Post on 08-Jun-2018
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11/14/13
Martin R. Chavez, MD FACOG
Director of Maternal Fetal Medicine
Winthrop University Hospital
Disclosure Dr. Martin R. Chavez is on the speaker bureau for:
Verinata Health, Inc. an Illumina Company
Sequenom Center for Molecular Medicine
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Objectives of the webinar are:1. Identify the value of NIPT in a high risk population and
the impact on managed care payers
2. Help payers to critically analyze and think about the NIPT market
3. Suggest a framework for data review from the providers in the NIPT market
4. Critically distinguish between the tests on the market and in the horizon
Definitions Non‐Invasive Prenatal Testing (NIPT)
Non‐Invasive Prenatal Screening (NIPS)
Cell free DNA
Maternal fraction
Fetal fraction (placental)
Sequencing (MPS, shotgun)
Full genome vs. Targeted sequencing
Single nucleotide polymorphism (SNP)
Nonpolymorphic loci
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Definitions Biomedical Informatics/algorithms
Turn Around Time (TAT)
Reporting
Risk adjustment
(<1/10,000 low risk or 1/100 high risk)
Negative, Suspected or Positive
Non‐reportable or undetectable fetal DNA fraction
Pre/post counseling for NIPT
NIPT Cell‐free DNA in Maternal Blood
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NIPT
http://en.wikipedia.org/wiki/File:Cell_free_fetal_DNA_shedding_into_maternal_bloodstream.pdf
NIPT in a high risk population AMA, 35 yo at the time of delivery for singleton
Abnormal serum screen (first or second trimester)
Abnormal ultrasound finding(s)
Prior pregnancy affected with T21/T18/T13 or Family hx
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NIPT in a high risk population The most common fetal trisomies are:
Trisomy 21 (Down syndrome) 53%
Trisomy 18 (Edwards syndrome) 13%
Trisomy 13 (Patau syndrome) 5%
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐71%
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 2012.
Impact on managed care payersCDC National Vital Statistics (2009)
~4 Million births
62% receive prenatal screening
~2.5 Million maternal screens/year
CDC National Vital Statistics (2009); http://www.cdc.gov/nchs/nvss.htmCAP Maternal Screening Participant Survey, 2011; http://www.cap.org/apps/docs/proficiency_testing/2011_surveys_catalog.pdfThomson Reuters MarketScan 2009 commercial claims database; http://depts.washington.edu/chaseall/pdfs/U%20Washington%20MarketScan%20Jan%202012%20CCAE_MDCR.pdf
~15% 1st trimester/~20% integrated/~65% 2nd trimester
200,000 invasive prenatal procedures for aneuploidy/year
~40,000 CVS/~160,000 amniocentesis
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History of Prenatal Testing Amniocentesis 1966
Serum screening 1980’s
NTD
Aneuploidy
Chorionic villus sampling 1980’s
Nuchal translucency 1990’s
NIPT, CMA 2012‐present
Impact on managed care payers
ACOG Practice Bulletin, Number 77, Jan 2007; www.ACOG.org
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Invasive diagnostic optionsTest/Trimester Sensitivity Specificity
CVS/1st trimester 99.25% 98.65%
Amniocentesis/2nd
trimester99.4% 99.5%
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 1986‐1992. Prenat Diagn. 1997 Sep;17(9):801‐20.
Mid‐trimester amniocentesis for prenatal diagnosis. Safety and accuracy. JAMA. 1976 Sep 27; 236(13): 1471‐6.
Chromosome Aberration Rates 1984
52,965 amniocenteses
97.7% of invasive procedures result in a normal karyotype
2010
68,489 amniocenteses
98.6% of invasive procedures result in a normal karyotype
Ferguson‐Smith MA, Yates JR. Maternal age‐specific rates for chromosomal aberrations and factors influencing them: Report of a collaborative European study on 52,965 amniocenteses. Prenat Diagn. 1984 Spring;4 Spec No:5‐44.
Grati FR, Barlocco A, Grimi B, Milani S, Frascoli G, et al. Chromosome abnormalities investigated by non‐invasive prenatal testing account for approximately 50% of fetal unbalances associated with relevant clinical phenotypes. Am J Med Genet Part A. 2010;152A:1434–1442.
