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Annu. Rev. Genom. Human Genet. 2014.15. Downloaded from www.annualreviews.org by University of Waikato on 06/11/14. For personal use only.
Noninvasive Prenatal Screening by Next-Generation Sequencing Anthony R. Gregg,1 Ignatia B. Van den Veyver,2 Susan J. Gross,3 Rajeevi Madankumar,4 Britton D. Rink,5 and Mary E. Norton6 1
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, Florida 32610; email: greggar@ufl.edu
2
Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas 77030; email: [email protected]
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Department of Obstetrics and Gynecology and Women’s Health, Albert Einstein College of Medicine, Yeshiva University, New York, NY 10461; email: [email protected]
4
Division of Maternal Fetal Medicine, Long Island Jewish Medical Center, New Hyde Park, New York 11040; email: [email protected]
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Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine, Ohio State University, Columbus, Ohio 43210; email: [email protected]
6
Department of Obstetrics, Gynecology, and Reproductive Sciences, Institute of Human Genetics, University of California, San Francisco, California 94143; email: [email protected]
Annu. Rev. Genomics Hum. Genet. 2014. 15:11.1–11.21 The Annual Review of Genomics and Human Genetics is online at genom.annualreviews.org This article’s doi: 10.1146/annurev-genom-090413-025341 c 2014 by Annual Reviews. Copyright All rights reserved
Keywords fetal aneuploidy, noninvasive prenatal testing, noninvasive prenatal screening, cell-free fetal DNA
Abstract Noninvasive prenatal screening (NIPS) has emerged as a highly accurate method of screening for fetal Down syndrome, with a detection rate and specificity approaching 100%. Challenging the widespread use of this technology are cost and the paradigm shift in counseling that accompanies any emerging technology. The expense of the test is expected to decrease with increased utilization, and well beyond the current NIPS technology, its components (fetal genome isolation, sequencing technology, and bioinformatics) will be utilized alone or in combinations to interrogate the fetal genome. The end goal is simple: to offer patients information early in pregnancy about fetal genomes without incurring procedural risks. This will allow patients an opportunity to make informed reproductive decisions based on precise fetal genomic information.
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OVERVIEW
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The identification of reduced α-fetoprotein (AFP) levels in maternal circulation in Down syndrome pregnancies in the mid-1980s (75) began an era of biomarker discovery in which researchers searched for the best approaches to prenatal Down syndrome risk assessment and diagnosis. Noninvasive testing using maternal serum has expanded, and improvements have been made in invasive diagnostic testing using chorionic villus sampling (CVS) and/or amniocentesis. Invasive tests entail procedure-related pregnancy loss; however, to date, only these types of tests are diagnostic, a major distinction from noninvasive screening tests (e.g., those relying on blood drawing and/or ultrasound). The goal continues to be a noninvasive diagnostic test for a range of significant fetal abnormalities that would be without risk of procedure-related pregnancy loss and appropriate for all pregnant patients at early gestational ages. CVS is performed at between 10 and 13 weeks’ gestation and carries an associated risk of miscarriage of approximately 0.2% (23). Amniocentesis, when performed for aneuploidy detection, is typically offered at 15 and 20 weeks’ gestation and carries an associated risk of miscarriage that has improved from 0.5% in the 1980s to 0.06% in the present (23, 41, 99). Relatively low risks aside, invasive (i.e., diagnostic) procedures are avoided by some because they are considered a prelude to pregnancy termination. Down syndrome screening based on age (≥35 years old at delivery) has a sensitivity (detection rate) of approximately 25–30% (98). Incorporation of maternal serum AFP as a screening tool for women 10)
High risk (retrospective) (8–34)
High risk (prospective) (9–18)
5.4
12.6
3
4.6
1
0
4
0.8
DR (%)
Spec (%)
T21: 100 T18: 100 T13: 100
T21: 100 T18: 100 T13: 100
T21: 100 T18: 97.2 T13: 78.6
T21: 100 T18: 97.4
T21: 100 T18: 100 T13: 100
T21: 100 T18: 100 T13: 100
T21: 100 T18: 100 T13: 100
T21: 100 T18: 93.3
T21: 100 T18: 100
T21: >99 T18: >99
T21: >99 T18: >99 T21: 100 T18: 98
T21: 99.8
T21: 99.7
T21: 100
T21: 98.6
PPV (%)
T21: 100 T18: 100 T13: 100
NA
T21: 100 T18: 100 T13: 100
T21: 98.8 T18: 94.8
NA
NA
T21: 97.5
T21: 98.6
FP (%)
T21: 0 T18: 0 T13: 0
NA
T21: 0 T18: 0 T13: 0
T21: 0.03 T18: 0.07
NA
NA
T21: 0.2
T21: 0.2
NPV (%)
T21: 100 T18: 100 T13: 100
NA
T21: 100 T18: 99.8 T13: 99.4
T21: 100 T18: 96.6
NA
NA
T21: 100
T21: 99.8
FN (%)
T21: 0 T18: 0 T13: 0
NA
T21: 0 T18: 2.8 T13: 21.4
T21: 0 T18: 2.6
NA
NA
T21: 0
T21: 1.4
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Abbreviations: DANSR, Digital Analysis of Selected Regions; DR, detection rate; Eup, euploidy; FN, false negative; FORTE, Fetal-Fraction Optimized Risk of Trisomy Evaluation; FP, false positive; MPS, massively parallel sequencing; NA, not applicable; NATUS/PS, Next-Generation Aneuploidy Testing Using SNPs/Parental Support; NPV, negative predictive value; PPV, positive predictive value; Spec, specificity; T, trisomy. a Cell-free fetal DNA fraction not reported (reported by all others).
