A method for determining presence or absence of a genetic alteration for a test subject, comprising: (a) obtaining a set of sequence reads obtained from circulating cell free sample nucleic acid from the test subject, wherein the sequence reads each comprise at least one single molecule barcode sequence that is a non-random oligonucleotide sequence; (b) assigning, by a computing system, the sequence reads to read groups according to a read group signature, wherein the read group signature comprises an SMB sequence and a start and end position of a nucleic acid fragment from the circulating cell free sample nucleic acid, and wherein the sequence reads comprising start and end positions and an SMB sequence similar to the read group signature are assigned to a read group identified by the read group signature; wherein the sequence reads comprising the start and end positions and the SMB sequence are determined to be similar to the read group signature when: i) an SMB sequence is identical to the SMB sequence of the read group signature, and a start and end position is identical to the start and end position of the read group signature; ii) an SMB sequence is identical to the SMB sequence of the read group signature, and a start and/or end position is different from the start and/or end position of the read group signature; or iii) an SMB sequence comprises one or more nucleotide differences compared to the SMB sequence of the read group signature, and a start and end position is identical to the start and end position of the read group signature; (c) generating, by the computing system, a consensus for each read group; and (d) determining, by the computing system, the presence or absence of a genetic alteration based on the consensus for each read group. (a) obtaining a set of sequence reads obtained from circulating cell free sample nucleic acid from the test subject, wherein the sequence reads each comprise at least one single molecule barcode sequence that is a non-random oligonucleotide sequence; (b) assigning, by a computing system, the sequence reads to read groups according to a read group signature, wherein the read group signature comprises an SMB sequence and a start and end position of a nucleic acid fragment from the circulating cell free sample nucleic acid, and wherein the sequence reads comprising start and end positions and an SMB sequence similar to the read group signature are assigned to a read group identified by the read group signature; wherein the sequence reads comprising the start and end positions and the SMB sequence are determined to be similar to the read group signature when: i) an SMB sequence is identical to the SMB sequence of the read group signature, and a start and end position is identical to the start and end position of the read group signature; ii) an SMB sequence is identical to the SMB sequence of the read group signature, and a start and/or end position is different from the start and/or end position of the read group signature; or iii) an SMB sequence comprises one or more nucleotide differences compared to the SMB sequence of the read group signature, and a start and end position is identical to the start and end position of the read group signature; i) an SMB sequence is identical to the SMB sequence of the read group signature, and a start and end position is identical to the start and end position of the read group signature; ii) an SMB sequence is identical to the SMB sequence of the read group signature, and a start and/or end position is different from the start and/or end position of the read group signature; or iii) an SMB sequence comprises one or more nucleotide differences compared to the SMB sequence of the read group signature, and a start and end position is identical to the start and end position of the read group signature; (c) generating, by the computing system, a consensus for each read group; and (d) determining, by the computing system, the presence or absence of a genetic alteration based on the consensus for each read group.