What is Generation®?
In January 2016, the UK National Screening Committee recommended systematic screening of all high risk pregnancies in the UK by NIPT1,2. In addition, clinical best practice guidelines from Australian and international medical societies recommend that all pregnant women, regardless of risk status, be offered the opportunity for discussion and choice regarding NIPT and other available prenatal screening and diagnostic tests3,4,5.
Generation® is a highly efficient, accurate, non-invasive prenatal screening test, based on Whole Genome Sequencing (“WGS”) with proprietary algorithms, that analyses circulating cell-free fetal DNA from a maternal blood sample from as early as 10 weeks gestation.
The clinical utility and benefit of the Generation® test has been demonstrated in all pregnant women – regardless of age or risk category – in numerous publications, including studies in the New England Journal of Medicine, as well as reports with cohorts of over 34,000 patients6,7,8,9.
The benefits of whole genome sequencing
WGS provides precise counts across the genome
BENEFITS of Generation®
Microarray has a lower resolution
DRAWBACKS of this method:
Targeted sequencing is limited to few chromosomes and loci
DRAWBACKS of this method:
Generation® has the lowest reported test failure rate
Test failures matter in NIPT, as they increase the risk of false negative and false positive results. There is the potential to increase false negative results if no action is taken following a test failure. A higher rate of aneuploidy in test failure samples also means that there is potentially increased invasive test utilisation for those returning a “high risk” result with other testing modalities.
Test failures also lead to increased turnaround times and clinician visits, with high failure rates demonstrated for redraws from these patients12.
The science of deeper sequencing
The Generation® NIPT analyses 28 million reads from sequencing data across the genome, enhancing the precision and accuracy of the test results. In addition, deep whole genome sequencing allows for accurate detection of sub-chromosomal abnormalities (SCA)10,11.
Unlike other tests that use restricted sequencing techniques, the whole genome sequencing approach generates rich and comprehensive results with more than 99% accuracy for trisomes 21, 18 and 13.
Generation® minimises test failures
1. Taneja et al. Prenatal diagnosis, Dec 2015 2. McCullough RM et al. PLoS One. 2014 3. Norton ME, et al. New Engl J Med 2015 4. Dar, et al. Am J Obstet Gynecol. 2014
What does the Generation® NIPT test for?
The Generation® NIPT screens for the most commonly seen and tested chromosomal anomalies, including trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome) and sex chromosome aneuploidies.
If Generation® Plus* is requested, the following more rarely occurring genetic abnormalities are also tested for:
* The cost of Generation® Plus is $450. It is highly recommended that testing for microdeletion syndromes be accompanied by specialised genetic counselling.
Generation® and Generation® Plus NIPT do NOT test for any genetic conditions not listed above, such as rarer chromosome abnormalities, or family specific mutations (such as cystic fibrosis). Testing for these conditions may be available by invasive methods. Please contact us if you require further information about this. Non-genetic conditions (such as neural tube defects) are similarly not tested for by NIPT.
Prenatal prevalence of reported chromosomal abnormalities
What are the performance characteristics for Generation® NIPT?
All screening tests carry a false positive and false negative rate. The Generation® NIPT provides highly accurate, near diagnostic information for the most common chromosomal abnormalities6,7,13
Who should be offered the Generation® NIPT test?
Numerous studies have conclusively demonstrated the benefits for NIPT in women with a high risk pregnancy, including:
In addition, there is significant evidence to suggest that women in a normal risk population could also benefit from NIPT, particularly for peace of mind.
Although serum biochemical screening with ultrasound is not as accurate as NIPT, patients should still be offered these tests as they are complementary tests which detect a larger range of abnormalities – including neural tube defects and non-genetic abnormalities. NIPT, biochemical testing and ultrasound testing measure different things; the genetic code versus biochemical function and fetal anatomy respectively.
Generation® NIPT is a new powerful investigative tool. Pregnancy is an important time for mothers and their fetuses, with tests, results, and recommendations carrying major clinical implications. Before proceeding with testing, it is important that all clinicians understand the purpose and performance of this test, and how to appropriately explain the results to their patients. We require that patients provide written consent ensuring that these issues have been discussed and understood by the patient and clinician.
Appropriate follow-up after NIPT
NIPT is an advanced screening test, which is highly accurate. Test results reporting that a chromosomal dosage abnormally is NOT DETECTED are likely to be true negative results and can continue to be followed up as per your practice’s protocols as appropriate for the pregnancy risk category. All test results where a chromosomal dosage abnormality is DETECTED should be followed up by an invasive diagnostic test (biopsy for CVS or amniotic fluid sample) for confirmatory diagnostic testing.
How do I organise for my patient to be tested?
More options for patients
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3) RANZCOG Statement on Prenatal screening and diagnosis of chromosomal and genetic abnormalities in the fetus in pregnancy C-Obs 59. Endorsed by RANZCOG: March 2015
4) ACOG Committee on Practice Bulletins. (2007) ACOG Practice Bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol. 109(1):217-227.
5) Society for Maternal-Fetal Medicine (SMFM) Publications Committee. #36: Prenatal aneuploidy screening using cell-free DNA. Am J Obstet Gynecol. 2015; S0002-9378(15)00324-5.
6) Bhatt S. Parsa S, Synder H, et al. Clinical Laboratory Experience with Noninvasive Prenatal testing Update on Clinically Relevant Metrics. ISPD 2014 poster.
7) Bianchi DW, Platt LD, Goldberg JD, et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012; 119:890-901.
8) Futch T, Spinosa J, Bhatt S, et al. Initial clinical laboratory experience in non-invasive prenatal testing for fetal aneuploidy from maternal plasma DNA samples. Prenat Diagn. 2013;33:569-574
9) Bianchi DW, Parker RL, Wentworth J et al. DNA Sequencing versus Standard Prenatal Aneuploidy Screening. N Engl J Med 2014; 370:799-808
10) Zhao C, Tynan J, Ehrich M, et al. Detection of fetal subchromosomal abnormalities by sequencing circulating cell-free DNA from material plasma. Clin Chem. 2015; 61(4):608-16
11) Wong FC, Lo YM. Prenatal Diagnosis Innovation: Genome Sequencing of Maternal Plasma. Annu Rev Med. 2016 Jan 14; 67:419-32.
12) 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; 124:210-8.
13) Verinata Health, Inc. (2012) Analytical Validation of the verifi Prenatal Test: Enhanced Test Performance for Detecting Trisomies 21, 18 and 13 and the Option for Classification of Sex Chromosome Status. Redwood City, CA.
14) 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;211:527.
15) Norton ME, Brar H, Weiss J, et al. Non-Invasive Chromosomal Evaluation (NICE) Study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012; 207(2):137.e1-137.e8.
16) Palomaki GE, Deciu C, Kloza EM, et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med. 2012. 14:296-305