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However, ctDNA detection remains challenging in early-stage and post-treatment MRD settings where ctDNA levels are minuscule giving a high risk for false negative results, which is balanced with the risk of false positive results from clonal hematopoiesis. To address these challenges, researchers have developed ever-more elegant approaches to lower the limit of detection (LOD) of ctDNA assays toward the part-per-million range and boost assay sensitivity and specificity by reducing sources of low-level technical and biological noise, and by harnessing specific genomic and epigenomic features of ctDNA. In this review, we highlight a range of modern assays for ctDNA analysis, including advancements made to improve the signal-to-noise ratio. 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