cfDNA, cell death-related and chromatin fragmented DNA molecules contained in blood plasma, has been used to detect transplant tissue rejection, prenatal fetal aneuploidy testing, tumour profiling, and early cancer detection in previous research. Nevertheless, prevalent liquid biopsy methods for cfDNA profiling depend on detecting germline or somatic genetic variations, which may be absent even in high disease burden-bearing patients and cancers with high tumour mutation rates.
Historically, the usage of fragmentomic features of cfDNA samples was shown to be another method to approach the problems mentioned. They demonstrated the capability to inform about the originated tissue classification of cfDNA molecules, which can help segregate tumour-related somatic mutations. However, current methods that use fragmentomic features, such as shallow whole genome sequencing (WGS) on cfDNA, do not fully cover all the tissues' effects and provide low sequencing depth and breadth to infer low-level, for example, gene level, properties. Hence, these methods require a high tumour burden from the patients.