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LAWRENCE D. PLATT, MD PROF OB GYN UCLA SCHOOL OF MEDICINE PERES CENTER FOR PEACE TEL AVIV YAFO JULY 1,2013 THE VERIFI® PRENATAL TEST – MAKING A DIFFERENCE.

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Presentation on theme: "LAWRENCE D. PLATT, MD PROF OB GYN UCLA SCHOOL OF MEDICINE PERES CENTER FOR PEACE TEL AVIV YAFO JULY 1,2013 THE VERIFI® PRENATAL TEST – MAKING A DIFFERENCE."— Presentation transcript:

1 LAWRENCE D. PLATT, MD PROF OB GYN UCLA SCHOOL OF MEDICINE PERES CENTER FOR PEACE TEL AVIV YAFO JULY 1,2013 THE VERIFI® PRENATAL TEST – MAKING A DIFFERENCE IN PATIENT SAFETY

2 THE VERIFI® PRENATAL TEST: NIPT TECHNOLOGY OVERVIEW Data adapted from Wellesley, D, et al., Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe. Eur J of Hum Gen, 11 January Prenatal Prevalence of Chromosomal Abnormalities Major fetal aneuploidies

3 PRENATAL SCREENING OPTIONS – RISK SCORE ACOG Practice Bulletin No. 77, January 2007 Integrated Screen 1 st Trimester 2 nd Trimester Serum Integrated Detection Rate (%) Down Syndrome Testing with 5% Screen Positive Rate.

4 CURRENT DIAGNOSTIC OPTIONS - KARYOTYPE Definitive answers, but are invasive and come with risk to the patient Most are unnecessary due to the high rate of false positives in screening** 1.Hahnemann JM, Vejerslev LO. Accuracy of cytogenetic findings on chorionic villus sampling (CVS)--diagnostic consequences of CVS mosaicism and non-mosaic discrepancy in centres contributing to EUCROMIC Prenat Diagn Sep;17(9): Mid-trimester amniocentesis for prenatal diagnosis. Safety and accuracy. JAMA Sep 27; 236(13): Trimester - TestSensitivitySpecificity 1 st – CVS99.25% % 1 2 nd - Amniocentesis99.4% % 2.

5 SPECTRUM OF PRENATAL TESTING *. Serum Screening Amnio NIPT Combined Serum Screens, NT, Ultra- sound *Not meant to represent percentage of accuracy SCREENINGDIAGNOSTIC SCREENING Risk scores are generated and modified based on biochemical analysis and population statistics DIAGNOSTIC Results are based entirely on genetic factors CVS

6 WHAT ARE THE GOALS OF NIPT? Reduce exposure of fetus to risk Reduce false positives Enable a high detection rate Testing that can easily be offered to all pregnant women.

7 TWO SOURCES OF FETAL DNA IN MATERNAL BLOOD Fetal cells 1 in a billion of total cell population Require isolation via mechanical and/or biochemical means Cell-free DNA (cfDNA) Maternal blood contains both maternal and fetal cfDNA 2–20% of total cfDNA is fetal.

8 FETAL CELL-FREE DNA IN MATERNAL BLOOD Released through apoptosis Fetal cfDNA likely arises from cytotrophoblastic cells of placenta Released into bloodstream as small DNA fragments ( bp) Reliably detected after 7+ weeks gestation Undetectable within hours postpartum A Reliable Analyte During Pregnancy.

9 Fetal DNA fragments in maternal blood. Cell free DNA fragments are then sequenced. Compare the individual sequenced chromosomes against a reference for analysis. DNA SEQUENCING USING CELL FREE DNA.

10 VERINATA’S MASSIVELY PARALLEL SEQUENCING (MPS)- A SUPERIOR APPROACH MPS Provides Precise, Across the Genome Coverage Targeted Sequencing is Limited to Few Chromosomes, Loci Benefits Lowest Assay Failure Rates <1% Ability to rapidly add new content to test menu. Verinata’s approach allows rapid evolution of product 22.8 Million reads Drawbacks High Assay Failure Rates of 4-12% Limited ability to add new content leads to static product profile 500K to 6.4M reads © 2013 Verinata. Content is proprietary and confidential.

11 DETECTION OF FETAL ANEUPLOIDY MPS Enables Precise Molecular Counting © 2013 Verinata. Content is proprietary and confidential. Fetal cfDNA (20%) Maternal cfDNA Chromosomes: 123 …… 21Trisomy 21 VS Counting NOT TO SCALE 10% more Chr21 cfDNA in T21

12 DUAL THRESHOLD CLASSIFICATION Indicates Borderline Results VS. Single Threshold Method verifi ® prenatal test Dual Threshold Trisomy Diploid © 2013 Verinata. Content is proprietary and confidential. 0.2 to 0.6 %

13 PUBLICATIONS IN MOST PRESTIGIOUS JOURNALS IN FIELD Large-scale, prospective and blinded clinical trials Only study in the industry that represents real-world clinical use High-risk patient population Singleton gestations analyzed Over 60 U.S. centers enrolled.