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Impact on managed care payers
Earlier screening/testing
Start as early as 9‐10 weeks gestation
Greater acceptance of patients and providers
Need for pre/post testing counseling
Reduction of invasive procedures
CVS or Amniocentesis
Committee opinions
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ACOG/SMFM Committee Opinion Number 545, December 2012
Maternal age 35 years or older at delivery
Fetal ultrasonographic findings indicating an increased risk of aneuploidy
History of a prior pregnancy with a trisomy
Positive test result for aneuploidy, including first trimester, sequential, or integrated screen, or a quadruple screen
Parental balanced Robertsonian translocation with increased risk of fetal trisomy 13 or trisomy 21
http://www.acog.org/Resources%20And%20Publications/Committee%20Opinions/Committee%20on%20Genetics/Noninvasive%20Prenatal%20Testing%20for%20Fetal%20Aneuploidy.aspx
Committee opinions
http://www.nsgc.org/Portals/0/Advocacy/NSGC%20NIPT%20White%20Paper.pdfhttps://www.acmg.net/docs/nips‐GiM_galley_text_130301.pdfhttp://www.ispdhome.org/public/news/2013/PositionStatementAneuploidy4apr2013.pdf
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Committee opinions
A negative or low risk result does not guarantee a “normal” fetus
In cases where a positive NIPT is resulted patient should be offered confirmatory diagnostic testing
Current market players AriosaDiagnostics, Inc.
Harmony
http://www.ariosadx.com
Natera, Inc. Panorama
http://www.panoramatest.com/about_us
Sequenom Center for Molecular Medicine MaterniT21 PLUS
http://www.sequenomcmm.com/home/
Verinata Health, Inc. an Illumina Company Verfi
http://www.verinata.com/
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Critically analyze the NIPT marketScreening D
iagnostic
CVS,AMNIO
SerumScreen
Critically analyze the NIPT market 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.
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Critically analyze the NIPT market Two major types of methodology
Whole Genome vs. targeted
Dual cutoff(NCV) vs. single cutoff (Z‐score)
Reported as: No Aneuploidy detected/Aneuploidy suspected/Aneuploidy detected
Negative/positive
Risk adjustment (<1/10,000 low risk or 1/100 high risk)
Un‐detectable/un‐reportable
Redraw rate
Critically analyze the NIPT market MPS
…CTAGCACCACGATTTAACTGGAGTAAAGACTTCCT….
TAGCACCACG GTAAAGACTT
Human Genome
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Critically analyze the NIPT market Harmony
digital analysis of selected regions (DANSR)
fetal‐fraction optimized risk of trisomy evaluation (FORTE)
Panoroma
Next‐generation Aneuploidy Test Using SNPs, NATUS algorithm
Critically analyze the NIPT marketDual cutoff Single cutoff
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Critically analyze the NIPT market Sample of report; aneuploidy detected from Verinata
Critically analyze the NIPT market Sample of report; aneuploidy suspected from Verinata
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Critically analyze the NIPT market Sample of report; negative from Sequenom
Critically analyze the NIPT market Sample of report; positive from Sequenom
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Critically analyze the NIPT market Sample of report; high risk from Natera
Critically analyze the NIPT marketCompany Whole
Genome Targeted Results reported as
Ariosa √ High‐risk( ≥1%)*Low‐risk (<1%)*
Natera √ High‐risk( ≥1%)*Low‐risk (<1%)*
Sequenom √ PositiveNegative
Verinata √ Aneuploidy detectedNo aneuploidy detectedAneuploidy suspected
* Risk score included
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Framework for data review Cost (only part of the picture)
The usual:
Sensitivity, Specificity, PPV, NPV
May differ for each trisomy
Non‐reportable rate or redraw rate
TAT, from office/lab to result
Number of samples run to date
Number of manuscripts supporting specific technology including n
Framework for data reviewCompany Insufficient fetal
DNAAssay failure Total No Result
Ariosa1 1.8% 2.8 4.6%
Natera2 ? ? 12.6%
Sequenom3 0.9% 1.1% 2%
Verinata4 3.0% ? 5.6%
1) Norton et al, Am J Obstet Gynecol 20122) Zimmermann et al, Prenat Diagn, 20123) Palomaki et al, Genet Med 2012 & Sequenom CMM4) Bianchi et al, Obstet Gynecol 2012
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Framework for data review
Spoonful of Medicine: a blog from Nature Medicine ‐ Nature Blogshttp://blogs.nature.com/spoonful/2013/02/competition‐intensifies‐over‐market‐for‐dna‐based‐prenatal‐tests.htm
Framework for data review Test characteristics change over time
Confounding factors arise over time and increasing sample sizes
Test characteristics reported by company should be validated by peer reviewed published research
Establishment of patient outcome registries
