegenerative diseases (Supplementary introduction).The cumulative assessment of DNAm levels at age-related CpGs allows the estimation of multi-tissue DNAm age (epigenetic clock), which could be more accurate for assessing biological age than chronological age.Hypermethylation of the CpG-island 5′ of the C9orf72-repeat and DNAm-age acceleration have been reported to be associated with C9orf72-disease duration and age of onset [9,10].However, epigenetic modifiers in genetically unexplained ALS patients are largely unknown.Hence, we conducted a genome-wide investigation of DNAm (Infinium MethylationEPIC chip) in samples from blood (n = 249) or tissues from the central nervous system (CNS) (n = 18) of mainly sporadic ALS patients (Table 1), and assessed the association of DNAm-age acceleration with disease age of onset and survival (Supplementary methods).Considering the reported 3-year error for estimating DNAm age, we classified the patients into three groups: normal aging (n = 82, DNAm-age acceleration between -3 and 3 years, median = 0.5 years), slow aging (n = 125, DNAm-age acceleration < -3 years, median = -6.3years), and fast aging (n = 42, DNAm-age acceleration > 3 years, median = 5.7 years).Multivariate linear regression analysis detected a highly significant association between blood-based DNAm-age acceleration and ALS age of onset (adjusted p value = 2.2E-16, B = -1.29,R 2 = 0.33, n = 249) (Supplementary methods, Fig. 1a), suggesting that for every 5-year increase in DNAm-age acceleration there is a 6.4-year earlier onset.Cox proportional hazard regression analysis revealed that a faster DNAm-age acceleration is significantly associated with an earlier age of onset [adjusted p value = 9.3E-16, hazard ratio (HR) = 2.12; 95% confidence interval (CI):1.76-2.54],suggesting that the hazard increased by 112% (Fig. 1c).The median age of onset in the fast aging group (48 years; 95%CI: 42-51) was 18 years younger than the slow aging group (66 years; 95%CI: 63-68).Significant results were not Electronic supplementary materialThe online version of this article (https ://
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.006 | 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".