14  Maternal age-related risks  Positive results on maternal serum screening  Abnormal ultrasound finding(s)  Prior pregnancy with aneuploidy  Parental Robertsonian translocation involving one of the tested chromosomes Patients Wanting Early, Accurate Test And Are At High Risk Of Aneuploidy Due To: WHICH PATIENTS SHOULD BE OFFERED NIPT?

15 VERIFI ® PRENATAL TEST OPTIONS Provides testing for chromosomes 21,13,18 Provides option for sex chromosome testing Monosomy X, XXX, XXY, XYY If no aneuploidy detected, fetal sex (XX, XY) reported Option to select on test requisition form No change to price, turnaround time © 2013 Verinata. Content is proprietary and confidential.

16 VERIFI ® PRENATAL TEST PERFORMANCE Sensitivity95% CISpecificity95% CI Trisomy 21>99.9%96.0 – %98.7 – Trisomy %86.2 – %98.5 – Trisomy %61.7 – 98.5>99.9%99.2 – Verinata Health, Inc. Data on file. Original Publication: * Bianchi et al. Obstetrics and Gynecology, Vol 119, No. 5, May 2012 Sensitivity95% CISpecificity95% CI Monosomy X 95.0%75.1 – %97.6 – 99.7 XX97.6%94.8 – %97.2 – 99.9 XY99.1%96.9 – %96.9 – 99.8 XXX, XXY, XYY Limited data of these more rare aneuploidies preclude performance calculations.

17 Source: ISPD Position Statement April 2013 LARGE CLINICAL TRIALS

18 SEX CHROMOSOME ANALYSIS

19 SEX CHROMOSOMES ANEUPLOIDY WHY ?

20 CONSIDERATION OF NIPT FOR CYSTIC HYGROMA Highly associated with common aneuploidies including monosomy X (Turner syndrome) that are associated with pregnancy loss and are medically significant at birth. Prevalence ~1:285 To study, we examined performance of NIPT for patients with cystic hygroma in the MELISSA study 20 Cystic hygroma Bianchi, et al, Obstetrics and Gynecology, Vol 121, No. 5, May 2013

21 MPS OF MATERNAL PLASMA DNA IN CYSTIC HYGROMA 21 Electronic clinical database of the MELISSA study was searched to identify women carrying singleton fetuses with cystic hygroma 113 cases were identified—69 (61%) had chromosome abnormalities, but 4 had abnormalities other than T21, T18, T13, or monosomy X Archived plasma samples were sequenced using updated chemistry Samples were classified for aneuploidy status of chromosomes 21, 18, 13, and presence or absence of monosomy X Bianchi, et al, Obstetrics and Gynecology, Vol 121, No. 5, May 2013

22 Obstet Gynecol 2013;121:1057–62 MPS and Fetal Nuchal Cystic Hygroma

23 CYSTIC HYGROMA: SEQUENCING RESULTS 113 cases 29/30 cases of T21 detected, 1 suspected 20/21 cases of monosomy X detected 10/10 cases of T18 detected 2/4 cases of T13 detected, 1 suspected None of the 44 euploid cases was called positive Bianchi, et al, Obstetrics and Gynecology, Vol 121, No. 5, May 2013

24 CONCLUSIONS AND PRACTICE IMPLICATIONS Using sequencing of 4 chromosomes, 61/65 (94%) of aneuploid cases were detected and two more were suspected Overall, 107/113 (95%) of cases were correctly classified 4 cases were “other” and 2 aneuploidies were not detected NIPT for aneuploidy can be considered as an immediate noninvasive point of care test at time of sonographic diagnosis of cystic hygroma. Allow management to move forward for women who decline, do not have access, or have a contraindication to an invasive procedure. 24

25 DISCORDANT RESULTS Second Trimester Ultrasound Male Genitalia VERIFY …… XY Amniocentesis ………46,XX WHAT NEXT??????????? Case

26 TEST PERFORMANCE IN “ REAL WORLD POPULATION” Initial clinical laboratory experience in noninvasive prenatal testing for fetal aneuploidy from maternal plasma DNA samples Tracy Futch1, John Spinosa2,3, Sucheta Bhatt1, Eileen De Feo2, Richard P. Rava4 and Amy J. Sehnert5* DOI: /pd.4123 May , 974 patients Positive Predictive value of 99.8% Negative Predictive Value of 99.92% Turn around time 5.1 days Assay failure rate of 0.7%

27 © 2013 Verinata. Content is proprietary and confidential.

