Abstract: Systems and methods for detecting a subtype of a disease state and for determining the development of a resistance mechanism in a disease are disclosed. One method may include: receiving, at an input component of the system, a set of sequence reads associated with a nucleic acid sample; generating, using a processor of the system and via analysis of the set of sequence reads, methylation data; and analyzing, using the processor, the methylation data to identify the subtype of the disease state. Another method may include: obtaining methylation data from a targeted methylation sequencing assay, applying the methylation data to a trained machine learning model, and receiving an output indicating whether MRD is present in a test subject and/or whether a resistance mechanism has been developed by a disease. Other aspects are described and claimed.

Abstract: In an aspect, a method of identifying a somatic or germline origin of a nucleic acid variant from a sample of nucleic acid molecules comprises: determining quantitative measures for the nucleic acid variant comprising total allele count and minor allele count for the nucleic acid variant; identifying an associated variable of the nucleic acid variant; determining quantitative value for the associated variable; generating a statistical model for expected germline mutant allele counts at a genomic locus of the nucleic acid variant; generating a probability value (p-value) for the nucleic acid variant based at least in part on the statistical model, the quantitative value, and at least one of the quantitative measures; and classifying the nucleic acid variant as (i) being of somatic origin when the p-value is below a predetermined threshold value, or as (ii) being of germline origin when the p-value is at or above the predetermined threshold value.

Abstract: The present disclosure provides methods and systems for detecting an allelic imbalance in a sample from a subject, comprising: (a) sequencing cell-free DNA molecules from the sample to generate sequence reads; (b) aligning at least a portion of the sequence reads to a reference sequence to produce aligned sequence reads; (c) for at least a portion of the plurality of aligned sequence reads, identifying a germline variant present at a mutant allele fraction (MAF) in the sample, thereby identifying a set of germline variants in the sample, wherein individual germline variants in the set of germline variants have corresponding MAF values; (d) determining a quantitative measure of the set of germline variants that are among a plurality of discrete ranges of MAF values; and (e) detecting the allelic imbalance based on a predetermined criterion by filtering the set of germline variants based on at least the quantitative measure.