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Noninvasive prenatal testing in the general obstetric population: Clinical performance and counseling considerations in over 85,000 cases.
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Evaluating Test Performance Metrics
Test performance metrics are essential both before and after patients undergo prenatal aneuploidy screening.
A test’s sensitivity and specificity can help you to:
Decide which prenatal screening option(s) to offer your patients
Determine which laboratory to use
Counsel patients about benefits and limitations of the aneuploidy screening options (detection rates and false positive rates)
Click on the below to view the sensitivity and specificity data table.
| Condition | Sensitivity | 95% CI | Specificity | 95% CI |
|---|---|---|---|---|
| Trisomy 21 | 99.2% | 98.5-99.6% | 99.91% | 99.86–99.95% |
| Trisomy 18 | 96.3% | 94.3–97.9% | 99.87% | 99.80–99.93% |
| Trisomy 13 | 91.0% | 85.0–95.6% | 99.87% | 99.74–99.95% |
NIPT performance for trisomies 21, 18, and 13 in singleton pregnancies as reported in a large, independent meta-analysis3
Data from a meta-analysis of 37 published NIPT studies between January, 2011 and January, 2015. Sensitivity and specificity are test specific, not patient specific. As such, they are not expected to change significantly based on an individual patient’s clinical picture (eg. maternal age, ultrasound findings).
Performance Metrics Considerations After Screening
Positive Predictive Value (PPV)
A test’s PPV can help you determine how likely a positive result is to be a true positive. PPV is based on the sensitivity and specificity of the test AND the prevalence of the condition in the population being tested.
Why Prevalence Matters for PPVs
Because the prevalence of autosomal trisomies (eg, trisomy 21) increases with maternal age, so do the PPVs. Trisomy 21 is the most prevalent autosomal trisomy in livebirths. Thus, the PPVs are higher for trisomy 21 than for trisomies 18 and 13, which are less common. The PPVs above are calculated based on age-related prevalence; the presence of other aneuploidy risk factors (e.g. ultrasound abnormalities) would likely increase the PPVs over those shown here.
Why Specificity Matters for PPVs
While PPVs are lower in younger women, PPVs for NIPT will be higher than those of traditional serum screening at all maternal ages because NIPT has significantly higher specificity (a lower false positive rate).5
For patients with a positive NIPT result:
Counsel the patient about the NIPT results, the likelihood of a true positive (PPV), and the recommendation for confirmatory diagnostic testing.9,10
To calculate a patient’s individual PPV, you may wish to use the PPV calculator endorsed by ACOG.11
Assessing Test Failure Rate
The verifi Prenatal Test has the lowest failure rate in the industry of 0.1%, excluding administered failed samples—that means that 99.9% of the time a result is provided12. It uses next-generation sequencing to analyze cfDNA fragments across the whole genome, which has proven advantages over other NIPT methodologies such as targeted sequencing and array-based methods. Test failure rates are substantially lower with whole-genome sequencing versus other methodologies.12-15
That’s important, and clinically relevant, because not only do test failures negatively impact patient care, they also adversely affect test metric parameters such as sensitivity, specificity, and PPV. By choosing the verifi Prenatal Test, the clinical impact of failures can be reduced.12
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The Illumina Difference
We’re committed to providing laboratories and health care partners with comprehensive solutions and test options to improve human health. Published data shows, that NGS with whole-genome sequencing (WGS) is the NIPT technology of choice—when compared to targeted approaches.
With over 99.7% of NIPT samples in these studies run on Illumina NGS technology, we’re helping advance breakthrough in prenatal screening. It’s what makes the verifi Prenatal Test, with the lowest failure rate of any noninvasive prenatal test on the market, the best choice for patients.
Click on the below to view the samples run data table.
| Test (Company) | Current technology platform | Platform provider | Number of published samples | ||
|---|---|---|---|---|---|
| Illumina NGS | Ion Proton NGS | Affymetrix array | |||
| Bambni Test (Berry Genomics) | NGS | Illumina | 3,268 | 0 | 0 |
| MaterniT21 PLUS Test (Sequenom) | NGS | Illumina | 293,243 | 0 | 0 |
| NIFTY Test (BGI) | NGS | Illumina | 168,655 | 0 | 0 |
| Panorama Prenatal Screen (Natera) | NGS | Illumina | 55,077 | 0 | 0 |
| PrenaTest (LifeCodexx AG) | NGS | Illumina | 504 | 0 | 0 |
| verifi Prenatal Test (Illumina) | NGS | Illumina | 113,561 | 0 | 0 |
| IONA Test (Premaltha) | NGS | Ion Proton | 0 | 684 | 0 |
| Harmony Prenatal Test (Arlosa)* | Array | Affymetrix | 44,313 | 0 | 1,677 |
| Total | 678,621 | 684 | 1,677 | ||
A PubMed search for "cell-free, DNA, prenatal," "noninvasive prenatal testing," and "noninvasive prenatal screening" was performed on November 30, 2015. All validation and clinical studies using unique samples were included, where a current clinical NIPT provider performed sample analysis. Case studies and studies published in a language other than English were excluded. A total of 59 published studies were surveyed. Data calculations on file. Illumina, Inc. 2015. NGS = next-generation sequencing; either whole-genome or targeted.
*In 2014, Ariosa switched from sequencing to arrays for clinical samples despite limited published data on this platform.
