Evaluation of harmonization methods to mitigate assay and cohort effects in plasma p-tau217

The growing number of assay platforms measuring blood-based biomarkers (BBMs) for Alzheimer's disease (AD) has introduced challenges in interpretability and comparability across assays. Differences across studies also limit comparability of data. To address these challenges, a systematic evaluation of harmonization methods is needed to support BBM data integration within or across studies.

Two multisite studies, Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 219) and Human Connectome Project (HCP, n = 111), were used to evaluate harmonization methods for mitigating assay and cohort effects in plasma phosphorylated tau 217 (p-tau217) measurements. Methods included various normalization, regression, and standardization approaches, including the recently developed CentiMarker. Assay effects were evaluated using repeated-measures data across assay platforms within each cohort, whereas cohort effects were assessed using pooled ADNI and HCP data. Harmonization performance was evaluated using distributional statistics and downstream modeling of p-tau217.

Quantile normalization and quantile mapping methods were most effective for mitigating assay effects, whereas conditional quantile mapping performed best for pooled multi-cohort data. These methods also preserved biological variability. In contrast, simple means adjustment and reference-based Z-score standardization were least effective for mitigating assay effects, whereas simple means adjustment, Z-score standardization, and quantile normalization were least effective for mitigating cohort effects. CentiMarker had minimal impact on assay or cohort effects.

Based on our evaluation, we recommend (conditional) quantile mapping for p-tau217 studies integrating data across multiple assays or cohorts. In contrast, we caution against using CentiMarker and Z-score-based methods, as they limit comparability and do not effectively mitigate technical variability.