IP Library › Granted Patent US 12,198,786
Granted Patent B2
US 12,198,786 · App. 16/952,847 · Granted Jan 14, 2025

Methods and processes for non-invasive assessment of genetic variations

Inventor: Gregory Hannum (San Diego, CA)
Assignee: SEQUENOM, INC.
G16B20/20G16B20/10G16B30/00G16B30/10G16B40/00
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,198,786
App. No.
16/952,847
Granted
Jan 14, 2025
Kind
B2
Abstract

Provided herein are methods, processes, systems and machines for non-invasive assessment of genetic variations. In particular, provided herein are methods, processes, systems and machines for non-invasive assessment of copy number variations. In some aspects, copy number variations include aneuploidies (e.g., trisomy 13, 18, or 21). In some aspects, copy number variations include microdeletions or microduplications.

Claims (25)

1. A system for reducing bias in sequence read counts for a test sample, the system comprising:

(a) a sequencing machine configured to

sequence circulating cell-free nucleic acid from a heterogeneous test sample by a non-targeted massively parallel sequencing process,

generate thousands to millions of sequence reads for the test sample, and

map the thousands to millions of sequence reads to a reference genome to generate mapped sequence reads;

(b) a bias reduction machine comprising

a memory; and

one or more microprocessors configured to perform, according to instructions in the memory, a process for reducing bias in counts of the sequence reads for the test sample, wherein the process comprises

(i) normalizing counts of the mapped sequence reads from the sequencing machine according to guanine and cytosine (GC) content, thereby generating normalized sequence read counts;

(ii) generating read densities from the normalized sequence read counts and a read density profile for the test sample from the read densities; and

(iii) adjusting the read density profile for the test sample by removing components of the read densities that correlate with one or more principal components from the read density profile, wherein the principal components are obtained from a training set of samples by a principal component analysis and represent one or more biases in a read density profile, thereby providing an adjusted read density profile for the test sample comprising adjusted read densities, wherein a plurality of biases is removed from the adjusted read density profile; and

(c) a report generator configured to report a presence or absence of a copy number variation in the test sample according to the adjusted read density profile.

2. The system of claim 1 , wherein the bias reduction machine adjusts the read density profile for the test sample by 2 to 10 principal components.

3. The system of claim 1 , wherein the plurality of biases is selected from fetal gender, sequence bias, fetal fraction, bias correlated with DNase I sensitivity, entropy, repetitive sequence bias, chromatin structure bias, polymerase error-rate bias, palindrome bias, inverted repeat bias, PCR amplification bias, and hidden copy number variation.

4. The system of claim 1 , wherein the read density profile for the test sample is determined according to median read densities for the test sample.

5. The system of claim 1 , wherein the read densities for the read density profile for the test sample are determined according to a process comprising use of a kernel density estimation.

6. The system of claim 1 , wherein the training set of samples comprises known euploid samples.

7. The system of claim 1 , wherein the training set of samples comprises at least 500 known euploid samples.

8. The system of claim 1 , wherein the principal components are obtained from median read densities for the samples in the training set.

9. The system of claim 1 , wherein the read densities for the samples in the training set are determined according to a process comprising use of a kernel density estimation.

10. The system of claim 1 , wherein (ii) further comprises filtering, according to a read density distribution, portions of the reference genome, thereby providing the read density profile for the test sample comprising read densities of filtered portions, wherein the read density distribution is determined for read densities of portions for multiple samples.

11. The system of claim 10 , wherein the multiple samples comprise a set of known euploid samples.

12. The system of claim 10 , wherein the filtering is based on a measure of uncertainty for the read density distribution.

