Measurement strategy alters inferred age-dependent accumulation and mortality risk of mosaic Y loss

Abstract Mosaic loss of Y chromosome (mLOY) is a widely used biomarker of biological aging, yet whether its inferred age-dependent accumulation and associated clinical risk are invariant to measurement strategy remains unclear. We compared intensity-based and phase-based quantification approaches in 223,251 men from the UK Biobank to determine how analytic definitions influence estimates of mLOY burden, risk thresholds and population prevalence. Phase-based quantification revealed a steeper and more stable age-dependent accumulation of mLOY and identified excess mortality risk at lower mosaic burdens than intensity-based metrics. These differences shifted the inferred onset of biological risk and expanded the proportion of individuals classified as affected from 5.3% to 19.2%. Conventional thresholding preferentially excluded low-burden mosaicism, compressing risk gradients and reducing statistical resolution for downstream associations. These findings show that analytic definitions materially alter inferred accumulation dynamics, risk thresholds and population prevalence of mosaic Y loss.