Abstract: A computer-implemented method for generating a tumor fraction estimate from a DNA sample of a subject is disclosed. The method may include receiving a dataset of methylation sequence reads from the sample of the subject. The method may also include dividing the dataset into a plurality of variants. The method may further include determining methylation states of the plurality of variants. The method may further include filtering the plurality of variants based on a bank of reference sequence reads to generate a filtered subset of variants. The bank may include reads generated from non-cancer samples and biopsy samples of a plurality of tissues of reference individuals. The counts of the methylation states of variants in the filtered subset are determined and input to a model that is trained based on recurrence rates of the variants in the reference sequence reads. The tumor fraction estimate may be generated by the model.

Abstract: Systems and methods for determining a source of a variant in a cell free nucleic acid sample include identifying a candidate variant in the cell free nucleic acid sample, determining a numerical score using a measure of first properties of a distribution of novel somatic mutations compared to a measure of second properties of a distribution of somatic variants matched in genomic nucleic acid, and determining a classification of the candidate variant using the numerical score, the classification indicating whether the candidate variant is more likely to be a new novel somatic mutation than a new somatic variant matched in genomic nucleic acid.