What is the biological significance of DNA methylation-based estimators of telomere length? An assessment using the paternal age at conception effect and measures of external validity
Bibliographic record
Abstract
DNA methylation (DNAm) based estimators of telomere length (TL) have been shown to better correlate with TL associated factors/outcomes than measured TL itself. Here, we examined the DNAm based estimator of TL (DNAmTL), the principal component version of DNAmTL (PCDNAmTL), qPCR measured TL (qPCR-TL), and southern blot measured TL in the same samples from a cohort from metropolitan Cebu, Philippines. In a pre-registered analysis, we examined the association between paternal age at conception (PAC) and offspring TL to better understand the meanings and utilities of PCDNAmTL and DNAmTL. We predicted that the nature of PCDNAmTL markings should determine whether they change in sperm with age and are passed on to the zygote like TL is. We failed to find an association between PAC and PCDNAmTL, but did find a positive association of paternal grandfather’s age at father’s conception predicting grandchild’s PCDNAmTL. Surprisingly, on almost all measures of external validity (correlations with parental TLs, southern blot TL, and age) qPCR-TL outperformed PCDNAmTL and DNAmTL. qPCR-TL showed a significantly stronger association with maternal qPCR-TL than PCDNAmTL and DNAmTL did. Similarly, qPCR-TL showed a significantly greater association with southern blot TL than PCDNAmTL or DNAmTL and the “kilobase” units of DNAm-based estimators of TL showed considerable deviations from southern blot derived kilobase measures. Also, surprisingly, for all of the measures of external validity DNAmTL outperformed PCDNAmTL. Overall, these findings suggest that PCDNAmTL and DNAmTL are not reliable indices of inherited aspects of TL and underscore uncertainty about the biological meaning of these measures.
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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 | 0.031 | 0.063 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.003 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 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".