Reduction of bias in genomic coverage measurements

A method of characterizing sample, the method comprising:

• labeling a plurality of sample molecules with a first label, wherein the sample molecules comprise a genome or genomic fragment;
• translocating the plurality of labeled sample molecules though a fluidic channel;
• detecting counts of signals from the labeled sample molecules so as to ascertain a pattern or plurality of patterns characteristic of the genome or genomic fragment;
• correlating signals from the labeled sample molecules to a reference to ascertain coverage of one or more regions of the genome or genomic fragment by the sample molecules;
• scaling the coverage depths of signals to a subset of coverage depths of signals corresponding to regions of the genome or genomic fragment that does not comprise a sex chromosome or a fragment thereof, thereby providing scaled coverage depths;
• and
• normalizing the scaled coverage depths by one, two, or three of:
• characteristic molecular length of the plurality of labeled sample molecules;
• or
• characteristic number of labels per interval for a plurality of intervals of the reference, wherein the reference comprises a plurality of intervals;
• or
• characteristic number of labels per molecule or characteristic number of labels within a segment of predetermined length per molecule,
• thereby generating a copy number profile of the sample molecules in which bias due to label density and bias due to factors other than label density in the copy number profile are minimized or eliminated.

A method of characterizing a sample, the method comprising:

• labeling a plurality of sequence-specific locations on a polynucleotide sequence of a sample molecule;
• linearizing at least a portion of the sample molecule in a fluidic channel;
• quantifying a signal from the labels on the sample molecule;
• correlating the signal from the labels to a reference;
• generating a copy number profile of the sample molecule;
• and
• determining a presence or absence of a genetic abnormality in the sample DNA when the quantity of the signal from the sample molecule differs from a quantity of the signal arising from a reference molecule.

A system for characterizing a sample, comprising:

• one or more chambers for labeling sample molecules with at least two labels;
• a fluidic channel for translocating the labeled sample molecules, wherein the fluidic channel is configured to elongate at least a portion of the sample molecule, and wherein the fluidic channel has a length of at least 10 nm and a cross-sectional diameter of less than 5000 nm;
• a device for detecting counts of signals arising from the labeled samples in the fluidic channels;
• and
• a processor in data communication with the device, wherein the processor is configured to generate a copy number profile of the sample and eliminate or minimize one or both of:
• biases caused by label density on the labeled sample molecules;
• or
• biases caused by factors other than label density of the labeled sample molecules.