Methods and processes for non-invasive assessment of genetic variations

Abstract

Provided herein are methods, processes and apparatuses for non-invasive assessment of genetic variations that make use of decision analyses. The decision analyses sometimes include segmentation analyses and/or odds ratio analyses.

1 . (canceled) 
     
     
         2 . A computer-implemented method for determining the presence or absence of a chromosome aneuploidy in a sample, comprising:
 (a) receiving input information comprising nucleic acid sequence reads of circulating cell-free nucleic acid from a test sample, mapping the nucleic acid sequence reads to portions of a reference genome, and determining counts of the nucleic acid sequence reads mapped to portions of the reference genome;   (b) determining a chromosome count representation according to the counts determined in (a);   (c) calculating a log odds ratio (LOR), wherein the LOR is the log of the quotient of (i) a first multiplication product of (1) a conditional probability of having a chromosome aneuploidy and (2) a prior probability of having the chromosome aneuploidy, and (ii) a second multiplication product of (1) a conditional probability of not having the chromosome aneuploidy and (2) a prior probability of not having the chromosome aneuploidy; and   (d) identifying the presence or absence of a chromosome aneuploidy according to the LOR and the chromosome count representation.   
     
     
         3 . The method of  claim 2 , wherein the chromosome count representation in (b) is counts for all portions in the chromosome divided by counts for all portions in autosomes. 
     
     
         4 . The method of  claim 2 , further comprising providing a z-score quantification of the chromosome count representation in (b). 
     
     
         5 . The method of  claim 4 , wherein the z-score is a subtraction product of the (i) chromosome count representation for the test sample less a (ii) median of a euploid count representation, divided by a (iii) median absolute deviation (MAD) of the euploid count representation, wherein the (i) chromosome count representation for the test sample is a ratio of counts in portions in the chromosome divided by counts in portions in the autosomes, and the (ii) median of the euploid count representation is the median of a ratio of counts in portions in the chromosome divided by counts in portions in autosomes for euploids. 
     
     
         6 . The method of  claim 2 , wherein the test sample is from a pregnant female bearing a fetus and the conditional probability of having the chromosome aneuploidy is determined according to a fetal fraction determined for the test sample, a z-score for the chromosome count representation for the test sample, and a fetal fraction-specific distribution of z-scores for the chromosome count representation. 
     
     
         7 . The method of  claim 6 , wherein the conditional probability of having the chromosome aneuploidy is an intersection between the z-score for the chromosome count representation for the test sample and a fetal fraction-specific distribution of z-scores for the chromosome count representation. 
     
     
         8 . The method of  claim 6 , wherein the conditional probability of not having the chromosome aneuploidy is an intersection between the z-score of the chromosome count representation for the test sample and a distribution of z-scores for the chromosome count representation in euploids. 
     
     
         9 . The method of  claim 2 , wherein the prior probability of having the chromosome aneuploidy and the prior probability of not having the chromosome aneuploidy are determined from multiple samples that do not include the test subject. 
     
     
         10 . The method of  claim 2 , further comprising determining whether the LOR is greater than zero or less than zero. 
     
     
         11 . The method of  claim 2 , further comprising determining a z-score quantification of the chromosome count representation for the test sample and determining whether it is less than, greater than or equal to a value of 3.95. 
     
     
         12 . The method of  claim 11 , further comprising determining the presence of a chromosome aneuploidy based, at least in part, on a determination that, for the test sample, (i) the z-score quantification of the chromosome count representation is greater than or equal to the value of 3.95, and (ii) the LOR is greater than zero. 
     
     
         13 . The method of  claim 11 , comprising determining the absence of a chromosome aneuploidy based, at least in part, on a determination that, for the test sample, (i) the z-score quantification of the chromosome representation is less than the value of 3.95, and/or (ii) the LOR is less than zero. 
     
     
         14 . The method of  claim 2 , wherein the counts of nucleic acid sequence reads mapped to portions of the reference genome are normalized counts. 
     
     
         15 . The method of  claim 14 , wherein the counts are normalized by a normalization process comprising GC-LOESS normalization and/or principal component normalization. 
     
     
         16 . The method of  claim 2 , wherein the chromosome aneuploidy is a trisomy or monosomy. 
     
     
         17 . The method of  claim 2 , wherein the nucleic acid sequence reads in (a) are obtained by a non-targeted multiplexed massively parallel sequencing process. 
     
     
         18 . The method of  claim 17 , wherein millions of nucleic acid fragments are sequenced by the non-targeted multiplexed massively parallel sequencing process. 
     
     
         19 . The method of  claim 2 , wherein the nucleic acid sequence reads in (a) are obtained by a non-targeted multiplexed massively parallel sequencing process performed with 1-fold coverage or fraction thereof. 
     
     
         20 . The method of  claim 2 , wherein the nucleic acid sequence reads in (a) comprise millions of nucleic acid sequence reads.