28 Test Cancellations: Rolling 6 month window, ending May 2013 Red text indicates a technical test failure Quantity Not Sufficient0.53% Cancelled by Phs/Pat0.23% Sample received beyond stability0.22% Gestational Age less than 10 Weeks0.15% Sample Improperly Labeled0.13% Test Valid for Singletons Only0.09% Interfering Substances (too much cfDNA)0.08% Duplicate Specimen0.04% Improper sample type0.03% NY State Permit Denied0.03% Internal Processing Error0.01% Unable to isolate sufficient cfDNA0.01% Sample integrity compromised0.01% Sample lost or destroyed during shipping0.01% Expired Tube0.01%

29 KEY DIFFERENTIATORS – CLINICAL TEST Low assay failure rate and need for re-draw (<1%) Low TAT (Average TAT 4 days, 95% 8 days) Sample requirement – 1 tube (7-10 mL) maternal blood only Weeks Matter! Broadest validated test menu including sex chromosomes Accept samples from ART pregnancies including egg donors Result type – Clear and descriptive for physicians Non risk score Independent of other pre-test factors (i.e., gestational age, maternal age) © 2013 Verinata. Content is proprietary and confidential.

30 NIPT TEST COMPARISON verifi® Verinata Harmony Ariosa MaterniT21 Sequenom NIPT Natera Result Types Aneuploidy Detected Aneuploidy Suspected No Aneuploidy Detected Risk score incorporating maternal, gestational age Positive Negative Risk score incorporating maternal, gestational age Assay Failure Rate <0.7% 4.6 – 4.9%1%5.9 – 12.6% Sample1 tube maternal blood 2 tubes maternal blood 2-4 tubes maternal blood (best with paternal sample) Egg Donors Yes (with data)NoYesNo Test Menu T21, T18, T13 Optional sex chromosome aneuploidies (Published data) T21, T18, T13 Y chromosome (optional)(not published) T21, T18, T13 Mandatory sex chromosome aneuploidies (not published) T21, T18, T13 Sex chromosome aneuploidies (only MX published) Published Clinical Validation Large-scale, blinded clinical validation Small, blinded clinical validation

31 NIPT IS A GAME CHANGER

32 EFFECT OF NIPT ON INVASIVE TESTING: EVMS

33 INVASIVE PROCEDURE UPDATE BY MONTH (7/2010 THROUGH 3/2013)

34 IMPACT OF INVASIVE TESTING IN PATIENTS WITH A POSITIVE FIRST OR SECOND TRIMESTER SCREEN

35 NIPT RESULTS FROM CFFM 6/1/2010 THROUGH 3/31/2013 POSITIVE FIRST AND SECOND TRIMESTER SCREEN 6/2010 – 10/201110/2011 – 3/2013 Total patients seen Total singleton, non-ONTD, patients seen Total procedures performed Total singleton, non-ONTD procedures performed Total patients seen 6/1/2010 – 3/31/2013:808 Total procedures performed 6/1/2010 – 3/31/2013:539 Total singleton, non-ONTD patients seen:728 Total singleton, non-ONTD procedures performed:500.

36 NIPT STATUS AND DECLINING INVASIVE TESTING

37 CHANGING TRENDS IN PRENATAL DIAGNOSIS THE PLATT EXPERIENCE 2010 (%)2011 (%)2012 (%) 2013 (%) Amnio Next slide CVS Next slide Total

38 CHANGING TRENDS IN PRENATAL DIAGNOSIS THE PLATT EXPERIENCE JANUARY THROUGH MAY BY YEAR 2010 (%)2011 (%)2012 (%) 2013 (%) Amnio CVS Total

39 Norton et al observed an increased uptake of NIPT following abnormal 1 st ∆ screening compared with abnormal 2 nd ∆ screening (56% vs 37%) This study revealed that women with a positive aneuploidy screening result are influenced by NIPT for their follow-up testing When the procedure-associated risk is eliminated, women may be less likely to decline testing UPTAKE OF NIPT IN WOMEN FOLLOWING POSITIVE ANEUPLOIDY SCREENING CHETTY S, GARABEDIAN MJ, NORTON ME. PRENAT DIAGN 2013; 33:

40 Rates of accepting/declining invasive PND vy socioeconomic characteristics Pre-NIPT (n=638)Post-NIPT (n=398)P value TOTAL ACCEPTING INVASIVE PND, N (%) Maternal age >35 yrs 301/638 (47.2) 185/349 (53.0) 156/398 (39.2) 94/234 (40.2) Race/ethnicity, n (%) Caucasian97/146 (66.4)53/110 (48.2)0.003 Hispanic80/289 (27/7)45/177 (25/4)0.593 Asian/Pacific Islander114/182 (62/6)56/106 (52/8)0.103 Other10/21 (47/6)2/5 (40.0)0.759 Insurance Medicaid71/258 (27.5)42/158 (26/6)0.835 Private230/380 (60.5)114/240 (47/5) UPTAKE OF NIPT IN WOMEN FOLLOWING POSITIVE ANEUPLOIDY SCREENING CHETTY S, GARABEDIAN MJ, NORTON ME. PRENAT DIAGN 2013; 33:

41 Rates of accepting/declining invasive PND vy socioeconomic characteristics Pre-NIPT (n=638)Post-NIPT (n=398)P value TOTAL DECLINING FURTHER TESTING, N (%) Maternal age >35 yrs 337/638 (52.8) 164/349 (47.0) 84/398 (21.2) 46/234 (19.7)) <0.001 Race/ethnicity, n (%) Caucasian49/146 (33.6)15/110 (13.6)<0.001 Hispanic209/289 (72.3)56/177 (31.6)<0.001 Asian/Pacific Islander68/182 ( /106 (12.3)<0.001 Other11/21 (52.4)0/5 (0.0)0.033 Insurance Medicaid187/258 (72.5)42/158 (26.6)<0.001 Private150/380 (39,5)41/240 (17) UPTAKE OF NIPT IN WOMEN FOLLOWING POSITIVE ANEUPLOIDY SCREENING CHETTY S, GARABEDIAN MJ, NORTON ME. PRENAT DIAGN 2013; 33:

42 Data for patients with initial PDC visit (January – March 2013) Totals # of pts offered NIPT at PDC 3,400 # of PNS screen positive pts offered/requested NIPT1,063 PNS screen positive patients accepting NIPT454 PNS screen positive patients declining NIPT609 # of patients offered/requesting NIPT for other indications (i.e., maternal age, US abnormality, US marker, etc.) 2337 Pts with other indications accepting NIPT661 Pts with other indications declining NIPT1676 # of patients coming to PDC with prior NIPT results through OB 147 TOTAL PATIENTS HAVING NIPT PERFORMED 1,262 CALIFORNIA PDC EXPERIENCE WITH NIPT

43 Data for patients with initial PDC visit (January – March 2013) Totals Total # of NIPT positive results 53 Number of NIPT positive patients having diagnostic procedures: 29 T21 confirmed by CVS/amnio/other16 T18 confirmed by CVS/amnio/other 3 T13 confirmed by CVS/amnio/other 3 45,X/other confirmed by CVS/amino/other 2 Normal karyotype (false positive) confirmed by CVS/amnio/other 5 SUB-TOTAL OF NIPT POSITIVE RESULTS W/ DIAGNOSIS 29 CALIFORNIA PDC EXPERIENCE WITH NIPT

44 Data for patients with initial PDC visit (January – March 2013) Totals Total # of NIPT indeterminate results 13 Number of NIPT indeterminate patients having diagnostic procedures: 4 T21 confirmed by CVS/amnio/other 0 T18 confirmed by CVS/amnio/other 1 T13 confirmed by CVS/amnio/other 0 45,X/other confirmed by CVS/amino/other1 Normal karyotype confirmed by CVS/amnio/other2 SUB-TOTAL OF NIPT INDETERMINATE RESULTS W/ DIAGNOSIS 4 CALIFORNIA PDC EXPERIENCE WITH NIPT

45 OFFICIAL SOCIETY STATEMENTS

46 The National Society of Genetic Counselors (NSGC) currently supports Noninvasive Prenatal Testing/Noninvasive Prenatal Diagnosis (NIPT/NIPD) as an option for patients whose pregnancies are considered to be at an increased risk for certain chromosome abnormalities. NSGC urges that NIPT/NIPD only be offered in the context of informed consent, education, and counseling by a qualified provider, such as a certified genetic counselor. Patients whose NIPT/NIPD results are abnormal, or who have other factors suggestive of a chromosome abnormality, should receive genetic counseling and be given the option of standard confirmatory diagnostic testing

47 cfDNA should not be part of routine prenatal lab assessment, but should be an informed patient choice after pretest counseling cfDNA should not be offered to low-risk women or women with multiple gestations – not yet sufficiently evaluated Negative cfDNA test result does not ensure an unaffected pregnancy Patient with a positive test should be referred for genetic counseling and offered invasive PND for confirmation cfDNA does not replace the accuracy and diagnostic precision of PND w/ CVS or amnio

