clinical advantages of snp-based non-invasive prenatal...

Trudy McKanna, MS, CGC

Manager, Medical Science Liaisons

Prenatal Genetic ScreeningClinical advantages of SNP-based non-invasive

prenatal screening

Not for further reproduction or use

1960s 1980s 1988 1996 1997 2011 – Present

Maternal

AgeMSAFP

Triple

Screen

Quad

Screen

FTS

NT/Serum

NIPT

Quantitative

NIPT

SNP

27% 36% 60–74% 70–81% 80–95% 66–>99% 92–>99%

All T21 T21

T18

T21

T18

T21

T18

T13

T21

T18

T13

SCA

T21

T18

T13

SCA

Triploidy

Microdeletions

Prenatal Screening

2


Women with pregnancies considered high risk due to ultrasound abnormalities, family history, advanced maternal and/or paternal

age should discuss their risks with their doctor and genetic counselor to determine which tests are appropriate for their situation.

Prenatal testing algorithm

3

What prenatal testing options should women be offered?

Women who do not want

testing during pregnancy

Women who want information but prefer

not to start with invasive procedures

Diagnostic testsScreening tests

Women who want to know as

much as possible

No testing

Panorama non-

invasive prenatal

test (NIPT)

Maternal serum

screening (MSS)

Chorionic villi

sampling (CVS)

or amniocentesis

Comparing Maternal Serum Screening (MSS) and Non-Invasive Prenatal Screening (NIPT)


5Quest Diagnostics 2014, www.questdiagnostics.com6Norton M et al. NEJM. 2015 Apr 23;372(17):1589-977Pergament et al. Obstet Gynecol. 2014 Aug;124(2 Pt 1):210-88Dar P et al. Am J Obstet Gynecol 2014 Nov;211(5):527

1Nicolaides K H et al. Ultrasound Obstet Gynecol. 2005;

25(3)221-6.2Wapner R et al. N Engl J Med. 2003; 349 (15); 1405-13.3Malone FD et al. N Eng J Med. 2005; 353(19): 2001-11.4PerkinElmer Labs / NTD 2013, http://ntdlabs.com/maternal-

marker-testing/.

Comparing Screening Options

5

Maternal Serum

Screening1–6

NIPT

(Panorama®)7–8

Gestational age ~11–22 wks 9+ wks

Nuchal Translucency Sometimes No

Open Neural Tube Defects Sometimes No

T21 Positive Predictive Value 3.4% 91%

False positive rate 5% <1%


Trisomy 21 Positive Predictive Value

6

1Norton et al, N Engl J Med 2015.

2Dar et al. Am J Obstet Gynecol 2014 Nov;211(5):527

MSS

265 women will undergo invasive testing

to discover 9 true positives.110 women will undergo invasive

testing to discover 9 true positives.2

NIPT


Screening for Trisomy 21

7

N Sensitivity False Positive Rate PPV

NIPT - Avg Risk (<35 years) 11,994100%

(82.4-100)0.05% 76.0%

NIPT - All Patients 15,841100%

(90.7-100)0.05% 80.9%

Standard Screening 15,84178.9%

(62.7-90.4)5.4% 3.4%


Screening for Trisomy 21

8

Norton M, et al. N Engl J Med. 2015 DOI: 10.1056/NEJMoa1407349

15,841 women

Standard Screening Cell-free DNA Screening

30 38True

Positives

854 9False

Positives

8 0False

Negatives


NIPT in Average Risk

9

>68,300 average risk patients evaluated in 8 studies

Nicolaides

AJOGGil

UOG

Song

Prenat Diag

Pergament

Obstet Gynecol

BCBSA TEC

Assessment

T21

Bianchi

NEJMZhang

UOG

Dar

AJOG

Norton

NEJM

BCBSA TEC

Assessment

T18, T13

ACOG

Guidance

(640)

2013 2014 2015


NIPT in Average Risk

10

>68,300 average risk patients evaluated in 8 studies

Nicolaides

AJOGGil

UOG

Song

Prenat Diag

Pergament

Obstet Gynecol

BCBSA TEC

Assessment

T21

Bianchi

NEJMZhang

UOG

Dar

AJOG

Norton

NEJM

BCBSA TEC

Assessment

T18, T13

ACOG

Guidance

(640)

2013 2014 2015


Low-Risk vs. High-Risk

11

1 Dar P et al. Am J Obstet Gynecol 2014 Nov;211(5):527

PPV is just as high in a low-risk population

How is this possible? Hypothesis: Older women have higher rates of confined placental

mosaicism (CPM).

