A method of determining a likelihood that a subject has cancer, comprising: a. partitioning cfDNA obtained from a test subject into two or more fractions based on methylation level using a methyl-binding domain, and, subsequently, on each fraction; b. capturing a plurality of sets of target regions from the cfDNA, wherein: I. the plurality of target region sets comprises a sequence-variable target region set and an epigenetic target region set, whereby a captured set of cfDNA molecules is produced; II. cfDNA molecules corresponding to the sequence-variable target region set are captured at a greater capture yield in the captured set of cfDNA molecules than cfDNA molecules corresponding to the epigenetic target region set; and III. the epigenetic target region set is selected from one or more of i) a hypermethylation variable target region set; ii) a hypomethylation variable target region set; and/or iii) a fragmentation variable target region set, wherein the fragmentation variable target region set comprises transcription start site regions and/or CTCF binding regions; optionally wherein the epigenetic target region set further comprises a methylation control target region set; c. sequencing the captured cfDNA molecules, wherein the captured cfDNA molecules of the sequence-variable target region set are sequenced to a greater depth of sequencing than the captured cfDNA molecules of the epigenetic target region set; d. obtaining a plurality of sequence reads generated by a nucleic acid sequencer from sequencing the captured cfDNA molecules; e. mapping the plurality of sequence reads to one or more reference sequences to generate mapped sequence reads; f. processing the mapped sequence reads corresponding to the sequence-variable target region set and to the epigenetic target region set to determine the likelihood that the subject has cancer. a. partitioning cfDNA obtained from a test subject into two or more fractions based on methylation level using a methyl-binding domain, and, subsequently, on each fraction; b. capturing a plurality of sets of target regions from the cfDNA, wherein: I. the plurality of target region sets comprises a sequence-variable target region set and an epigenetic target region set, whereby a captured set of cfDNA molecules is produced; II. cfDNA molecules corresponding to the sequence-variable target region set are captured at a greater capture yield in the captured set of cfDNA molecules than cfDNA molecules corresponding to the epigenetic target region set; and III. the epigenetic target region set is selected from one or more of i) a hypermethylation variable target region set; ii) a hypomethylation variable target region set; and/or iii) a fragmentation variable target region set, wherein the fragmentation variable target region set comprises transcription start site regions and/or CTCF binding regions; optionally wherein the epigenetic target region set further comprises a methylation control target region set; I. the plurality of target region sets comprises a sequence-variable target region set and an epigenetic target region set, whereby a captured set of cfDNA molecules is produced; II. cfDNA molecules corresponding to the sequence-variable target region set are captured at a greater capture yield in the captured set of cfDNA molecules than cfDNA molecules corresponding to the epigenetic target region set; and III. the epigenetic target region set is selected from one or more of i) a hypermethylation variable target region set; ii) a hypomethylation variable target region set; and/or iii) a fragmentation variable target region set, wherein the fragmentation variable target region set comprises transcription start site regions and/or CTCF binding regions; optionally wherein the epigenetic target region set further comprises a methylation control target region set; i) a hypermethylation variable target region set; ii) a hypomethylation variable target region set; and/or iii) a fragmentation variable target region set, wherein the fragmentation variable target region set comprises transcription start site regions and/or CTCF binding regions; c. sequencing the captured cfDNA molecules, wherein the captured cfDNA molecules of the sequence-variable target region set are sequenced to a greater depth of sequencing than the captured cfDNA molecules of the epigenetic target region set; d. obtaining a plurality of sequence reads generated by a nucleic acid sequencer from sequencing the captured cfDNA molecules; e. mapping the plurality of sequence reads to one or more reference sequences to generate mapped sequence reads; f. processing the mapped sequence reads corresponding to the sequence-variable target region set and to the epigenetic target region set to determine the likelihood that the subject has cancer.