13. The system of claim 1 , wherein the test sample is a test sample from a pregnant female.

14. The system of claim 1 , wherein the sequencing process is performed with 1-fold coverage or fraction thereof.

Assignments (2)
CORRECTIVE ASSIGNMENT TO CORRECT THE STATE OF INCORPORTION INSIDE THE ASSIGNMENT DOCUMENT PREVIOUSLY RECORDED AT REEL: 055896 FRAME: 0411. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT . Recorded May 18, 2021
From: HANNUM, GREGORY
To: SEQUENOM, INC.
Reel/Frame 056282/0125 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 12, 2021
From: HANNUM, GREGORY
To: SEQUENOM, INC.
Reel/Frame 055896/0411 →
Continuity (3)
Continuation 14505423 · Oct 2, 2014
Provisional Application 61887081 · Oct 4, 2013
Related Publication 20210158898A1 · May 27, 2021
References Cited (400)
US 4683195A · Mullis et al. · 1987 [cited by applicant]
US 4683202A · Mullis · 1987 [cited by applicant]
US 5075212A · Rotbart · 1991 [cited by applicant]
US 5091652A · Mathies et al. · 1992 [cited by applicant]
US 5432054A · Saunders et al. · 1995 [cited by applicant]
US 5445934A · Fodor · 1995 [cited by applicant]
US 5670325A · Lapidus et al. · 1997 [cited by applicant]
US 5720928A · Schwartz et al. · 1998 [cited by applicant]
US 5786146A · Herman et al. · 1998 [cited by applicant]
US 5928870A · Lapidus et al. · 1999 [cited by applicant]
US 5939598A · Kucherlapati et al. · 1999 [cited by applicant]
US 6015714A · Baldarelli et al. · 2000 [cited by applicant]
US 6090550A · Collinge et al. · 2000 [cited by applicant]
US 6100029A · Lapidus et al. · 2000 [cited by applicant]
US 6214558B1 · Shuber et al. · 2001 [cited by applicant]
US 6214560B1 · Yquerabide et al. · 2001 [cited by applicant]
US 6235475B1 · Brenner et al. · 2001 [cited by applicant]
US 6258540B1 · Lo et al. · 2001 [cited by applicant]
US 6263286B1 · Gilmanshin et al. · 2001 [cited by applicant]
US 6403311B1 · Chan · 2002 [cited by applicant]
US 6566101B1 · Shuber et al. · 2003 [cited by applicant]
US 6617133B1 · Deamer · 2003 [cited by applicant]
US 6772070B2 · Gilmanshin et al. · 2004 [cited by applicant]
US 6818395B1 · Quake et al. · 2004 [cited by applicant]
US 6927028B2 · Dennis et al. · 2005 [cited by applicant]
US 6936422B2 · Akeson et al. · 2005 [cited by applicant]
US 7005264B2 · Su et al. · 2006 [cited by applicant]
US 7169560B2 · Lapidus et al. · 2007 [cited by applicant]
US 7279337B2 · Zhu · 2007 [cited by applicant]
US 7282337B1 · Harris · 2007 [cited by applicant]
US 7947454B2 · Akeson et al. · 2011 [cited by applicant]
US 7960105B2 · Schwartz et al. · 2011 [cited by applicant]
US 7972858B2 · Meller et al. · 2011 [cited by applicant]
US 8688388B2 · Dzakula et al. · 2014 [cited by applicant]
US 10964409B2 · Hannum · 2021 [cited by applicant]
US 20010014850A1 · Gilmanshin et al. · 2001 [cited by applicant]
US 20010049102A1 · Huanq et al. · 2001 [cited by applicant]
US 20020006621A1 · Bianchi · 2002 [cited by applicant]
US 20020045176A1 · Lo et al. · 2002 [cited by applicant]
US 20020110818A1 · Chan · 2002 [cited by applicant]
US 20020119469A1 · Shuber et al. · 2002 [cited by applicant]
US 20020164629A1 · Quake et al. · 2002 [cited by applicant]
US 20030013101A1 · Balasubramanian · 2003 [cited by applicant]
US 20030082600A1 · Olek et al. · 2003 [cited by applicant]
US 20030180779A1 · Lofton-Day et al. · 2003 [cited by applicant]
US 20030207326A1 · Su et al. · 2003 [cited by applicant]
US 20030232346A1 · Su · 2003 [cited by applicant]
US 20040081993A1 · Cantor et al. · 2004 [cited by applicant]
US 20040110208A1 · Chan et al. · 2004 [cited by applicant]
US 20040137470A1 · Dhallan et al. · 2004 [cited by applicant]
US 20050019784A1 · Su et al. · 2005 [cited by applicant]
US 20050095599A1 · Pittaro et al. · 2005 [cited by applicant]
US 20050112590A1 · Boom et al. · 2005 [cited by applicant]
US 20050147980A1 · Berlin et al. · 2005 [cited by applicant]
US 20050164241A1 · Hahn et al. · 2005 [cited by applicant]
US 20050227278A1 · Wall · 2005 [cited by applicant]
US 20050287592A1 · Kless · 2005 [cited by applicant]
US 20060046258A1 · Lapidus et al. · 2006 [cited by applicant]
US 20060063171A1 · Akeson et al. · 2006 [cited by applicant]
US 20060068440A1 · Chan et al. · 2006 [cited by applicant]
US 20060252071A1 · Lo et al. · 2006 [cited by applicant]
US 20070065823A1 · Dressman et al. · 2007 [cited by applicant]
US 20070202525A1 · Quake et al. · 2007 [cited by applicant]
US 20080020390A1 · Mitchell et al. · 2008 [cited by applicant]
US 20080070792A1 · Stoughton et al. · 2008 [cited by applicant]
US 20080081330A1 · Kahvejian et al. · 2008 [cited by applicant]
US 20080138809A1 · Kapur et al. · 2008 [cited by applicant]
US 20080187915A1 · Polansky et al. · 2008 [cited by applicant]
US 20080233575A1 · Harris · 2008 [cited by applicant]
US 20090026082A1 · Rothberq et al. · 2009 [cited by applicant]
US 20090029377A1 · Lo et al. · 2009 [cited by applicant]
US 20090075252A1 · Harris · 2009 [cited by applicant]
US 20090129647A1 · Dimitrova et al. · 2009 [cited by applicant]
US 20090191565A1 · Lapidus et al. · 2009 [cited by applicant]
US 20090197257A1 · Harris · 2009 [cited by applicant]
US 20090317817A1 · Oeth et al. · 2009 [cited by applicant]
US 20090317818A1 · Ehrich et al. · 2009 [cited by applicant]
US 20100105049A1 · Ehrich et al. · 2010 [cited by applicant]
US 20100112575A1 · Fan et al. · 2010 [cited by applicant]
US 20100112590A1 · Lo et al. · 2010 [cited by applicant]
US 20100138165A1 · Fan et al. · 2010 [cited by applicant]
US 20100151471A1 · Faham et al. · 2010 [cited by applicant]
US 20100216151A1 · Lapidus et al. · 2010 [cited by applicant]
US 20100216153A1 · Lapidus et al. · 2010 [cited by applicant]
US 20100109197A1 · Stoddart et al. · 2010 [cited by applicant]
US 20100261285A1 · Goldstein et al. · 2010 [cited by applicant]
US 20100310421A1 · Oliver et al. · 2010 [cited by applicant]
US 20100330557A1 · Yakhini et al. · 2010 [cited by applicant]
US 20110086769A1 · Oliphant et al. · 2011 [cited by applicant]
US 20110159601A1 · Golovchenko et al. · 2011 [cited by applicant]
US 20110171634A1 · Xiao et al. · 2011 [cited by applicant]
US 20110174625A1 · Akeson et al. · 2011 [cited by applicant]
US 20110177498A1 · Clarke et al. · 2011 [cited by applicant]
US 20110177517A1 · Rava et al. · 2011 [cited by applicant]
