Methods and systems for determining the cellular origin of cell-free dna

A method of determining a cellular origin of at least a subset of deoxyribonucleic acid (DNA) molecules from a cell-free DNA (cfDNA) sample obtained from a subject at least partially using a computer, the method comprising:

• (a) identifying one or more sets of DNA molecules of unknown cellular origin from the cfDNA sample that each comprise one or more member DNA molecules that each comprise at least one genomic region in common with one another from sequence information obtained from the cfDNA sample;
• (b) determining a distribution of one or more properties among the one or more member DNA molecules within each of the one or more sets of DNA molecules from epigenetic information and/or the sequence information obtained from the cfDNA sample to generate one or more distribution sets, which properties are selected from the group consisting of:
• a length of a given DNA molecule, an offset of a midpoint of a given DNA molecule from a midpoint of the at least one genomic region of the given DNA molecule, and an epigenetic status or pattern exhibited by a given DNA molecule;
• (c) estimating a fraction of member DNA molecules, if any, within each of the one or more distribution sets that originate from a targeted cellular origin to generate a fraction estimate for each of the one or more distribution sets for the cfDNA sample;
• (d) aggregating the fraction estimates for the cfDNA sample to generate a sample classification score for the cfDNA sample;
• and,
• (e) classifying the cfDNA sample as comprising DNA molecules from cells of the targeted cellular origin when the sample classification score for the cfDNA sample exceeds a reference classification score, thereby determining the cellular origin of at least the subset of DNA molecules from the cfDNA sample obtained from the subject.