NIPT Findings* Clinical Outcomes**

N High-Risk Calls (%) TP FP PPV

Low-Risk (<35 years) 11,629 117 (1.0%) 34 5 87.2%

High-Risk (≥35 years) 11,642 274 (2.4%) 87 18 82.9%

(Trisomies 21/18/13 and monosomy X combined)


Professional Society Statements on NIPT

12

Recommends “informing all pregnant women that NIPS

is the most sensitive screening option for traditionally

screened aneuploidies”2016

“…supports prenatal cell-free DNA (cfDNA) screening,

also known as NIPT of NIPS as an option for pregnant

patients”2016

“any patient may choose cell-free DNA analysis as a

screening strategy for common aneuploidies regardless

of her risk status”2015

“Different scenarios are possible, including NIPT as an

alternative first tier option”2015

“The following protocol options are currently considered

appropriate: 1. cfDNA screening as a primary test

offered to all pregnant women.”2015


ACMG Statement on NIPT

13


ACMG Highlights

• “…NIPS is the most sensitive screening option for traditionally screened aneuploidies”

• No test should be offered without reliable fetal fraction measurement and reporting

• Support for select microdeletion screening– Sensitivity, specificity, PPV and NPV should be reported

• Screening not supported for rare autosomal trisomies and genome-wide CNVs

14

Gregg A et al Genet Med. 2016 Jul 28. doi: 10.1038/gim.2016.97. [Epub ahead of print]

The SNP Advantage


Cell-free DNA (cfDNA)

16


The Evolution of NIPT

17

2011 2012 2013 2014-2017

Other labs enter domestic

NIPT space using

1st generation counting

technologies

1st generation:

Quantitative or

“Counting”

2nd generation:

Qualitative or

“SNP-based”


NIPT Methodologies

18

Counting SNP


Our Technology

19

Proprietary SNP analysis distinguishes between maternal & fetal DNA


DNA “fingerprints”

• Panorama® is the only NIPT

on the market that distinguishes

between maternal and fetal DNA.

• Panorama® can identify

different DNA “fingerprints”

in a maternal blood

sample, such as those

from a vanishing twin.

20


Clinical Advantages of SNP

• Fetal fraction

• Maternal contribution

• Vanishing twins

• Fetal sex accuracy

• Triploidy/complete mole

21

Panorama® uniquely differentiates between maternal and fetal DNA


What is a Microdeletion?

• Microdeletions vary in size

• Karyotype can usually only

visually detect >7–10 MB

• Outcome depends on size

& genes involved

22

Microdeletion


Incidence out of 100,000 Live Births

0

20

40

60

80

100

120

140

23


Rethink screening

24

1Snijders, et al. Ultrasound Obstet Gynecol 1999;13:167–170. 2Combined prevalence using higher end of published ranges from Gross et al. Prenatal Diagnosis 2011; 39, 259-266; and www.genetests.org. Total prevalence may range from 1/1071 - 1/2206.

Microdeletions are more common than Down syndrome in younger women

Maternal Age

Panorama®

Microdeletions

Panel2

Down

Syndrome1

1/2000

1/1000

1/500

1/250

20 22 24 26 28 30 32 34


Low Risk result

25


High Risk result

26


22q11.2 deletion High Risk result

27

The test has been developed and its performance characteristics determined by the

CLIA-certified laboratory performing the test. This test has not been cleared or approved

by the U.S. Food and Drug Administration (FDA). Although FDA does not currently clear

or approve laboratory-developed tests in the U.S., certification of the laboratory is required

under CLIA to ensure the quality and validity of the tests.

© 2017 Natera, Inc. All Rights Reserved

clinical advantages of snp-based non-invasive prenatal...

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