A method of providing copy number determinations, comprising: performing a multiplex amplification on a sample to generate a set of sample amplicons; performing a multiplex amplification on a matched control to generate a set of control amplicons; joining adaptors having a first barcode sequence to the sample amplicons to create a sample library; joining adaptors having a second barcode sequence to the control amplicons to create a control library; sequencing the sample and control libraries substantially simultaneously to avoid intra-run sequencing variations to generate a plurality of reads; identifying reads as either sample reads or control reads based on the presence of the first or second barcode sequence; mapping the sample reads and control reads to a reference genome; computing a sample coverage for a plurality of tiles based on the sample reads that map to the tiles, wherein the tiles are non-overlapping target regions of the reference genome and each tile comprises at least 100 bases and a coverage for a tile is determined based on a number of reads that map to the tile and on a number of bases in overlaps of the reads; computing a baseline coverage for the tiles based on the control reads that map to the tiles; normalizing the sample coverage for a tile based on the sample coverage mode and normalizing the baseline coverage for the tile based on the control coverage mode across the plurality of tiles; determining a score function for each tile of the plurality of tiles being in a plurality of ploidy states based on the normalized sample coverage and the normalized baseline coverage for the tiles, wherein the score function is a likelihood function; determining a maximum likelihood path across the tiles and through the ploidy states; and providing a copy number determination based on the maximum likelihood path. performing a multiplex amplification on a sample to generate a set of sample amplicons; performing a multiplex amplification on a matched control to generate a set of control amplicons; joining adaptors having a first barcode sequence to the sample amplicons to create a sample library; joining adaptors having a second barcode sequence to the control amplicons to create a control library; sequencing the sample and control libraries substantially simultaneously to avoid intra-run sequencing variations to generate a plurality of reads; identifying reads as either sample reads or control reads based on the presence of the first or second barcode sequence; mapping the sample reads and control reads to a reference genome; computing a sample coverage for a plurality of tiles based on the sample reads that map to the tiles, wherein the tiles are non-overlapping target regions of the reference genome and each tile comprises at least 100 bases and a coverage for a tile is determined based on a number of reads that map to the tile and on a number of bases in overlaps of the reads; computing a baseline coverage for the tiles based on the control reads that map to the tiles; normalizing the sample coverage for a tile based on the sample coverage mode and normalizing the baseline coverage for the tile based on the control coverage mode across the plurality of tiles; determining a score function for each tile of the plurality of tiles being in a plurality of ploidy states based on the normalized sample coverage and the normalized baseline coverage for the tiles, wherein the score function is a likelihood function; determining a maximum likelihood path across the tiles and through the ploidy states; and providing a copy number determination based on the maximum likelihood path. <EOS>