Methods and systems for detecting genetic variants

A method for estimating a number of non-uniquely tagged double-stranded cell-free deoxyribonucleic acid (cfDNA) molecules, comprising:

• (a) non-uniquely tagging a plurality of cfDNA molecules from a sample of a subject with a set of duplex tags comprising molecular barcodes from a set of molecular barcodes to generate non-uniquely tagged parent polynucleotides, wherein the cfDNA molecules that map to a mappable base position of a reference sequence are tagged with a number of different molecular barcodes ranging from at least 2 to fewer than a number of the cfDNA molecules that map to the mappable base position;
• (b) amplifying a plurality of the non-uniquely tagged parent polynucleotides to produce amplified progeny polynucleotides;
• (c) sequencing a plurality of the amplified progeny polynucleotides to produce a set of sequencing reads;
• (d) determining, from among a plurality of sequencing reads from the set of sequencing reads, a quantitative measure of individual cfDNA molecules for which both strands are detected;
• (e) determining, from among a plurality of sequencing reads from the set of sequencing reads, a quantitative measure of individual cfDNA molecules for which only one strand is detected;
• and
• (f) estimating a number of non-uniquely tagged double-stranded cfDNA molecules based on the quantitative measures determined in steps (d) and (e), wherein the number of non-uniquely tagged double-stranded cfDNA molecules comprises individual cfDNA molecules for which neither cfDNA strand is detected.