48

49 ISPD Position Statement April 2013 Reliable cfDNA screening methods have only been reported for trisomy 21 and 18. cfDNA screening results have been reported for trisomy 13 but the numbers are not large and efficacy appears to be less than for trisomies 21 and 18. cfDNA screening results have also been reported for sex chromosome aneuploidy and the efficacy is unacceptably low. There are insufficient data available to judge whether any specific cfDNA screening method is most effective. The tests should not be considered to be fully diagnostic and therefore are not a replacement for amniocentesis and CVS. Analytic validity trials have been mostly focused on patients who are at high risk. Efficacy in low risk populations has not yet been fully demonstrated. There is insufficient information to know how well the test will perform in multiple gestation pregnancies

50 In a proportion of cases there is insufficient fetal cfDNA in the maternal plasma specimen or there is test failure for other reasons. Specific independently developed laboratory minimum standards, quality control, proficiency testing and inspection requirements have not yet been developed for this testing. It has not been demonstrated that the test can be provided in a cost-effective, timely, and equitable manner to total populations ISPD Position Statement April 2013

51 FUTURE HORIZONS

52 Large studies in low-risk populations Studies in multiple gestations Detection of sub-chromosomal abnormalities cfDNA and pregnancy complications Treatment of genetic syndromes (Downs)

53 CELL-FREE FETAL DNA IN MULTIPLES Study Objective : Effects of Multiple Gestation on Aneuploidy Detection and the Relative Cell-free Fetal DNA (cffDNA) per Fetus About.com Presented at SMFM, Feb. 2013

54 RESULTS: FF/FETUS DISTRIBUTION FOR TWIN AND SINGLETON PREGNANCIES © 2013 Verinata. Content is proprietary and confidential.

55 RESULTS: CALCULATED FFS FOR TWINS ChorionicityKaryotypeTotal FFFF/Fetus Dichorionic (n=19) (Both male) 46,XY/46,XY 47,XY+21/46,XY Dichorionic ([n=26) (different genders) 46,XY/46,XX0.068 Monochorionic (n=3)46,XY/46,XY 47, XY+18/47,XY Singleton (n=160)46,XY0.126

56 RESULTS: DEEPER SEQUENCING (16 TWINS) Sequencing with more sequence tags/sample (180M versus 25M) reduces the standard deviation of the measurement and increases the NCV The measurement leads to more confidence at the same FF per fetus NCVs for Trisomy 21 and 18 Increase with Deeper Sequencing © 2013 Verinata. Content is proprietary and confidential.

57 CONCLUSIONS FROM THE STUDY Autosomal Aneuploidies in 2 Twin Cases Here Were Correctly Classified However, Deeper Sequencing is Required to Classify Samples from Multiple Gestations with High Confidence due to the Lower Fetal Fraction per Fetus The Deeper Sequencing Approach Provides a “Safety Net”, Thereby Reducing the Potential Number of False Negative Cases © 2013 Verinata. Content is proprietary and confidential.

58 Am J Obstet Gynecol 2012;207:374.e1-6. The performance of screening for trisomy 21 and trisomy 18 by NIPT using chromosome-selective sequencing in a routine population is as effective as previously reported in high-risk groups with DR 99% and FPR 1%.

59 Am J Obstet Gynecol 2012;207:374.e1-6. On the basis of existing data, NIPT can potentially be used in universal screening for trisomies 21 and 18 in all singleton pregnancies and the main limiting factor for such widespread application of the test at present is the associated cost.

60 N Engl J Med 2012; 367 (23): CHROMOSOMAL MICROARRAY FOR PND

61 NON-INVASIVE SUBCHROMOSOMAL ANALYSIS Noninvasive Detection of Fetal Subchromosome Abnormalities via Deep Sequencing of Maternal Plasma Anupama Srinivasan 1, Diana W. Bianchi 2, Hui Huang 1, Amy J. Sehnert 1 and Richard P. Rava The American Journal of Human Genetics, Volume 92, Issue 2, , 10 Jan 2013

62 CFDNA AND DETECTION OF 22Q11 Clin chem. 2012; 58:

63 This work shows that in nonmosaic cases, it is possible to obtain a fetal molecular karyotype by MPS of maternal plasma cfDNA that is equivalent to a chromosome microarray and in some cases is better than a metaphase karyotype Am J Hum Genet 2013;92:167-76

64 Exciting Time Advancement in ultrasound technology Early & accurate diagnosis of fetal congenital abnormalities NIPT on cfDNA in maternal plasma Early screening of fetal karyotypic abnormalities Expand access for fetal intervention © 2013 Verinata. Content is proprietary and confidential.

