A method of generating a sequencing library with cell free DNA (cfDNA) of less than 300bp, the method comprising the steps of: a) providing a biological sample that has been obtained from a subject, where the sample comprises cfDNA; b) contacting the biological sample with at least a first primer/probe set and at least a second primer probe/set, each of which comprises at least one oligonucleotide probe that is detectably labeled and at least two oligonucleotide primers and the labels are different for each primer/probe set, under conditions such that the first primer/probe set is capable of initiating synthesis of a first amplicon of less than 300 bp in length and the second primer/probe set is capable of initiating synthesis of a second amplicon of 300 bp or greater in length; c) amplifying, if present, the first target sequence and the second target sequence using droplet digital PCR (ddPCR); d) monitoring for detection of the label of the oligonucleotide probe from the first primer/probe set as an indication of hybridization to the first target sequence and detection of the label of the oligonucleotide probe from the second primer/probe set as an indication of hybridization to the second target sequence; e) determining the quantity of cfDNA in the biological sample, wherein the amount of amplifiable copies of cfDNA is indicated by comparing the number of the detected label of the oligonucleotide probe from the first primer/probe set with the number of the detected label of the oligonucleotide probe from the second primer/probe set, wherein the number of the detected label of the oligonucleotide probe is determined with ddPCR by counting nucleic acid molecules encapsulated in discrete, volumetrically defined, water-in-oil droplet partitions that support PCR amplification, and wherein a greater number of the detected label of the oligonucleotide probe from the first primer/probe set compared to the number of the detected label of the oligonucleotide probe from the second primer/probe set indicates an increased quantity of cfDNA in the biological sample; and f) generating a sequencing library with the cfDNA based on the quantity of cfDNA in the sample. a) providing a biological sample that has been obtained from a subject, where the sample comprises cfDNA; b) contacting the biological sample with at least a first primer/probe set and at least a second primer probe/set, each of which comprises at least one oligonucleotide probe that is detectably labeled and at least two oligonucleotide primers and the labels are different for each primer/probe set, under conditions such that the first primer/probe set is capable of initiating synthesis of a first amplicon of less than 300 bp in length and the second primer/probe set is capable of initiating synthesis of a second amplicon of 300 bp or greater in length; c) amplifying, if present, the first target sequence and the second target sequence using droplet digital PCR (ddPCR); d) monitoring for detection of the label of the oligonucleotide probe from the first primer/probe set as an indication of hybridization to the first target sequence and detection of the label of the oligonucleotide probe from the second primer/probe set as an indication of hybridization to the second target sequence; e) determining the quantity of cfDNA in the biological sample, wherein the amount of amplifiable copies of cfDNA is indicated by comparing the number of the detected label of the oligonucleotide probe from the first primer/probe set with the number of the detected label of the oligonucleotide probe from the second primer/probe set, wherein the number of the detected label of the oligonucleotide probe is determined with ddPCR by counting nucleic acid molecules encapsulated in discrete, volumetrically defined, water-in-oil droplet partitions that support PCR amplification, and wherein a greater number of the detected label of the oligonucleotide probe from the first primer/probe set compared to the number of the detected label of the oligonucleotide probe from the second primer/probe set indicates an increased quantity of cfDNA in the biological sample; and wherein the number of the detected label of the oligonucleotide probe is determined with ddPCR by counting nucleic acid molecules encapsulated in discrete, volumetrically defined, water-in-oil droplet partitions that support PCR amplification, and wherein a greater number of the detected label of the oligonucleotide probe from the first primer/probe set compared to the number of the detected label of the oligonucleotide probe from the second primer/probe set indicates an increased quantity of cfDNA in the biological sample; and f) generating a sequencing library with the cfDNA based on the quantity of cfDNA in the sample.