US 20110201507A1 · Rava et al. · 2011 [cited by applicant]
US 20110224087A1 · Quake et al. · 2011 [cited by applicant]
US 20110230358A1 · Rava · 2011 [cited by applicant]
US 20110288780A1 · Rabinowitz et al. · 2011 [cited by applicant]
US 20110294699A1 · Lee et al. · 2011 [cited by applicant]
US 20110312503A1 · Chuu et al. · 2011 [cited by applicant]
US 20110319272A1 · Fan et al. · 2011 [cited by applicant]
US 20120046877A1 · Hyland et al. · 2012 [cited by applicant]
US 20120122701A1 · Ryan et al. · 2012 [cited by applicant]
US 20120141712A1 · Otaka et al. · 2012 [cited by applicant]
US 20120165203A1 · Quake et al. · 2012 [cited by applicant]
US 20120184449A1 · Hixson et al. · 2012 [cited by applicant]
US 20120214678A1 · Rava et al. · 2012 [cited by applicant]
US 20120264115A1 · Rava · 2012 [cited by applicant]
US 20120270212A1 · Rabinowitz et al. · 2012 [cited by applicant]
US 20120270739A1 · Rava et al. · 2012 [cited by applicant]
US 20130012399A1 · Meyers · 2013 [cited by applicant]
US 20130015793A1 · Qin et al. · 2013 [cited by applicant]
US 20130022977A1 · Lapidus et al. · 2013 [cited by applicant]
US 20130034546A1 · Rava et al. · 2013 [cited by applicant]
US 20130052913A1 · Schmid et al. · 2013 [cited by applicant]
US 20130085681A1 · Deciu · 2013 [cited by examiner]
US 20130096011A1 · Rava et al. · 2013 [cited by applicant]
US 20130103320A1 · Dzakula · 2013 [cited by applicant]
US 20130109981A1 · Uesaka · 2013 [cited by applicant]
US 20130130921A1 · Gao et al. · 2013 [cited by applicant]
US 20130130923A1 · Ehrich et al. · 2013 [cited by applicant]
US 20130150253A1 · Deciu et al. · 2013 [cited by applicant]
US 20130196317A1 · Lapidus et al. · 2013 [cited by applicant]
US 20130237431A1 · Lo et al. · 2013 [cited by applicant]
US 20130245961A1 · Lo et al. · 2013 [cited by applicant]
US 20130261983A1 · Dzakula et al. · 2013 [cited by applicant]
US 20130288244A1 · Deciu et al. · 2013 [cited by applicant]
US 20130304392A1 · Deciu et al. · 2013 [cited by applicant]
US 20130309666A1 · Deciu et al. · 2013 [cited by applicant]
US 20130325360A1 · Deciu et al. · 2013 [cited by applicant]
US 20130338933A1 · Deciu et al. · 2013 [cited by applicant]
US 20140100792A1 · Deciu et al. · 2014 [cited by applicant]
US 20140180594A1 · Kim et al. · 2014 [cited by applicant]
US 20140235474A1 · Tanq et al. · 2014 [cited by applicant]
US 20140242588A1 · Van Den Boom et al. · 2014 [cited by applicant]
US 20140322709A1 · Lapidus et al. · 2014 [cited by applicant]
US 20150005176A1 · Kim et al. · 2015 [cited by applicant]
US 20150100244A1 · Hannum · 2015 [cited by applicant]
US 20150347676A1 · Zhao et al. · 2015 [cited by applicant]
US 20160034640A1 · Zhao et al. · 2016 [cited by applicant]
US 20160110497A1 · Dzakula et al. · 2016 [cited by applicant]
CA 2851537A1 · 2013 [cited by applicant]
CN 101137760A · 2008 [cited by applicant]
CN 101971178A · 2011 [cited by applicant]
CN 102203787A · 2011 [cited by applicant]
CN 102459648A · 2012 [cited by applicant]
CN 102625854A · 2012 [cited by applicant]
CN 102985561A · 2013 [cited by applicant]
CN 103108960A · 2013 [cited by applicant]
CN 105555968A · 2016 [cited by applicant]
JP 2017500620A · 2017 [cited by applicant]
WO WO00006770 · 2000 [cited by applicant]
WO WO01032887 · 2001 [cited by applicant]
WO WO02042496 · 2002 [cited by applicant]
WO WO03000920 · 2003 [cited by applicant]
WO WO03106620 · 2003 [cited by applicant]
WO WO05023091 · 2005 [cited by applicant]
WO WO06056480 · 2006 [cited by applicant]
WO 2006097049A1 · 2006 [cited by applicant]
WO WO07140417 · 2007 [cited by applicant]
WO WO07147063 · 2007 [cited by applicant]
WO WO08121828 · 2008 [cited by applicant]
WO WO2008157264 · 2008 [cited by applicant]
WO WO09007743 · 2009 [cited by applicant]
WO WO09032779 · 2009 [cited by applicant]
WO WO09032781 · 2009 [cited by applicant]
WO WO09046445 · 2009 [cited by applicant]
WO WO10004265 · 2010 [cited by applicant]
WO WO10033578 · 2010 [cited by applicant]
WO WO10033639 · 2010 [cited by applicant]
WO WO10056728 · 2010 [cited by applicant]
WO WO10059731 · 2010 [cited by applicant]
WO WO10065470 · 2010 [cited by applicant]
WO WO10115016 · 2010 [cited by applicant]
WO WO11034631 · 2011 [cited by applicant]
WO WO11038327 · 2011 [cited by applicant]
WO WO11050147 · 2011 [cited by applicant]
WO WO11057094 · 2011 [cited by applicant]
WO 2011090558A1 · 2011 [cited by applicant]
WO WO11087760 · 2011 [cited by applicant]
WO WO11090556 · 2011 [cited by applicant]
WO WO11090559 · 2011 [cited by applicant]
WO WO11091063 · 2011 [cited by applicant]
WO WO11102998 · 2011 [cited by applicant]
WO WO11143659 · 2011 [cited by applicant]
WO WO11146632 · 2011 [cited by applicant]
WO WO12012703 · 2012 [cited by applicant]
WO WO12088348 · 2012 [cited by applicant]
WO WO12088456 · 2012 [cited by applicant]
WO WO12103031 · 2012 [cited by applicant]
WO WO12108920 · 2012 [cited by applicant]
WO WO12118745 · 2012 [cited by applicant]
WO WO2012141712 · 2012 [cited by applicant]
WO WO12177792 · 2012 [cited by applicant]
WO WO13000100 · 2013 [cited by applicant]
WO WO2013015793 · 2013 [cited by applicant]
WO WO13052907 · 2013 [cited by applicant]
WO WO13052913 · 2013 [cited by applicant]
WO WO13055817 · 2013 [cited by applicant]
WO WO13109981 · 2013 [cited by applicant]
WO WO13177086 · 2013 [cited by applicant]
WO WO13192562 · 2013 [cited by applicant]
WO WO2014039556 · 2014 [cited by applicant]
WO WO14055790 · 2014 [cited by applicant]
WO WO14116598 · 2014 [cited by applicant]
WO WO14055774 · 2014 [cited by applicant]
WO WO2014165596 · 2014 [cited by applicant]
WO WO2014190286 · 2014 [cited by applicant]
WO WO2015040591 · 2015 [cited by applicant]
WO 2015054080A1 · 2015 [cited by applicant]
WO WO2015051163 · 2015 [cited by applicant]
WO WO2015183872 · 2015 [cited by applicant]
WO WO16019042 · 2016 [cited by applicant]
Koboldt et al., Massively Parallel Sequencing Approaches for Characterization of Structural Variation, 2012, Methods Mol Biol, 838: 369-384 (Year: 2012). [cited by examiner]
Adinolfi et al., “Rapid detection of aneuploidies by microsatellite and the quantitative fluorescent polymerase chain reaction.” Prenat Diagn. Dec. 1997;17(13) : 1299-311. [cited by applicant]
Agarwal et al., “Commercial landscape of noninvasive prenatal testing in the United States” Prenatal Diagnosis (2013) 33(6):521-531. [cited by applicant]