65 How does Verifi® make pregnancy safer?

66 NIPT MAKING PRENATAL DIAGNOSIS SAFER 1. NIPT broadens the available prenatal testing options for women 2. NIPT offers an alternative to invasive diagnostic testing for women with screen positive fetuses With high sensitivity and specificity for T18 and T21 (T13 performance somewhat poorer comparatively)

67 NIPT MAKING PRENATAL DIAGNOSIS SAFER 3. NIPT offers reassurance to those women for whom invasive diagnostic testing was not an acceptable option 4. NIPT removes the risk of procedure-related risks and women may be less likely to decline testing

68 THANK YOU תודה

69 1 ST TRIMESTER CONTINGENT SCREENING FOR T21 BY BIOMARKERS AND MATERNAL BLOOD CELL-FREE DNA TESTING NICOLAIDES KH, ET AL. ULTRASOUND OBSTET GYNECOL 2013; DOI: /UOG (AHEAD OF PUBLICATION) Objective of study is to define cut-offs w/DRs and FPRs in T21 screening using maternal age and combinations of 1 st ∆ biomarkers to determine which women should undergo contingent maternal blood cell-free DNA (cfDNA) testing March 2006 through May 2012, prospective analysis using biomarkers (NT, DV-PIV at 11+0 to 13+6 weeks, and ß-hCG, PAPP-A, PIGF, and AFP at 8+0 to 13+6 weeks

70 1 ST TRIMESTER CONTINGENT SCREENING FOR T21 BY BIOMARKERS AND MATERNAL BLOOD CELL-FREE DNA TESTING NICOLAIDES KH, ET AL. ULTRASOUND OBSTET GYNECOL 2013; DOI: /UOG (AHEAD OF PUBLICATION) Contingent screening offers 98% DR of T21 fetuses; overall invasive testing rate <0.5% can be potentially achieved through cfDNA testing to 36% combined test alone 21% using combined test + PIGF and AFP 11% using combined test + PIGF, AFP and DV-PIV Conclusion: Effective 1 st trimester screening for T21 with DR of 98% and invasive testing rate <05% can be potentially achieved by contingent screening incorporating biomarkers and cfDNA.

71 POTENTIAL REASONS FOR DISCORDANT RESULTS Technology MPS counting statistics follow a normal distribution Classification cut-off sets likely false positive rate 3 standard deviations above mean cut-off yields 0.13% FP 4 standard deviations above mean cut-off yields 0.003% FP Biology Placental mosaicism reflected in cfDNA (similar to CVS) Vanishing twin may be reflected in cfDNA Maternal Fetal fraction

72 DISCORDANT RESULTS Maternal aneuploidy NIPT: Detected XXX CVS: 46,XX Maternal karyotype: Mosaic 46,XX[44]/45,X[5]/47,XXX[1] Co-twin demise NIPT: Detected 13 Amnio: normal karyotype Co-twin demise reported in first trimester Low fetal fraction False negative T21 Case Discussion

73 DISCORDANT RESULTS Confined placental mosaicism NIPT: Detected 13 CVS FISH: mosaicism for trisomy 13 Cultured CVS: normal karyotype Amnio (FISH and cultured cells): normal karyotype Maternal malignancy NIPT: Double detected 13 and 18 (confirmed on repeat testing) Amnio: normal karyotype Patient diagnosed with cancer postpartum Case Discussion

74 DISCORDANT RESULTS Maternal aneuploidy NIPT: Detected XXX CVS: 46,XX Maternal karyotype: Mosaic 46,XX[44]/45,X[5]/47,XXX[1] Co-twin demise NIPT: Detected 13 Amnio: normal karyotype Co-twin demise reported in first trimester Low fetal fraction False negative T21 Case Discussion

75 SUMMARY VERIFI® TEST Low assay failure rate and need for re-draw (<1%) Lowest TAT in industry (Average TAT 4 days, 95% 8 days) Sample requirement – 1 tube (7-10 mL) maternal blood only Weeks Matter! Broadest validated test menu including sex chromosomes Accept samples from ART pregnancies including egg donors Result type – Clear and descriptive for physicians Non risk score Independent of other pre-test factors (i.e., gestational age, maternal age) © 2013 Verinata. Content is proprietary and confidential.

