Patent SG-11201806595U-A (SG)
Title: Using cell-free dna fragment size to determine copy number variations
Inventor: DUENWALD SVEN
IPC: G16H10/40
Filed: 2016-12-20
Abstract: INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property -, Organization IIIMI41101110101011111 HO 11111011101110011001111101110111110 ill OEN International Bureau ... .1 j (10) International Publication Number (43) International Publication Date ..... ....r;,' WO 2017/136059 Al 10 August 2017(10.08.2017) WIPO I PCT (51) International Patent Classification: JONES, Keith W.; 499 Illinois Street, #210, San Fran- C12Q 1/68 (2006.01) G06F 19/22 (2011.01) cisco, California 94158 (US). CHEN, Gengxin; 499 G06F 19/24 (2011.01) G06F 19/00 (2011.01) Illinois Street, #210, San Francisco, California 94158 G06F 19/18 (2011.01) (US). SKVORTSOV, Dimitri; 499 Illinois Street, #210, San Francisco, California 94158 (US). (21) International Application Number: PCT/US2016/067886 (74) Agents: ZHOU, Feng et al.; WEAVER AUSTIN VIL- LENEUVE & SAMPSON LLP, P. 0. Box 70250, Oak- (22) International Filing Date: land, California 94612-0250 (US). 20 December 2016 (20.12.2016) (25) Filing Language: English (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (26) Publication Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (30) Priority Data: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 62/290,891 3 February 2016 (03.02.2016) US HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, 15/382,508 16 December 2016 (16.12.2016) US KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, (71) Applicant: VERINATA HEALTH, INC. [US/US]; 5200 MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, Illumina Way, San Diego, California 92122 (US). NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, (72) Inventors: DUENWALD, Sven; 499 Illinois Street, #210, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, San Francisco, California 94158 (US). COMSTOCK, ZA, ZM, ZW. _ David A.; 499 Illinois Street, #210, San Francisco, Califor- - nia 94158 (US). BARBACIORU, Catalin; 499 Illinois (84) Designated States (unless otherwise indicated, for every _ Street, #210, San Francisco, California 94158 (US). kind of regional protection available): ARIPO (BW, GH, CHUDOVA, Darya I.,; 5931 Taormino Avenue, San Jose, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, California 95123 (US). RAVA, Richard P.; 711 Edge- TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, wood Road, Redwood City, California 94062 (US). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, = [Continued on next page] (54) Title: USING CELL-FREE DNA FRAGMENT SIZE TO DETERMINE COPY NUMBER VARIATIONS (57) : Disclosed are methods for determining copy number vari- ms 702 I . equencin data = _ 713A 1 7 7139 coverage coverage l short fragm al ents fragments , 713C ation (CNV) known or suspected to be associated with a variety of medical Relative R fre uenc conditions. In some embodiments, methods are provided for determining y of q short copy number variation of fetuses using maternal samples comprising mater- fragments nal and fetal cell free DNA. In some embodiments, methods are provided = — Convert & de multiplex (if I 1 i 71 for determining CNVs known or suspected to be associated with a variety of appficabie) Normalize binned site to total NES value disclosed herein provide methods _ . 1 1 medical conditions. Some embodiments = Alignment • 7 8 Remove global wave, flowcell/batch specific to improve the sensitivity and/or specificity of sequence data analysis by de- riving a fragment size parameter. In some implementations, information 3 71 I i 718 . Tag flitering 8 Binning Correct for GC level from fragments different of sizes are used to evaluate copy number vari- In some implementations, t from ations. one or more -statistics obtained coy- _ ! 7 9 information the interest is used to Compute count. Principle Component Analysis erage of sequence of evaluate copy num- ber In implementations, fetal fraction variations. some one or more estim- 722 = ates are more t-statistics to determine copy number combined with one or Single sample filter 1 variations. _ 72 nEnrichment d tar- etover reference Enrichment of target over reference Enrichment of target ave r reference 729 73r 7 Il One or more Fetal Fractions I statistic t statistic t statistic tz. kin Pass 1: coverage-ell fragments Ploidy Likelihood Pass 2: M coverage - short fragments Pass 3: — -- Figure 2E Il fiaquency of short fra \ .. IN Il © N O WO 2017/136059 Al MIDEDIM01101 DIVIIMMEMIIIM100III11111111111111110111111111111 DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, before the expiration of the time limit for amending the LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, SI, SK, SM, TR), OAPI GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (BF, BJ, CF, CG, CI, RS, CM, SE, GA, claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) Published: — with international search report (Art. 21(3))