DANSR, FORTE
Ariosa Diagnostics
MPS
Failure (%)
ARI
Sequenom
N
Company
Reference
Study population (weeks of gestation)
Method
Selected validation studies for noninvasive prenatal screening
Table 3
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literacy coupled with the rapid pace at which these technologies advance, thus leading to gaps in the provision of care (14). All of the professional organizations acknowledge that pre- and posttest counseling are fundamental to the provision of noninvasive prenatal testing, and many of them also recognize the lack of resources and training to meet this need (3, 40, 57). Several aspects of NIPS suggest that it is different from other currently available screening tests—for example, in its superior sensitivity and specificity for aneuploidy detection but lack of information on other conditions (e.g., adverse pregnancy outcomes, structural birth defects, and rare aneuploidies). In the current model of prenatal risk assessment, owing to cost and feasibility, many women who undergo prenatal screening do not have detailed genetic counseling (13). When Bangsgaard & Tabor (10) studied informed choice in the setting of first-trimester risk assessment for Down syndrome, they found that 20% of patients were not given information about the test prior to testing. There are empirical data to suggest that health care providers regard informed consent as less important for NIPS than for invasive testing (107). Although noninvasive testing removes the need to discuss procedure-related risk, it does not alter the potential significance of the information patients receive. Further, patients must understand that noninvasive testing is not diagnostic and must consider the alternative testing strategies, including invasive testing if the screening test indicates an increased risk for aneuploidy. The widespread direct-to-consumer and direct-to-practitioner marketing of NIPS along with patient demand could lead to the routinization of prenatal testing and erosion of informed decision-making opportunities. Providers of genetic services may need to explore alternative ways to educate patients, including written information and online resources, to complement direct provider encounters. Depending on the complexity of the results, more in-depth posttest counseling may be indicated. Uninformative or inconclusive results should prompt a review of alternative testing strategies. The issue of pregnancy termination associated with increased uptake of prenatal screening for aneuploidy is debated in the medical literature and will become more relevant with NIPS (13). Future studies will be necessary to elucidate how women understand and react to complex genetic results.
INTEGRATION INTO CLINICAL CARE Challenging the Current Paradigm The role of NIPS in aneuploidy screening and prenatal diagnosis is evolving. This test has been called disruptive, a term used to describe innovations that displace existing technologies with something generally more efficient and worthwhile (31). In many ways, NIPS fits that description: It is a far more effective screening test for Down syndrome than current multiple-marker screening with serum analytes and nuchal translucency ultrasound (7, 17, 27, 35, 54, 83, 89, 102). However, it also cannot provide information about the range of possible conditions based on multiple-marker screening (e.g., adverse pregnancy outcomes) (11), and it is much more expensive than current screening. No screening modality detects as many chromosomal abnormalities as invasive diagnostic testing, especially if a chromosomal microarray is used (111). NIPS has been proposed as a firsttier screening test, a second-tier screening test, and a replacement for diagnostic testing. Each of these approaches has benefits and costs, and the test is currently being utilized in all three contexts. Using NIPS as a first-tier, universal screening test entails performing NIPS instead of (or in addition to) multiple-marker screening on all pregnant women. Using NIPS as a secondtier approach entails offering NIPS to high-risk patients (Table 1) as an alternative to invasive testing or other screening. It has also been suggested that NIPS—which, as described above, www.annualreviews.org • Noninvasive Prenatal Screening and NGS
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was initially referred to as noninvasive prenatal diagnosis—is a reasonable alternative to invasive diagnostic testing. In fact, many of the cost-effectiveness analyses that have been reported, much of the ethical discussion that has occurred, and most of what is written in the lay press focus on the benefits of NIPS over amniocentesis, implying, if not explicitly stating, that noninvasive prenatal testing is a diagnostic test.
