Circulating tumor DNA (ctDNA) is an accessible biomarker for cancer detection, molecular stratification, therapeutic monitoring, and post-treatment surveillance. Compared to traditional tissue biopsy, ctDNA as liquid biopsy is minimally invasive and can be performed serially to monitor tumor evolution or response to any drug therapy. Due to these advantages, ctDNA is being rapidly adopted in precision medicine. However, ctDNA sequencing assays face major challenges such as cell-free DNA exists as small fragments, and only a small fraction (< 0.01-0.1 %) of cell-free DNA is tumor-derived as we call ctDNA. In addition, ctDNA sequencing assays are also affected by a range of experimental variables and artifacts.