Rare cell analysis using sample splitting and DNA tags

A method for performing prenatal diagnosis of a fetal chromosomal aneuploidy in a biological sample obtained from a pregnant female subject, wherein the biological sample includes nucleic acid molecules, the method comprising:

• receiving the biological sample;
• sequencing at least a portion of a plurality of the nucleic acid molecules contained in the biological sample, wherein the sequenced portion represents a fraction of the human genome;
• based on the sequencing:
• determining a first amount of a first chromosome from sequences identified as originating from the first chromosome;
• determining a second amount of one or more second chromosomes from sequences identified as originating from one of the second chromosomes;
• determining a parameter from the first amount and the second amount;
• comparing the parameter to one or more cutoff values;
• and based on the comparison, determining a classification of whether a fetal chromosomal aneuploidy exists for the first chromosome.

A computer program product comprising a computer readable medium encoded with a plurality of instructions for controlling a computing system to perform an operation for performing prenatal diagnosis of a fetal chromosomal aneuploidy in a biological sample obtained from a pregnant female subject, wherein the biological sample includes nucleic acid molecules, the operation comprising the steps of:

• receiving data from a random sequencing of a portion of the nucleic acid molecules contained in the biological sample obtained from a pregnant female subject, wherein the biological sample includes nucleic acid molecules, wherein the portion represents a fraction of the human genome;
• based on the data from the random sequencing:
• determining a first amount of a first chromosome from sequences identified as originating from the first chromosome;
• determining a second amount of one or more second chromosomes from sequences identified as originating from one of the second chromosomes;
• determining a parameter from the first amount and the second amount;
• comparing the parameter to one or more cutoff values;
• and based on the comparison, determining a classification of whether a fetal chromosomal aneuploidy exists for the first chromosome.

A method for performing prenatal diagnosis of a fetal chromosomal aneuploidy in a biological sample obtained from a pregnant female subject, wherein the biological sample includes nucleic acid molecules, the method comprising:

• receiving the biological sample;
• calculating a number N of sequences to be analyzed based on a desired accuracy;
• randomly sequencing at least N of the nucleic acid molecules contained in the biological sample, wherein the portion represents a fraction of the human genome;
• based on the random sequencing:
• determining a first amount of a first chromosome from sequences identified as originating from the first chromosome;
• determining a second amount of one or more second chromosomes from sequences identified as originating from one of the second chromosomes;
• determining a parameter from the first amount and the second amount;
• comparing the parameter to one or more cutoff values;
• and based on the comparison, determining a classification of whether a fetal chromosomal aneuploidy exists for the first chromosome.

A method for performing prenatal diagnosis of a fetal chromosomal aneuploidy in a sample from a human suspected of being pregnant, that is pregnant, or that has been pregnant, wherein the sample includes nucleic acids, the method comprising:

• obtaining the sample;
• sequencing nucleic acids in the sample to produce partial or complete genome sequence;
• based on the sequencing:
• quantifying DNA from a chromosome suspected of being aneuploid;
• quantifying DNA from one or more second chromosomes;
• combining DNA quantity information from each chromosome;
• comparing the information to a pre-determined value;
• and based on the comparison, determining the presence or absence of fetal aneuploidy.

A computer program comprising a computer executable logic recorded on a computer readable medium configured to support and execute functions for determining a prenatal diagnosis of a fetal chromosomal aneuploidy in a sample from a human suspected of being pregnant, that is pregnant, or that has been pregnant, wherein the sample includes nucleic acids, including acts of receiving data from the one or more genomic DNA regions analyzed by sequencing nucleic acids in the sample to produce partial or complete genome sequence;

• based on the sequencing:
• quantifying DNA from a chromosome suspected of being aneuploid;
• quantifying DNA from one or more second chromosomes;
• combining DNA quantity information from each chromosome;
• comparing the information to a pre-determined value;
• and based on the comparison, determining the presence or absence of fetal aneuploidy.

A method for performing prenatal diagnosis of a fetal chromosomal aneuploidy in a sample from a human suspected of being pregnant, that is pregnant, or that has been pregnant, wherein the sample includes nucleic acids, the method comprising

• obtaining the sample;
• calculating a number of sequence reads required to be analyzed to detect ploidy changes with high levels of confidence;
• sequencing nucleic acids in the sample to produce partial or complete genome sequence;
• obtaining the number of sequence reads required to be analyzed to detect ploidy changes with high levels of confidence;
• based on the sequencing:
• quantifying DNA from a chromosome suspected of being aneuploid;
• quantifying DNA from one or more second chromosomes;
• combining information from each chromosome;
• comparing the information to a pre-determined value;
• and based on the comparison, determining the presence or absence of fetal aneuploidy.