76 APPENDIX

77 Product Profile 77 Chromosomes Analyzed 21, 18, 13, and (Optional) X and Y Blood draw requirement 1 blood tube (7-10mL) Patient Eligibility Validated in high risk pregnancies Singletons at ≥10 weeks gestation Sample collection On-site collection kits, ambient shipping Turn-around time Average of 4 days with 95% within 8 days Clinical Support In-house genetic counselors for consultation with healthcare providers Cancellation Rate <1% (0.14% current rate)

78 VERIFI ® PRENATAL TEST Red alert at top to highlight abnormal results Abnormal results are highlighted in red Comments included to provide additional guidance Test claims restated as reference Test Report

79 VERIFI ® PRENATAL TEST LIMITATIONS Test designed to detect full chromosomal aneuploidies, and has been validated for chromosomes 21, 18, 13, X and Y. Possibility test results might not reflect the chromosomes of the fetus, but may reflect chromosomal changes to the placenta or of the mother. Does not eliminate the possibility of other chromosomal abnormalities, birth defects, or other genetic disorders. Not currently for use in multiple gestations. © 2013 Verinata. Content is proprietary and confidential.

80 VERIFI ® PRENATAL TEST DISCLAIMERS If definitive diagnosis desired, invasive procedures are suggested to confirm detected and suspected (borderline) results. Test results should always be used in the context of all available clinical findings. How the test is used is at the discretion of the healthcare provider. © 2013 Verinata. Content is proprietary and confidential.

81 FOLLOW-UP AND OUTCOMES All “Detected” and “Suspected” results are called out to a client by a Genetic Counselor Outbound Calls Collect relevant pre-test indication when calling result Indicate interest to collect follow-up information if/when available Call (or fax request) for follow-up at or near due date Inbound Calls Record information that is called from sites If discordance, file complaint and follow internal process

82 VERIFI ® TEST ADVANTAGES Non-invasive reassurance, available as early 10 weeks Not affected by maternal factors (like serum screen) Can be used in IVF and with egg-donor pregnancies Higher sensitivity and specificity compared to analyte screen Low (<1%) false positive rate Very low false negative rate TAT: Average of 4 days with 95% within 8 days Failure rate of <1%

83 CASE EXAMPLES

84 CASE 1 Patient Profile: 33 year old woman at 10 weeks gestation with a history of a prior miscarriage affected with Down syndrome Genetic Counseling: Screening CVS/amniocentesis verifi ® prenatal test Ultrasound Too early for conventional serum screening and detailed ultrasound and concerned about undergoing CVS/amniocentesis due to procedural loss rate verifi ® prenatal test Results (option of sex chromosome analysis elected): Chromosome 21 – aneuploidy detected Chromosome 18 – no aneuploidy detected Chromosome 13 – no aneuploidy detected Sex chromosomes – no aneuploidy detected (XY) Primary Screen for High Risk Patients

85 CASE 1 verifi ® prenatal test – chromosome 21 aneuploidy detected Received results prior to 12 weeks gestation Suggestive of trisomy 21 in fetus Patient now has information earlier in pregnancy and has more time to make informed decisions regarding testing options and pregnancy management. Counseling considerations

86 CASE 2 Patient Profile: 40 year old woman with 1 in 32 risk for Down syndrome on serum screening. Genetic Counseling: amniocentesis verifi ® prenatal test ultrasound verifi ® prenatal test Results: Chromosome 21 – no aneuploidy detected Chromosome 18 – no aneuploidy detected Chromosome 13 – no aneuploidy detected Secondary Screen for Screen Positive Patients

87 CASE 2 Serum screen - screen positive for Down syndrome (1 in 32) Serum screening can have screen/false positive rate (FPR) in women 40+ of 20% (NOTE: FPR dependent upon type of screening utilized) verifi ® prenatal test – no aneuploidy detected for chromosomes 21, 18 and 13 Normal ultrasound - reassuring but need to discuss limitations Patient comfortable declining amniocentesis and avoids risk of procedural loss Counseling Considerations

88 CASE 3 Patient Profile: 38 year old woman with history of infertility who conceived via in vitro fertilization (IVF). Genetic Counseling: Screening Declined serum screening due to sub-optimal detection rates for trisomies CVS/Amniocentesis Considering invasive testing but fearful of procedural loss verifi ® prenatal test Ultrasound verifi ® prenatal test Results (option of sex chromosome analysis elected): Chromosome 21 – no aneuploidy detected Chromosome 18 – no aneuploidy detected Chromosome 13 – no aneuploidy detected Sex chromosomes – no aneuploidy detected (XX) High Risk Patient Considering CVS/Amniocentesis

89 CASE 3 verifi ® prenatal test – no aneuploidy detected Normal ultrasound - reassuring but need to discuss limitations Patient comfortable declining invasive testing due to NIPT results and normal ultrasound. Procedural risks avoided. Counseling Considerations