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Distinguishing between the test
Benn P, et al, Non‐invasive prenatal testing for aneuploidy: current status and future prospects.Ultrasound Obstet Gynecol. 2013 Jul;42(1):15‐33. http://onlinelibrary.wiley.com/doi/10.1002/uog.12513/pdf
Distinguishing between the test
http://onlinelibrary.wiley.com/doi/10.1002/uog.12513/pdf
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Distinguishing between the test
Benn P, et al, Non‐invasive prenatal testing for aneuploidy: current status and future prospects. Ultrasound Obstet Gynecol. 2013 Jul;42(1):15‐33. http://onlinelibrary.wiley.com/doi/10.1002/uog.12513/pdf
Distinguishing between the test
Benn P, et al, Non‐invasive prenatal testing for aneuploidy: current status and future prospects. Ultrasound Obstet Gynecol. 2013 Jul;42(1):15‐33. http://onlinelibrary.wiley.com/doi/10.1002/uog.12513/pdf
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Distinguishing between the test Shotgun sequencing (Verinata, Sequenom)
All fragments are run (several million total)
Targeted sequencing Fragments containing specific sequences are selected before run via PCR using specific primers
Selection of nonpolymorphic loci (Ariosa) ~400 loci per chromosome of interest
Each 56 base pairs in length
Selection of polymorphic SNPs (Natera) SNP = single nucleotide polymorphism characterized, common type of genetic variation among people > 10,000 total over all chromosomes of interest
On the horizon Cellscape
Clarity
http://www.cellscapecorp.com/
Other start ups in the pipeline
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On the horizon
The American Journal of Human Genetics (2013), http://dx.doi.org/10.1016/j.ajhg.2012.12.006The American Journal of Human Genetics (2013), http://dx.doi.org/10.1016/j.ajhg.2012.12.006
44The American Journal of Human Genetics (2013), http://dx.doi.org/10.1016/j.ajhg.2012.12.006
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On the horizon More information
micro deletions and duplications
Single gene disorders
Application in whole genome/exome sequencing
Faster TAT
On the horizon Cheaper
(as the technology advances usually cost is reduced)
Low risk populations
Challenges: replacement of current options
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Thank you Questions?
References http://en.wikipedia.org/wiki/File:Cell_free_fetal_DNA_shedding_into_maternal_bloodstream.pdf 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 2012 CDC National Vital Statistics (2009); http://www.cdc.gov/nchs/nvss.htm CAP Maternal Screening Participant Survey, 2011;
http://www.cap.org/apps/docs/proficiency_testing/2011_surveys_catalog.pdf Thomson Reuters MarketScan 2009 commercial claims database;
http://depts.washington.edu/chaseall/pdfs/U%20Washington%20MarketScan%20Jan%202012%20CCAE_MDCR.pdf
ACOG Practice Bulletin, Number 77, Jan 2007; www.ACOG.org Hahnemann JM, Vejerslev LO. Accuracy of cytogenetic findings on chorionic villus sampling (CVS)—
diagnostic consequences of CVS mosaicism and non‐mosaic discrepancy in centrescontributing to EUCROMIC 1986‐1992. Prenat Diagn. 1997 Sep;17(9):801‐20.
Mid‐trimester amniocentesis for prenatal diagnosis. Safety and accuracy. JAMA. 1976 Sep 27; 236(13): 1471‐6.
Ferguson‐Smith MA, Yates JR. Maternal age‐specific rates for chromosomal aberrations and factors influencing them: Report of a collaborative European study on 52,965 amniocenteses. Prenat Diagn.1984 Spring;4 Spec No:5‐44
Grati FR, Barlocco A, Grimi B, Milani S, Frascoli G, et al. Chromosome abnormalities investigated by non‐invasive prenatal testing account for approximately 50% of fetal unbalances associated with relevant clinical phenotypes. Am J Med Genet Part A. 2010;152A:1434–1442
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References• http://www.acog.org/Resources%20And%20Publications/Committee%20Opinions/Committee%20
on%20Genetics/Noninvasive%20Prenatal%20Testing%20for%20Fetal%20Aneuploidy.aspx
• http://www.nsgc.org/Portals/0/Advocacy/NSGC%20NIPT%20White%20Paper.pdf
• https://www.acmg.net/docs/nips‐GiM_galley_text_130301.pdf
• http://www.ispdhome.org/public/news/2013/PositionStatementAneuploidy4apr2013.pdf
• Norton et al, Am J Obstet Gynecol 2012
• Zimmermann et al, Prenat Diagn, 2012
• Palomaki et al, Genet Med 2012 & Sequenom CMM
• Bianchi et al, Obstet Gynecol 2012
• Spoonful of Medicine: a blog from Nature Medicine ‐ Nature Blogs http://blogs.nature.com/spoonful/2013/02/competition‐intensifies‐over‐market‐for‐dna‐based‐prenatal‐tests.html
• Benn P, et al, Non‐invasive prenatal testing for aneuploidy: current status and future prospects. Ultrasound Obstet Gynecol. 2013 Jul;42(1):15‐33. http://onlinelibrary.wiley.com/doi/10.1002/uog.12513/pdf
• The American Journal of Human Genetics (2013), http://dx.doi.org/10.1016/j.ajhg.2012.12.006