Title: Impact of methodological assumptions and covariates on the cutoff estimation in ROC analysis

Abstract: The Receiver Operating Characteristic (ROC) curve stands as a cornerstone in assessing the efficacy of biomarkers for disease diagnosis. Beyond merely evaluating performance, it provides with an optimal cutoff for biomarker values, crucial for disease categorization. While diverse methodologies exist for threshold estimation, less attention has been paid to integrating covariate impact into this process. Covariates can strongly impact diagnostic summaries, leading to variations across different covariate levels. Therefore, a tailored covariate-based framework is imperative for outlining covariate-specific optimal cutoffs. Moreover, recent investigations into cutoff estimators have overlooked the influence of ROC curve estimation methodologies. This study endeavors to bridge this gap by addressing the research void. Extensive simulation studies are conducted to scrutinize the performance of ROC curve estimation models in estimating different cutoffs in varying scenarios, encompassing diverse data-generating mechanisms and covariate effects. Additionally, leveraging the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, the research assesses the performance of different biomarkers in diagnosing Alzheimer's disease and determines the suitable optimal cutoffs.