Figure 1. From Digital to Analog circulating tumor DNA (ctDNA) Signals.

Advances in sequencing capacity over the past decade have enabled a transition from digital to analog signal detection for cancer liquid biopsies. Initially, ctDNA assays targeted individual mutations that were known to be highly specific for cancer. Since then, targeted sequencing and whole-genome sequencing have enabled the study of multiple mutations. As the number of mutations targeted has increased over time, detection algorithms have shifted to aggregating or integrating signals across multiple mutations, which might be considered pseudoanalog. Recently, deep sequencing of truly analog features of cfDNA may indicate whether the overall signal is tumor-derived or not, independent of the presence of a sequence alteration.