Akeson et al., “Microsecond Time-Scale Discrimination Among Polycytidylic Acid, Polyadenylic Acid, and Polyuridylic Acid as Homopolymers or as Segments Within Single RNA Molecules,” Biophysical Journal vol. 77 Dec. 1999… [cited by applicant]
Alkan et al., “Personalized copy number and segmental duplication maps using next-generation sequencing”, Nature Genetics, vol. 41, No. 10, Oct. 30, 2009 (Oct. 30, 2009), pp. 1061-1067, and Supplementary Information 1-6… [cited by applicant]
Alkan, C., et al., Personalized copy number and segmental duplication maps using next generation sequencing. Nat Genet, 2009. 41(1O): p. 1061-7. [cited by applicant]
Amicucci et al., “Prenatal Diagnosis of Myotonic Dystrophy Using Fetal DNA Obtained from Maternal Plasma,” Clin. Chem. 46:301-302, 2000. [cited by applicant]
Anantha et al., “Porphyrin binding to quadrupled T4G4.” Biochemistry. Mar. 3, 1998;37(9) :2709-14. [cited by applicant]
Armour et al., “Measurement of locus copy number by hybridisation with amplifiable probes.” Nucleic Acids Res. Jan. 15, 2000;28(2):605-9. [cited by applicant]
Armour et al., “The detection of large deletions or duplications in genomic DNA.” Hum Mutat. Nov. 2002;20(5):325-37. [cited by applicant]
Ashkenasy et al., “Recognizing a Single Base in an individual DNA Strand: A Step Toward Nanopore DNA Sequencing,” Angew Chem Int. Ed Engl. Feb. 18, 2005; 44(9): 1401-1404. [cited by applicant]
Ashoor, et al., (2012): Chromosome-selective sequencing of maternal plasma cell-free DNA for first trimester detection of trisomy 21 and trisomy 18, American Journal of Obstetrics and Gynecology, doi: 10.1016/i.aioa.201… [cited by applicant]
Aston et al. “Optical mapping and its potential for large-scale sequencing project,” (1999) Trends Biotechnol. 17(7) :297-302. [cited by applicant]
Aston et al. “Optical mapping: an approach for fine mapping,” (1999) Methods Enzymol. 303:55-73. [cited by applicant]
Avent et al., “Non-invasive diagnosis of fetal sex; utilization of free fetal DNA in maternal plasma and ultrasound,” Prenatal Diagnosis, 2006, 26:598-603. [cited by applicant]
Avent, “Refining noninvasive prenatal diagnosis with single-molecule next-generation sequencing” Clin. Chem. (2012) 58(4):657-658. [cited by applicant]
Beaucage and Caruthers, Tetrahedron Letts., 22:1859-1862 (1981). [cited by applicant]
Benjamin et al., “Summarizing and correcting the GC content bias in high-throughput sequencing” Nucleic Acids Research (2012) 40(10):e72. [cited by applicant]
Berger et al., “Universal bases for hybridization, replication and chain termination,” (2000) Nucleic Acids Res. 28(15): 2911-2914. [cited by applicant]
Bergstrom et al. “Synthesis, Structure, and Deoxyribonucleic Acid Sequencing with a Universal Nucleoside: 1-(2′-Deoxy-.beta.-D-ribofuranosyl)-3-nitropyrrole,” (1995) J. Am. Chem. Soc.117, 1201-1209. [cited by applicant]
Bianchi et al., “Isolation of fetal DNA from nucleated erythrocytes in maternal blood,” PNAS, 1990,87(9): 3279-3283. [cited by applicant]
Boeva et al., “Control-free calling of copy number alterations in deep-sequencing data using GC-content normalization” Bioinformatics (2011) 27(2):268-269. [cited by applicant]
Bollen, “Bioconductor: Microarray versus next-generation sequencing tool sets” retrieved from the internet: http://dspace.library.uu.nl/bitstream/handle/187 4/290489/Sander Bollen writing assignment.pdf, retrieved on Se… [cited by applicant]
Borsenberger et al, “Chemically Labeled Nucleotides and Oligonucleotides Encode DNA for Sensing with Nanopores,” J. Am. Chem. Soc., 131, 7530-7531, 2009. [cited by applicant]
Branton et al, “The potential and challenges of nanopore sequencing”, Nature Biotechnology, 26:1146-1153, 2008. [cited by applicant]
Braslavsky et al., “Sequence information can be obtained from single DNA molecules,” PNAS, 2003, 100(7): 3960-3964. [cited by applicant]
Brizot et al., “Maternal serum hCG and fetal nuchal translucency thickness for the prediction of fetal trisomies in the first trimester of pregnancy.” Br J Obstet Gynaecol. Feb. 1995;102(2):127-32. [cited by applicant]
Brizot et al., “Maternal serum pregnancy-associated plasma protein A and fetal nuchal translucency thickness for the prediction of fetal trisomies in early pregnancy.” Obstet Gynecol. Dec. 1994;84(6):918-22. [cited by applicant]
Brown and Lin “Synthesis and duplex stability of oligonucleotides containing adenine-guanine analogues,” (1991) Carbohydrate Research 216, 129-139. [cited by applicant]
Brown et al. A step-by-step guide to non-linear regression analysis of experimental data using a Microsoft Excel spreadsheet Computer Methods and Programs in Biomedicine vol. 65, pp. 191-200 (2001). [cited by applicant]
Brown, L., et al., Validation of QF-PCR for prenatal aneuploidy screening in the United States. Prenat Diaqn, 2006. 26(11): p. 1068-74. [cited by applicant]
Bruch et al., Trophoblast-like cells sorted from peripheral maternal blood using flow cytometry: a multiparametric study involving transmission electron microscopy and fetal DNA amplification,: Prenatal Diagnosis 11 :78… [cited by applicant]
Brunger, “Free R value: a novel statistical quantity for assessing the accuracy of crystal structures,” Nature 355, 472-475 (Jan. 30, 1992); doi: 10.1038/355472a0. [cited by applicant]
Bullard et al., “Evaluation of statistical methods for normalization and differential expression in mRNA-Seq experiments,” Bioinformatics 201O, 11:94, pp. 1-13. [cited by applicant]
Burlingame et al. Anal. Chem. 70:647R-716R (1998). [cited by applicant]
Campbell et al., “identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing.” Nat Genet. Jun. 2008;40(6):722-9. doi: 10.1038/ng.128. Epub Apr. 27, 2008. [cited by applicant]
Canick et al., “DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations,” Prenat Diaan. May 14, 2012:1-5. [cited by applicant]
Canick et al., “The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies” Prenat. Diagn. (2013) 33(7):667-674. [cited by applicant]
Canick, et al., “A New Prenatal Blood Test for Down Syndrome (RNA),” Jul. 2012 found on the internet at: clinicaltrials.gov/show/ A 15NCT00877292. [cited by applicant]
