A stability-selected panel of 209 CpG sites, paired with five-nearest-neighbor imputation and Ridge regression, predicted chronological age from whole blood with a mean absolute error of 4.24 years and r = 0.934 in held-out samples. When probe failures were simulated using 42 empirical templates from degraded tissue samples, local reconstruction outperformed simple mean replacement by 0.365 years of root-mean-square error, with the advantage widening as data loss increased. Performance held in an external cohort (r = 0.835), though with age-dependent calibration bias.
Key Points
- 209-CpG panel predicted chronological age within 4.24 years
- Nearest-neighbor imputation beat mean replacement under heavy probe failure
- External cohort validation held at r = 0.835 despite calibration bias
Longevity Analysis
Methylation clocks are only as trustworthy as the arrays that feed them, and incomplete probe data is routine in archived, degraded, or low-input samples. Reconstructing missing values from the nearest biological neighbors rather than substituting a population average preserves the individual signal that makes repeat testing meaningful — the difference between tracking a person's trajectory and tracking noise. For anyone using epigenetic measurement to guide decisions about regenerative capacity or immune aging, the technical handling of missing data directly determines whether an observed change reflects the body or the assay. Age-dependent calibration drift in the external cohort is a reminder that these readouts require cohort-specific interpretation before they inform any intervention.
Original published by Wiley Aging Cell, by Xiangteng Zhao, Yanhong Lu, Biqing Huang, Zijie Wang, Tong Yu, Ruoqi Zhao, Shiwen Yu, Shushan Wei, Yeting Zeng .