Technologies for cancer screening and early diagnosis have a great impact on clinical outcomes for patients with cancer, and their implementation is an important public health strategy. Liquid biopsy approaches that use a blood test to analyse cell-free DNA (cfDNA) in the plasma show promise as screening tests, as they are minimally invasive. However, developing these assays for clinical use has proven to be difficult. The contribution of tumour DNA to the pool of cfDNA in plasma is small in the early stages of cancer, so highly sensitive methods are required for effective screening. Moreover, tumour-derived cfDNAs differ between individuals, owing to genetic variation and differences in the phenotypes of specific tumours. To account for this heterogeneity, sensitive methods that integrate multiple data types are needed.