Cann et al., “A heterodimeric DNA polymerase: evidence that members of Euryarchaeota possess a distinct DNA polymerase.” 1998, Proc. Natl. Acad. Sci. USA 95:14250. [cited by applicant]
Cariello et al., “Fidelity of Thermococcus litoralis DNA polymerase (Vent) in PCR determined by denaturing gradient gel electrophoresis,” Nucleic Acids Res. Aug. 11, 1991 ;19(15):4193-8. [cited by applicant]
Carlson et al., “Molecular Definition of 22q11 Deletions in 151 Velo-Cardio-Facial Syndrome Patients,” The American Journal of Human Genetics, vol. 61, Issue 3, 620-629, Sep. 1, 1997. [cited by applicant]
Chan et al. “Size Distribution of Maternal and Fetal DNA in Maternal Plasma,” (2004) Clin. Chem. 50:88-92. [cited by applicant]
Chandrananda et al., “Investigating and correcting plasma DNA sequencing coverage bias to enhance aneuploidy discovery” PloS One (2014) 9:e86993. [cited by applicant]
Chen et al., “Noninvasive Prenatal Diagnosis of Fetal Trisomy 18 and Trisomy 13 by Maternal Plasma DNA Sequencing,” PLoS One, Jul. 2011, vol. 6, issue 7, e21791, pp. 1-7. [cited by applicant]
Chen et al., “A method for noninvasive detection of fetal large deletions/duplications by low coverage massively parallel sequencing” Prenatal Diagnosis (2013) 33(6) :584-590, and supplementary material pp. 1-6. [cited by applicant]
Chiang et al., High-resolution mapping of copy-number alterations with massively parallel sequencing, Nat Methods. Jan. 2009 ; 6(1): 99-103. [cited by applicant]
Chien et al., “Deoxyribonucleic acid polymerase from the extreme thermophile Thermus aquaticus,” 1976, J. Bacteoriol, 127: 1550-1557. [cited by applicant]
Chim et al. (2008). “Systematic search for placental DNA-methylation markers on chromosome 21: toward a maternal plasma-based epigenetic test for fetal trisomy 21.” Clin Chem 54(3): 500-11. [cited by applicant]
Chiu et al. “Maternal plasma DNA analysis with massively parallel sequencing by ligation for noninvasive prenatal diagnosis of trisomv 21.” Clin Chem 56(3): 459-63.(201 O). [cited by applicant]
Chiu et al. (2008). “Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma.” Proc Natl Acad Sci U S A 105(51): 20458-20463. [cited by applicant]
Chiu et al., “Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study,” BMJ 2011 ;342:c7401, 1-9. [cited by applicant]
Chiu et al., “Prenatal exclusion of thalassaemia major by examination of maternal plasma,” Lancet 360:998-1 OOO, 2002. [cited by applicant]
Chu et al. (2009). “Statistical model for whole genome sequencing and its application to minimally invasive diagnosis of fetal genetic disease.” Bioinformatics 25(1O): 1244-50. [cited by applicant]
Chung et al., “Discovering transcription factor binding sites in highly repetitive regions of genomes with multi-read analysis of Ch IP-Seq data” PLoS Computational Biology (2011) 7(7):e1002111. [cited by applicant]
Cohen et al. (2005): GC Composition of the Human Genome: In Search of Isochores. Mole Biol. Evol. 22(5):1260-1272. [cited by applicant]
Costa et al., “Fetal RHO genotyping in maternal serum during the first trimester of pregnancy” British Journal of Haematology (2002) 119:255-260. [cited by applicant]
Costa et al., “New Strategy for Prenatal Diagnosis of X-Linked Disorders” N. Engl. J. Med. 346:1502, 2002. [cited by applicant]
Cunningham et al., in Williams Obstetrics, McGraw-Hill, New York, p. 942, 2002. [cited by applicant]
Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. 6.3.1-6.3.6(1989). [cited by applicant]
D'Alton ME,, “Prenatal diagnostic procedures.” Semin Perinatol. Jun. 1994; 18(3) : 140-62. [cited by applicant]
Dan et al., “Clinical application of massively parallel sequencing-based prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11,105 pregnancies with mixed risk factors” Prenatal Diagnosis (2012) 32:1225-1… [cited by applicant]
Dan et al., “Prenatal detection of aneuploidy and imbalanced chromosomal arrangements bv massively parallel sequencing,” PLoS One 7(2): e27835. (2012). [cited by applicant]
Data Sheet: Illumina Sequencing: TruSeq RNA and DNA Sample Preparation Kits v2, Publication No. 970-2009-039 Apr. 27, 2011. [cited by applicant]
Davanos et al., “Relative quantitation of cell-free fetal DNA in maternal plasma using autosomal DNA markers” Clinica Chimica Acta (2011) 412:1539-1543. [cited by applicant]
Deamer et al., “Nanopores and Nucleic Acids: Prospects for ultrarapid sequencing.” Focus TiBtech Apr. 2000, (vol. 18) pp. 147-151. [cited by applicant]
Derrien et al. (2012) Fast Computation and Applications of Genome MappaBility. PLoS One 7(1): e30377, doi: 10.1371/journal.pone.0030377. [cited by applicant]
Dhallan et al., “Methods to increase the percentage of free fetal DNA recovered from the maternal circulation,” J. Am. Med. Soc. 291(9): 1114-1119, Mar. 2004). [cited by applicant]
Diaz and Sabino, “Accuracy of replication in the polymerase chain reaction. Comparison between Thermotoga maritima DNA polymerase and Thermus aquaticus DNA polymerase.” Diaz RS, Sabino EC. 1998 Braz J. Med. Res, 31: 123… [cited by applicant]
Ding et al., “A high-throughput gene expression analysis technique using competitive PCR and matrix-assisted laser desorption ionization time-of-flight MS.” Proc Natl Acad Sci U S A. Mar. 18, 2003;100(6):3059-64. Epub M… [cited by applicant]
DNA Replication 2nd edition, Kornberg and Baker, W. H. Freeman, New York, N.Y. (1991). [cited by applicant]
DNAcopy [online],[retrieved on Apr. 24, 2013], retrieved from the internet <URL:*>http://bioconductor .org/packages/2.12/Bioc/html/DNAcopy.html. [cited by applicant]
Dohm et al., “Substantial Biases in ultra-short read data sets from high-throughput DNA sequencing,” Nucleic Acids Res. Sep. 2008;36(16):e105. Epub Jul. 26, 2008. [cited by applicant]
Donoho and Johnstone (1995), “Wavelab and Reproducible Research,” Stanford University, Stanford CA 94305, USA, pp. 1-27. [cited by applicant]
Drmanac et al., “Sequencing by hybridization: towards an automated sequencing of one million M13 clones arrayed on membranes,” Electrophoresis, 13(8): p. 566-573, 1992. [cited by applicant]
Edelmann, L., et al., A common molecular basis for rearrangement disorders on chromosome 22q11. Hum Mol Genet, 1999. 8(7): p. 1157-67. [cited by applicant]
Egger et al., “Reverse transcription multiplex PCR for differentiation between polio- and enteroviruses from clinical and environmental samples.” J Clin MicroBiol. Jun. 1995;33(6) :1442-7. [cited by applicant]
