The countdown paradox: A time-varying effect analysis of age at biomarker-clock event as a predictor of MCI symptom onset
Zhu, Y.; Pettigrew, C.; Soldan, A.; Moghekar, A.; Albert, M.; Bandeen-Roche, K.; Wang, M.-C.
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Research focused on Alzheimer's disease (AD) 'biomarker clocks' seeks to identify ages at which AD pathological landmarks occur (e.g., initiation of amyloid accumulation) and are meaningfully related to disease outcomes (e.g., symptom onset). However, the standard approach for assessing the association between age at biomarker-clock event and remaining time to clinical symptom onset can create a structural artifact. We term it here the 'countdown paradox', because the remaining time to symptom onset shrinks as the age at biomarker-clock event increases, resulting in spurious associations between age at biomarker-clock event and the remaining time. In simulations, the standard analysis produced false positive rates up to 100% and hazard ratios above 1 regardless of true effect direction. Analyses of five biomarkers across two cohorts showed consistent patterns. To address the issue, we proposed a time-varying effect analysis, which maintains nominal type I error and helps distinguish genuine from artifactual associations.
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