Methods and systems for analyzing nucleic acid molecules

A method of determining presence or absence of a cancer in a subject, the method comprising:

• (a) obtaining a cell-free DNA sample from the subject, wherein the cell-free DNA sample comprises methylated cell-free DNA and unmethylated cell-free DNA;
• (b) contacting the sample with one or more agents that discriminates between the methylated cell-free DNA and unmethylated cell-free DNA to provide contacted methylated cell-free DNA and contacted methylated cell-free DNA;
• (c) enriching the contacted methylated cell-free DNA, or amplicons thereof, and contacted unmethylated cell-free DNA, or amplicons thereof, for target regions using target-specific probes to provide captured DNA, wherein the target regions comprise cancer-associated differentially methylated regions (DMRs), and wherein the DMRs exhibit differential methylation between DNA obtained from healthy subjects and DNA obtained from subjects having the cancer;
• (d) sequencing the captured DNA, or amplicons thereof, to provide sequence information;
• and
• (e) determining the presence or absence of the cancer in the subject by inputting features derived from the set of sequence reads into a trained classifier, wherein the trained classifier is trained using data obtained from subjects who have the cancer, subjects who do not have cancer, and/or subjects who have other types of cancer.