Test Failures May Lead to Invasive Procedures.†
Theoretical example of the number of invasive procedures requested due to NIPT failure and false positive rates of the assays. Failure rates include assay failures and samples rejected due to low fetal fraction. Assay failure rate for the Harmony test is based on NGS studies and may not be consistent with actual test results achieved using the array-based Harmony Test currently in use.12-18
†Affected pregnancies with a screening test failure were excluded from the number of detected T21.
Advancing Breakthroughs with Genomic Solutions in NIPT
Evolving noninvasive screening options, such as noninvasive prenatal tests (NIPT), offer early genetic screening for chromosomal conditions using just one tube of blood—as early as 10 weeks into a patient’s pregnancy.
Other types of prenatal screening and diagnostic tests may require more than one office visit, multiple blood draws, or carry a higher risk of false positive results. Diagnostic tests, such as chorionic villus sampling (CVS) or amniocentesis, provide definite results for most chromosome conditions but have an associated risk of miscarriage.
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Login NowNIPT Poses Minimal Risk to the Mother or Baby
NIPT analyzes cell free fetal and maternal DNA from a blood sample to screen for common chromosome conditions including trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome).
NIPT poses minimal risk to the mother or baby with high detection rates and low false positives. The American Congress of Obstetricians and Gynecologists (ACOG) and International Society of Prenatal Diagnosis (ISPD), along with other professional societies, have stated that NIPT is an available screening option for all pregnant women.1,2
The verifi Prenatal Test is one such noninvasive test that screens for aneuploidy of chromosomes 21, 18, and 13. Additional screening is available for sex chromosome aneuploidies and select microdeletions in singleton pregnancies. In twin pregnancies, screening for aneuploidy in chromosomes 21, 18, and 13 and the option to screen for the absence of the Y chromosome is available. The results are reported in approximately 3–5 days after the sample is received. Depending on demand, the time to report may vary.
References
- Committee Opinion No. 640: Cell-free DNA Screening for Fetal Aneuploidy. Obstet Gynecol. 2015;126(3):e31-37.
- Benn P, Borrell A, Chiu RWK, et al. Position statement from the Chromosome Abnormality Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn. 2015;35(8):725-734.
- Gil MM, Quezada MS, Revello R, Akolekar R, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2015;45(3):249-266.
- Gardner RJM, Sutherland GR, Shaffer LG. Parental age counseling and screening for fetal trisomy. Chromosome abnormalities and genetic counseling. 4 ed: Oxford University Press; 2012:403-416.
- Benn P, Curnow KJ, Chapman S, Michalopoulos SN, Hornberger J, Rabinowitz M. An Economic Analysis of Cell-Free DNA Non-Invasive Prenatal Testing in the US General Pregnancy Population. PLoS One. 2015;10(7):e0132313.
- Wellesley D, Dolk H, Boyd PA, et al. Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe. Eur J Hum Genet. 2012;20(5):521-526.
- Bianchi DW, Parker RL, Wentworth J, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014;370(9):799-808.
- Malone FD, Canick JA, Ball RH, et al. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med. 2005;353(19):2001-2011
- Committee Opinion No. 640: Cell-free DNA Screening for Fetal Aneuploidy. Obstet Gynecol. 2015;126(3):e31-37.
- Practice Bulletin No. 163: Screening for Fetal Aneuploidy. Obstet Gynecol. 2016;127(5):979-981.
- The American Congress of Obstetricians and Gynecologists. NIPT Cell Free DNA Screening Predictive Value Calculator. National Society of Genetic Counselors (NSGC) and Perinatal Quality Foundation (PQF). Endorsed December 2015. 2015; http://www.acog.org/Resources-And-Publications/Endorsed-Documents. Accessed January 28, 2015.
- Taneja PA, Snyder HL, de Feo E, et al. Noninvasive prenatal testing in the general obstetric population: clinical performance and counseling considerations in over 85 000 cases. Prenat Diagn. 2016: 36(3): 237-43.
- McCullough RM, Almasri EA, Guan X, et al. Non-invasive prenatal chromosomal aneuploidy testing—clinical experience: 100,000 clinical samples. PLoS One. 2014: 9(10):e109173.
- Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015: 372(17): 1589-97.
- Dar P, Curnow KJ, Gross SJ, et al. Clinical experience and follow-up with large scale single-nucleotide polymorphism-based noninvasive prenatal aneuploidy testing. Am J Obstet Gynecol. 2014: 211(5): 527.e1-527.e17.
- Pergament E, Cuckle H, Zimmermann B, et al. Single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk and low-risk cohort. Obstet Gynecol. 2014;124(2 Pt 1):210-218.
- Nicolaides KH. Screening for fetal aneuploidies at 11 to 13 weeks. Prenat Diagn. 2011;31(1):7-15.
- Wald NJ, Rodeck C, Hackshaw AK, et al. SURUSS in perspective. Semin Perinatol. 2005;29(4):225-235.
The verifi Prenatal Test was developed by, and its performance characteristics were determined by Verinata Health, Inc. a wholly owned subsidiary of Illumina, Inc. The VHI laboratory is CAP-accredited and certified under the Clinical Laboratory Improvement Amendments (CLIA) as qualified to perform high complexity clinical laboratory testing. It has not been cleared or approved by the U.S. Food and Drug Administration.