Ehrich et al., Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting, American Journal of Obstetrics and Gynecology—Amer J Obstet Gynecol, vol. 204, No. 3, pp. 2… [cited by applicant]
Eiben et al., “First-trimester screening: an overview.” J Histochem Cytochem. Mar. 2005;53(3) :281-3. [cited by applicant]
Ensenauer, R.E., et al., Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients. Am J Hum Genet, 2003. 73(5): p. 1027-40. [cited by applicant]
Extended European Search Report dated Dec. 2, 2015 in European Application No. EP11745050.2, filed on Feb. 9, 2011 and published as EP 2 536 852 on Dec. 26, 2012. [cited by applicant]
Fan et al., “Analysis of the size distributions of fetal and maternal cell-free DNA by paired-end sequencing” Clinical Chemistry (2010) 56(8):1279-1286. [cited by applicant]
Fan et al., (2008). “Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood.” Proc Natl Acad Sci U S A 105(42): 16266-71. [cited by applicant]
Fan et al., (201O). “Sensitivity of noninvasive prenatal detection of fetal aneuploidy from maternal plasma using shotgun sequencing is limited only by counting statistics. ” PLoS One 5(5): e10439. [cited by applicant]
Forabosco et al., “Incidence of non-age-dependent chromosomal abnormalities: a population-based study on 88965 amniocenteses” European Journal of Human Genetics (2009) 17:897-903. [cited by applicant]
Gebhard et al., “Genome-wide profiling of CpG methylation identifies novel targets of aberrant hypermethylation in myeloid leukemia.” Cancer Res. Jun. 15, 2006;66(12) :6118-28. [cited by applicant]
Goya, R., et a!. (2010) SNVMix: predicting single nucleotide variants from next generation sequencing of tumors, [cited by applicant]
Grati, “Chromosomal Mosaicism in Human Feta-Placental Development: Implications for Prenatal Diagnosis” J. Clin. Med. (2014) 3:809-837. [cited by applicant]
Haar, Alfred (191O) “Zur Theorie der orthogonalen Funktionensysteme”, Mathematische Annalen 69 (3): 331-371, English translation “On the Theory of Orthogonal Function Systems” 1-37. [cited by applicant]
Hahn et al., “Cell-free nucleic acids as potential markers for preeclampsia.” Placenta. Feb. 2011;32 Suppl:S17-20. doi: 10.1016/j.placenta.2010.06.018. [cited by applicant]
Harris et al., “Single-molecule DNA sequencing of a viral genome.” Science. Apr. 4, 2008;320(5872) :106-9. doi: 10.1126/science.1150427. [cited by applicant]
Herzenberg et al., “Fetal cells in the blood of pregnant women: detection and enrichment by fluorescence-activated cell sorting,” PNAS 76:1453-1455, 1979. [cited by applicant]
Hill, Craig, “Gen-Probe Transcription mediated Amplification: System Principles,” Jan. 1996 h ⋅ /www.qen-probe.com/pdfs/tma whiteppr.pdf. [cited by applicant]
Hinds et al., “Whole-genome patterns of common DNA variation in three human populations” Science (2005) 307:1072-1079. [cited by applicant]
Hinnisdaels et al., “Direct cloning of PCR products amplified with Pwo DNA polymerase,” 1996, Biotechniques, 20: 186-188. [cited by applicant]
Hsu et al., “A model-based circular binary segmentation algorithm for the analysis of array CGH data” BMC Research Notes (2011) 4:394. [cited by applicant]
Hsu, S. Self, D. Grove, T. Randolph, K. Wang, J. Delrow, L. Loo, and P. Porter, “Denoising array-based comparative genomic hybridization data using wavelets”, Biostatistics (Oxford, England), vol. 6, No. 2, pp. 211-226,… [cited by applicant]
Huber et al. “High-resolution liquid chromatography of DNA fragments on non-porous poly(styrene-divinylbenzene) particles,” Nucleic Acids Res. 21(5):1061-1066, 1993. [cited by applicant]
Hudecova et al., “Maternal plasma fetal DNA fractions in pregnancies with low and high risks for fetal chromosomal aneuploidies” PLoS One (2014) 9(2):e88484. [cited by applicant]
Hudson et al., “An STS-Based Map of the Human Genome,” Science, vol. 270, pp. 1945-1954 (1995). [cited by applicant]
Hulten et al., “Rapid and simple prenatal diagnosis of common chromosome disorders: advantages and disadvantages of the molecular methods FISH and QF-PCR.” Reproduction. Sep. 2003;126(3) :279-97. [cited by applicant]
Human Genome Mutations, D. N. Cooper and M. Krawczak, BIOS publishers, 1993. [cited by applicant]
Hupe,P. et al. (2004) “Analysis of array CGH data: from signal ratio to gain and loss of DNA regions”, Bioinformatics, 20, 3413-3422. [cited by applicant]
Huse et al., “Accuracy and quality of massively parallel DNA pyrosequencing” Genome Biology (2007) 8(7):R143. [cited by applicant]
International Preliminary Report on patentability mailed on Apr. 14, 2016 in International Application No. PCT/US2014/058885, filed on Oct. 2, 2014 and published as WO 2015/051163 on Apr. 9, 2015. [cited by applicant]
International Preliminary Report on patentability mailed on Apr. 21, 2016 in International Application No. PCT/US2014/059156, filed on Oct. 3, 2014 and published as WO 2015/054080 on Apr. 16, 2015. [cited by applicant]
International Preliminary Report on patentability mailed on Aug. 6, 2015 in International Application No. PCT/US2014/012369, filed Jan. 21, 2014 and published as WO 2014/116598 on Jul. 31, 2014. [cited by applicant]
International Preliminary Report on patentability mailed on Dec. 3, 2015 in International Application No. PCT/US2014/039389, filed on May 23, 2014 and published as WO 2014/190286 on Nov. 27, 2014. [cited by applicant]
International Preliminary Report on patentability mailed on Oct. 15, 2015 in International Application No. PCT/US2014/032687, filed on Apr. 2, 2014 and published as WO 2014/165596 on Oct. 9, 2014. [cited by applicant]
International Search Report and Written Opinion dated Jan. 5, 2016 in International Application No. PCT/US2015/042701, filed on Jul. 29, 2015. [cited by applicant]
International Search Report and Written Opinion dated Oct. 2, 2015 in International Application No. PCT/US2015/032550, filed on May 27, 2015 and published as WO 2015/183872 on Dec. 3, 2015. [cited by applicant]
International Search Report and Written Opinion mailed on Sep. 24, 2014 in International Application No. PCT/US2014/043497, filed on Jun. 20, 2014. [cited by applicant]
