Systems and methods for tumor fraction estimation from small variants

A method of estimating a tumor fraction f of a subject, the method comprising:

• (A) sequencing a first plurality of nucleic acid fragment sequences from a liquid biological sample obtained from the subject, wherein the liquid biological sample comprises blood, whole blood, plasma, serum, urine, fecal, saliva, sweat, or tears obtained from the subject;
• (B) sequencing a second plurality of nucleic acid fragment sequences from a solid tumor sample obtained from the subject, wherein an average coverage rate for at least one of the first plurality of nucleic acid fragment sequences and the second plurality of nucleic acid fragment sequences is less than 5000×;
• (C) determining a plurality of estimated smoothed noise rates corresponding to a plurality of allele positions, wherein the plurality of allele positions comprise a range between one million to ten million allele positions, each respective estimated smoothed noise rate evi in the plurality of estimated smoothed noise rates is determined using nucleic acid fragment sequences, in electronic form, obtained from each non-cancer sample in a cohort of non-cancer samples mapping to a corresponding allele position vi in the plurality of allele positions, and each respective estimated smoothed noise rate evi for the corresponding allele position specifies how often a tumor allele appears at the corresponding allele position in non-cancer samples;
• (D) determining a variant allele count svi,t for each respective allele position v;
• in the plurality of allele positions using the first plurality of nucleic acid fragment sequences, thereby obtaining a plurality of variant allele counts for the subject;
• (E) determining a coverage svi for each respective allele position vi in the plurality of allele positions using the first plurality of nucleic acid fragment sequences, thereby obtaining a plurality of coverages for the subject;
• (F) determining a solid variant allele fraction a;
• for each respective allele position vi in the plurality of allele positions using the second plurality of nucleic acid fragment sequences, thereby obtaining a plurality of solid variant allele fractions;
• (G) determining, using a computer system comprising a processor coupled to non-transitory memory, the tumor fraction f of the subject based on Ds comprising (i) the plurality of estimated smoothed noise rates, (ii) the plurality of variant allele counts, (iii) the plurality of coverages, and (iv) the plurality of solid variant allele fractions, wherein (ii) and (iii) are determined based on the first plurality of nucleic acid fragment sequences from the liquid biological sample, and (iv) is determined based on the second plurality of nucleic acid fragment sequences from the solid tumor sample;
• and
• (H) modifying a treatment regimen for the subject based, at least in part, on a value of the tumor fraction f of the subject, wherein the treatment regimen comprises applying an agent for cancer to the subject, wherein the agent for cancer is a hormone, an immune therapy, radiography, or a cancer drug, and wherein the modification to the treatment regimen comprises intensifying or discontinuing the agent.