Data-Driven Thresholding Statistically Biases ATN Profiling across Cohort Datasets - 21/11/24
, D. Domingo-Fernández 1, M. Hofmann-Apitius 1, 2, C. Birkenbihl 1, 2, 3, ⁎ the Alzheimer’s Disease Neuroimaging Initiative
the Japanese Alzheimer’s Disease Neuroimaging Initiative
the Alzheimer’s Disease Repository Without Borders Investigators
the European Prevention of Alzheimer’s Disease (EPAD) Consortium
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Abstract |
Background |
While the amyloid/tau/neurodegeneration (ATN) framework has found wide application in Alzheimer’s disease research, it is unclear if thresholds obtained using distinct thresholding methods are concordant within the same dataset and interchangeable across cohorts.
Objectives |
To investigate the robustness of data-driven thresholding methods and ATN profiling across cohort datasets.
Design and Setting |
We evaluated the impact of thresholding methods on ATN profiles by applying five commonly-used methodologies across cohort datasets. We assessed the generalizability of disease patterns discovered within ATN profiles by clustering individuals from different cohorts who were assigned to the same ATN profile.
Participants and Measurements |
Participants with available CSF amyloid-β 1–42, phosphorylated tau, and total tau measurements were included from eleven AD cohort studies.
Results |
We observed high variability among obtained ATN thresholds, both across methods and datasets that impacted the resulting profile assignments of participants significantly. Clustering participants from different cohorts within the same ATN category indicated that identified disease patterns were comparable across most cohorts and biases introduced through distinct thresholding and data representations remained insignificant in most ATN profiles.
Conlusion |
Thresholding method selection is a decision of statistical relevance that will inevitably bias the resulting profiling and affect its sensitivity and specificity. Thresholds are likely not directly interchangeable between independent cohorts. To apply the ATN framework as an actionable and robust profiling scheme, a comprehensive understanding of the impact of used thresholding methods, their statistical implications, and a validation of results is crucial.
Il testo completo di questo articolo è disponibile in PDF.Key words : ATN framework, biomarker profiles, CSF thresholds, Alzheimer’s disease, cohort studies
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| Alzheimer’s Disease Neuroimaging Initiative: Data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at ADNI_Acknowledgement_List.pdf Japanese Alzheimer’s Disease Neuroimaging Initiative: Data used in preparation of this article were obtained from the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) database deposited in the National Bioscience Database Center Human Database, Japan (Research ID: hum0043. v1, 2016). As such, the investigators within J-ADNI contributed to the design and implementation of J-ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of J-ADNI investigators can be found at: hum0043-j-adni-authors. Data used in preparation of this article were obtained from the Alzheimer’s Disease Repository Without Borders (ARWiBo) database (www.arwibo.it). As such, the researchers within the ARWiBo contributed to the design and implementation of ARWiBo and/or provided data but did not participate in analysis or writing of this report. A complete listing of ARWiBo researchers can be found in the Acknowledgments. Data used in preparation of this article were obtained from the Longitudinal Cohort Study (LCS), delivered by the European Prevention of Alzheimer’s Disease (EPAD) Consortium. As such investigators within the EPAD LCS and EPAD Consortium contributed to the design and implementation of EPAD and/or provided data but did not participate in analysis or writing of this report. A complete list of EPAD Investigators can be found at: 202010_List-of-epadistas.pdf Consent Statement: All investigated cohort studies acquired ethical approval from their respective review boards, adhered to the Helsinki declaration, and retrieved informed consent from their participants for data collection and sharing. The publication guidelines of each individual cohort study were followed and the manuscript was submitted and approved by all data owners that requested manuscript clearing. |
Vol 11 - N° 1
P. 185-195 - Gennaio 2024 Ritorno al numero
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