Invitation to Pay Additional Fees and Partial International Search Report dated Oct. 14, 2015 in International Application No. PCT/US2015/042701, filed on Jul. 29, 2015. [cited by applicant]
James/James “Mathematics Dictionary,” Fifth Edition, Chapman & Hall, International Thomson Publishing, 1992, pp. 266-267 270. [cited by applicant]
Jensen et al. “High-Throughput Massively Parallel Sequencing for Fetal Aneuploidy Detection from Maternal Plasma” Mar. 6, 2013. PLoS One 8(3): e57381. [cited by applicant]
Jensen et al., “Detection of microdeletion 22q11.2 in a fetus By next-generation sequencing of maternal plasma,” Clin Chem. Jul. 2012;58(7) :1148-1151. [cited by applicant]
Jiang et al., “Feta/Ouant: Deducing Fractional Fetal DNA Concentration from Massively Parallel Sequencing of DNA in Maternal Plasma,” Bioinformatics, Nov. 15, 2012;28(22) :2883-2890. [cited by applicant]
Jing et al. (1998) Proc Natl Acad Sci USA. 95(14) :8046-51. [cited by applicant]
Johnston et al., “Autoradiography using storage phosphor technology,” Electrophoresis. May 1990; 11 (5) :355-360. [cited by applicant]
Joos et al., “Covalent attachment of hybridizable oligonucleotides to glass supports,” Analytical Biochemistry 247:96-101, 1997. [cited by applicant]
Jorgez et al.. “Improving Enrichment of Circulating Fetal DNA for genetic Testing: Size Fractionation Followed By Whole Gene Amplification.” Fetal Diagnosis and Therapy, Karger Basel, CH, vol. 25, No. 3 Jan. 1, 2009, pp… [cited by applicant]
Juncosa-Ginesta et al., “Improved efficiency in site-directed mutagenesis by PCR using a [cited by applicant]
Jurinke et al. (2004) Mol. Biotechnol. 26, 147-164. [cited by applicant]
Kalinina et al., “Nanoliter scale PCR with TaqMan detection.” Nucleic Acids Res. May 15, 1997;25(1 O):1999-2004. [cited by applicant]
Kato et al., “A new packing for separation of DNA restriction fragments by high performance liquid chromatography,” J. Biochem, 95(1):83-86, 1984. [cited by applicant]
International Human Genome Sequencing Consortium initial sequencing and analysis of the human qenome Nature vol. 409, pp. 860-921 (2001). [cited by applicant]
International Preliminary Report on patentability and Written Opinion mailed on Jan. 9, 2014 in International Application No. PCT/US2012/043388, filed on Jun. 20, 2012 and published as WO 2012/177792 on Dec. 27, 2012. [cited by applicant]
International Preliminary Report on patentability and Written Opinion mailed on Apr. 24, 2014 in International Application No. PCT/US2012/059592, filed on Oct. 10, 2012 and published as WO 2013/055817 on Apr. 18, 2013. [cited by applicant]
International Preliminary Report on patentability mailed on Apr. 16, 2015 in International Application No. PCT/US2013/063314, filed on Oct. 3, 2013 and published as WO 2014/055790 on Apr. 10, 2014. [cited by applicant]
International Preliminary Report on patentability mailed on Apr. 16, 2015 in International Application No. PCT/US2013/063287, filed Oct. 3, 2013. [cited by applicant]
International Preliminary Report on patentability mailed on Dec. 31, 2014 in International Application No. PCT/US2013/047131, filed on Jun. 21, 2013 and published as WO 2013/192562 on Dec. 27, 2013. [cited by applicant]
International Preliminary Report on patentability mailed on Feb. 27, 2014 in International Application No. PCT/US2012/059123, filed on Oct. 5, 2012 and published as WO 2013/052913 on Apr. 11, 2013. [cited by applicant]
International Preliminary Report on patentability mailed on Jul. 31, 2014 in International Application No. PCT/US2013/022290, filed on Jan. 18, 2013 and published as WO 2013/109981 on Jul. 25, 2013. [cited by applicant]
International Preliminary Report on patentability mailed on Jun. 9, 2014 in International Application No. PCT/US2012/059114, filed on Oct. 5, 2012 and published as WO 2013/052907 on Apr. 11, 2013. [cited by applicant]
International Search Report and Written Opinion dated: Apr. 5, 2013 in International Application No. PCT/US2012/043388 filed: Jun. 20, 2012 and published as : WO 12/177792 Dec. 27, 2012. [cited by applicant]
International Search Report and Written Opinion dated: Jul. 4, 2013 in International Application No. PCT/US2013/022290 filed: Jan. 18, 2013, and published as : WO/2013/109981 on Jul. 25, 2013. [cited by applicant]
International Search Report and Written Opinion dated: Mar. 6, 2013 in International Application No. PCT/US2012/059592 filed: Oct. 1O, 2012. [cited by applicant]
International Search Report and Written Opinion dated: Sep. 26, 2012 in International Application No. PCT/US2011/066639 filed: Dec. 21, 2011 and published as : WO 12/088348 Jun. 28, 2012. [cited by applicant]
International Search Report and Written Opinion mailed on Apr. 2, 2014 in International Application No. PCT/US2013/063314, filed on Oct. 3, 2013 and published as WO 2014/055790 on Apr. 1O, 2014. [cited by applicant]
International Search Report and Written Opinion mailed on Dec. 13, 2013 in International Application No. PCT/US2013/063287, filed Oct. 3, 2013. [cited by applicant]
International Search Report and Written Opinion mailed on Dec. 17, 2014 in International Application No. PCT/US2014/039389, filed on May 23, 2014 and published as WO 2014/190286 on Nov. 27, 2014. [cited by applicant]
International Search Report and Written Opinion mailed on Feb. 18, 2015 in International Application No. PCT/US2014/058885, filed on Oct. 2, 2014. [cited by applicant]
International Search Report and Written Opinion mailed on Jul. 14, 2014 in International Application No. PCT/US2014/032687, filed on Apr. 2, 2014. [cited by applicant]
International Search Report and Written Opinion mailed on Sep. 9, 2013 in International Application No. PCT/US2012/059123, filed on Oct. 5, 2012 and published as WO/2013/052913 on Apr. 11, 2013. [cited by applicant]
International Search Report and Written Opinion mailed on Sep. 9, 2013 in International Application No. PCT/US2012/059114, filed on Oct. 5, 2012 and published as WO/2013/052907 on Apr. 11, 2013. [cited by applicant]
International Search Report and Written Opinion mailed on Sep. 18, 2013 in International Application No. PCT/US2013/047131, filed on Jun. 21, 2013 and published as WO 2013/192562 on Dec. 27, 2013. [cited by applicant]