90 CASE 4 Patient Profile: 41 year old woman at 34 weeks gestation diagnosed with ultrasound findings of large echogenic kidneys and ventricular septal defect Negative integrated screen (1/800 DS; 1/5000 T18; negative ONTD) Genetic Counseling: Ultrasound findings suspicious for trisomy 13 Amniocentesis Patient declined as she would not alter course of pregnancy verifi ® prenatal test verifi ® prenatal test Results: Chromosome 21 – no aneuploidy detected Chromosome 18 – no aneuploidy detected Chromosome 13 – aneuploidy detected Patients Who Have Abnormal Ultrasound Findings

91 CASE 4 verifi ® prenatal test – chromosome 13 aneuploidy detected Consistent with ultrasound findings Suggestive of trisomy 13 in fetus Patient continues to decline amniocentesis but now pregnancy management decisions can be made regarding delivery. Counseling Considerations

92 POTENTIAL FUTURE DIRECTIONS Testing in low- risk population Further testing in multiple gestations Further study of mosaicism Sub- chromosomal abnormalities Other whole autosomes © 2013 Verinata. Content is proprietary and confidential.

93 NON-INVASIVE SUBCHROMOSOMAL ANALYSIS Noninvasive Detection of Fetal Subchromosome Abnormalities via Deep Sequencing of Maternal Plasma Anupama Srinivasan 1, Diana W. Bianchi 2, Hui Huang 1, Amy J. Sehnert 1 and Richard P. Rava The American Journal of Human Genetics, Volume 92, Issue 2, , 10 Jan 2013

94 SUB-CHROMOSOME PUBLICATION Purpose of the Study: To determine sequencing analysis necessary to detect fetal subchromosomal abnormalities from a maternal blood sample Blinded Analysis of 11 Samples from MELISSA 10 cases with subchromosomal abnormalities Duplications, deletions, derivative chromosomes, mosaic cases Trisomy 20 was used as a control Proof-of-Principle Study in AJHG

95 RESULTS 7 Non-Mosaic Samples: All Subchromosomal Abnormalities Detected. For karyotypes with unknown genetic material, deep MPS identified both translocation breakpoint as well as chromosomal origin of unknown material Detected microdeletion as small as 300kb 4 Mosaic Samples: Subchromosomal Abnormalities not Detected. Non-detection due to lack of sequence in human genome, or post-zygotic error All Subchromosomal Abnormalities Detected in Non-Mosaic Samples

96 SUBCHROMOSOME ANALYSIS Sample from the study Multiple sub- chromosome abnormalities detected in one sample Laboratory personnel were blinded to karyotype Example

97 RESULTS Abnormalities as small as 300kb detected Precise location of abnormalities concordant with karyotype Abnormalities Detected by Deep MPS Concordant with Karyotype

98 RESULTS Deep MPS provided additional detection of abnormalities NOT identified by karyotype Provides additional information not seen on karyotype All abnormalities < 1 Mb Additional Abnormalities Detected by Deep MPS

99 SUBCHROMOSOME ANALYSIS Study Shows the Ability of Deep MPS Technology to Detect Fetal Subchromosomal Abnormalities Non- Invasively Deep MPS Can Provide Greater Resolution and Can Detect Fetal Subchromosomal Abnormalities at a Resolution of 100kb Across the Genome Given the Cost of the Method, a Deep MPS Test for Sub- Chromosome Abnormalities Could Be Available in the Near Future… Proof-of-Principle Study Recently Published in AJHG

100 CENTER FOR FETAL MEDICINE RESULTS 6/1/2010 THROUGH 3/31/2013 6/2010 – 10/201110/2011 – 3/2013 Total patients seen Total singleton, non-ONTD, patients seen Total procedures performed Total singleton, non-ONTD procedures performed Follow-up patients from the California PDC screening program with positive 1 st /2 nd trimester screening results Total patients seen 6/1/2010 – 3/31/2013:808 Total procedures performed 6/1/2010 – 3/31/2013:539 Total singleton, non-ONTD patients seen:728 Total singleton, non-ONTD procedures performed:500

101 NIPT STATUS AND INVASIVE PROCEDURE UPTAKE

102

103 INVASIVE PROCEDURE UPDATE BY MONTH (7/2010 THROUGH 3/2013)

104 CENTER FOR FETAL MEDICINE: # OF INVASIVE PROCEDURES 18 MONTHS PRIOR & 18 MONTHS AFTER INTRODUCTION OF NIPT

105

106 January through May each year

107 LAWRENCE D. PLATT, MD TEL AVIV JULY 2,2013 THE VERIFI® PRENATAL TEST – MAKING A DIFFERENCE IN PATIENT SAFETY


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