International Search Report and Written Opinion mailed on May 9, 2014 in International Application No. PCT/US2014/012369, filed Jan. 21, 2014. [cited by applicant]
Invitation to Pay Additional Fees and Partial Search Report dated: Jan. 18, 2013 in International Application No. PCT/US2012/059592 filed: Oct. 1O, 2012. [cited by applicant]
Invitation to Pay Additional Fees and Partial Search Report dated: Jul. 3, 2013 in International Application No. PCT/US2012/059123 filed: Oct. 5, 2012 and published as: WO/2013/052913 on Apr. 11, 2013. [cited by applicant]
Khandjian, “UV crosslinking of RNA to nylon membrane enhances hybridization signals,” Mol. Bio. Rep. 11: 107-115, 1986. [cited by applicant]
Kim et al., “Determination of fetal DNA fraction from the plasma of pregnant women using sequence read counts” Prenat. Diaon. (2015) 35(8):810-815. [cited by applicant]
Kim et al., “Identification of significant regional genetic variations using continuous CNV values in aCGH data” Genomics (2009) 94(5):317-323. [cited by applicant]
Kitzman et al., (2012): Noninvasive whole-genome sequencing of a human fetus. Science Translational Medicine, 4 (137) :137ra76. [cited by applicant]
Kornberg and Baker, W. H. Freeman, New York, N.Y. (1991). [cited by applicant]
Kulkarni et al., “Global DNA methylation patterns in placenta and its association with maternal hypertension in pre-eclampsia.” DNA Cell Biol. Feb. 2011;30(2):79-84. doi: 10.1089/dna.2010.1084. Epub Nov. 2, 201O. [cited by applicant]
Lai et al. (1999) Nat Genet. 23(3) :309-13. [cited by applicant]
Lai et al., (2005). Comparative analysis of algorithms for identifying amplifications and deletions in arrav CGH data. Bioinformatics, 21, 19:3763-70. [cited by applicant]
Langmead et al., “Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.” Genome Biol. 2009;10(3):R25. doi: 10.1186/GB-2009-10-3-r25. Epub Mar. 4, 2009. [cited by applicant]
Lecomte and Doubleday, “Selective inactivation of the 3′ to 5′ exonuclease activity of Escherichia coli DNA polymerase I by heat,” 1983, Polynucleotides Res. 11 :7505-7515. [cited by applicant]
Leek et al., “Tackling the widespread and critical impact of batch effects in high throughput data” Nature Reviews Genetics (2010) 11 :733-739. [cited by applicant]
Lefkowitz et al., “Clinical validation of a noninvasive prenatal test for genomewide detection of fetal copy number variants” American Journal of Obstetrics & Gynecology (Dec. 2, 2015) S0002-9378(16)00318-5. doi: 10.101… [cited by applicant]
Levin, “It's prime time for reverse transcriptase,” Cell 88:5-8 (1997). [cited by applicant]
Li et al., “Detection of paternally inherited fetal point mutations for beta-thalassemia using size-fractionated cell-free DNA in maternal plasma.,” J. Amer. Med. Assoc. 293:843-849, 2005. [cited by applicant]
Li et al., “Mapping short DNA sequencing reads and calling variants using mapping quality scores.” Genome Res. Nov. 2008;18(11) :1851-8. doi: 10.1101/gr.078212.108. Epub Aug. 19, 2008. [cited by applicant]
Liao et al., (2012): Noninvasive Prenatal Diagnosis of Fetal Trisomy 21 by Allelic Ratio Analysis Using Targeted Massively Parallel Sequencing of Maternal Plasma DNA. PLoS One, 7(5): e38154, p. 1-7. [cited by applicant]
Liao, G.J., et al., Targeted massively parallel sequencing of maternal plasma DNA permits efficient and unbiased detection of fetal alleles. Clin Chem, 2010. 57(1): p. 92-101. [cited by applicant]
Lin and Brown, (1989) Nucleic Acids Res. 17:10373-10383. [cited by applicant]
Lin and Brown, (1992) Nucleic Acids Res. 20:5149-5152. [cited by applicant]
Liu et al., “CUSHAW: a CUDA compatible short read aligner to large genomes based on the Burrows-Wheeler transform” Bioinformatics (2012) 28(14) :1830-1837. [cited by applicant]
Innis et al., PCR Protocols: A Guide to Methods and Applications, Innis et al., eds, 1990. [cited by applicant]
Lo “Recent advances in fetal nucleic acids in maternal plasma.” J Histochem Cytochem. Mar. 2005;53(3) :293-296. [cited by applicant]
Lo et al. (1997). “Presence of fetal DNA in maternal plasma and serum.” Lancet 350(9076): 485-487. [cited by applicant]
Lo et al. (2007). “Digital PCR for the molecular detection of fetal chromosomal aneuploidy.” Proc Natl Acad Sci U S A 104(32): 13116-21. [cited by applicant]
Lo et al. (2007). “Plasma placental RNA allelic ratio permits noninvasive prenatal chromosomal aneuploidy detection.” Nat Med 13(2): 218-23. [cited by applicant]
Lo et al., “Fetal DNA in maternal plasma: application to non-invasive blood group genotyping of the fetus” Transfus. Clin. Biol. (2001) 8:306-310. [cited by applicant]
Lo et al., “Prenatal Diagnosis of Fetal RhD Status by Molecular Analysis of Maternal Plasma, ” N. Engl. J. Med. 339:1734-1738, 1998. [cited by applicant]
Lo et al., “Quantative Abnormalities of Fetal NDA in Maternal Serum in Preeclampsia,” Clin. Chem. 45:184-188, 1999. [cited by applicant]
Lo et al., “Increased Fetal DNA Concentrations in the Plasma of Pregnant Women Carrying Fetuses with Trisomy 21,” Clin. Chem. 45:1747-1751, 1999. [cited by applicant]
Lo YM, et al.(1998) Am J Hum Genet 62:768-775. [cited by applicant]
Lo, Y.M., et al., Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med, 2010. 2(61): p. 61ra91. [cited by applicant]
Loakes and Brown (1994) Nucleic Acids Res. 22, 4039-4043. [cited by applicant]
Lun et al. (2008). “Microfluidics digital PCR reveals a higher than expected fraction of fetal DNA in maternal plasma.” Clin Chem 54(10): 1664-72. [cited by applicant]
Lundberg et al., “High-fidelity amplification using a thermostable DNA polymerase isolated from Pyrococcus furiosus,” 1991 Gene, 108:1-6. [cited by applicant]
Mann et al., “Development and implementation of a new rapid aneuploidy diagnostic service within the UK National Health Service and implications for the future of prenatal diagnosis.” Lancet. Sep. 29, 2001;358 (9287) :1… [cited by applicant]
Margulies et al., “Genome sequencing in microfabricated high-density picolitre reactors.” Nature. Sep. 15, 2005;437 (7057):376-80. Epub Jul. 31, 2005. [cited by applicant]
Mazloom, Amin, “Gender Prediction with Bowtie Alignments using Male Specific Reaions,” May 1o, 2012. [cited by applicant]
Metzker ML., “Sequencing technologies—the next generation.” Nat Rev Genet. Jan. 201O;11(1) :31-46. doi: 10.1038/nrg2626. Epub Dec. 8, 2009. [cited by applicant]