Noninvasive Prenatal Screening as a First-Tier Test
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If NIPS were offered to all pregnant women as a first-tier screening test, the rate of detection of fetal trisomies 21, 18, and 13 would be very high. But the proportion of patients that attempt NIPS and do not obtain a result owing to inadequate fetal DNA, failed sequencing, or other problems with the test has been reported to be as low as 0.8% and as high as 12.6%, depending on the specific platform (Table 3). Failed results are more common in overweight and obese women, although the precise rate of failed testing and the likelihood of success on a redraw are unknown. At what body mass index cutoff the test is no longer worth attempting and in what circumstances a repeat attempt is worthwhile are also unknown. First-trimester screening or integrated screening approaches that include nuchal translucency and maternal serum screening may identify aneuploidies beyond those currently detectable with NIPS. A retrospective review of all karyotypes detected in response to first-trimester screening found that one-third of chromosomal abnormalities were abnormalities other than trisomy 21, 18, or 13 (2). Overall, approximately 16% of chromosomal abnormalities detected by invasive testing following abnormal first-trimester screening would not be detected by NIPS. In another recent publication on NIPS in a population of women of all ages undergoing first-trimester screening, NIPS detected 55% of the total chromosomal abnormalities (8 of 8 cases of trisomy 21 and 2 of 3 cases of trisomy 18, but no other abnormalities), whereas first-trimester screening detected 100% (all trisomy 21 and trisomy 18 cases as well as 7 other deletions, duplications, and other abnormalities) (80). In addition, screening for neural tube and ventral wall defects is an important component of current screening protocols that must be considered. Recommendations that a maternal serum AFP test or detailed ultrasound be performed in patients that undergo primary NIPS for aneuploidy screening are important to assure that patients continue to have risk assessment for neural tube and ventral wall defects.
Noninvasive Prenatal Screening as a Second-Tier Test Professional practice guidelines suggest that NIPS is an option for high-risk patients (Table 1). The justification for this limitation is that the test has not been validated in low- or averagerisk women. Prior ACOG guidelines, in contrast, have recognized that all prenatal tests should be available to all women regardless of maternal age (4, 5), and this contradiction in the NIPS recommendations has been discussed (84). Offering NIPS to all pregnant women eliminates the difficulties associated with offering the test to only selected groups but comes at considerable financial cost. A strategy of concurrently ordering both NIPS and first- and second-trimester screening (alone or in combination) together has become the default in many practices because of confusion about the appropriate role of this test. However, such a strategy will greatly increase costs without current evidence of incremental benefit.
Cost Considerations Several cost-effectiveness analyses of NIPS have been performed (17, 52, 85, 100). The assumptions and comparisons vary between the analyses, and therefore the conclusions are somewhat 11.14
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different. One analysis compared use of NIPS in women aged 35 and older as a diagnostic as opposed to a screening tool (85). The authors compared the costs and outcomes when amniocentesis confirmation was performed with those when the NIPS was assumed to be diagnostic without a need for confirmation. Assuming published rates of invasive testing uptake and termination for trisomy 21, they estimated that confirmatory amniocentesis would be required in 5,780 patients overall and that this would lead to 29 procedure-related miscarriages; in cases where amniocentesis confirmation was not required, they estimated that there would be 2,424 terminations of normal fetuses based on false-positive results. Therefore, although there are costs associated with the confirmatory amniocentesis, the number of false-positive terminations far outweighs the number of procedure-related losses in this model. Another analysis evaluated the costs of avoiding a Down syndrome birth using different approaches to NIPS compared with conventional screening (52). The authors found that the most cost-effective approach was a contingent policy in which all women undergo conventional screening and the 10–20% at highest risk are then offered NIPS. Offering NIPS to all women as a first-tier test would result in marginal costs of $1.4–$8.0 million per affected fetus detected, depending on the NIPS cost (varying between $500 and $2,000 per test). Economic analyses sponsored by Sequenom and Verinata found that the use of NIPS in high-risk women could be justified based on cost savings if the unit cost of NIPS was less than 96% of invasive testing (17) or less than $1,200 (100). An analysis from Ariosa Diagnostics considered a risk-based model in which women over 35 years old and women with positive results from conventional screening are offered NIPS as a follow-up test (85). This approach was also found to be cost effective when compared with conventional screening (52).
SUMMARY NIPS is and will continue to challenge the landscape of prenatal screening. Its components— isolation of cffDNA, novel PCR applications, next-generation sequencing bioinformatics, and proprietary statistical analyses—culminate in a future that has potential that goes beyond the noninvasive identification of Down syndrome. Potential future directions include the prenatal diagnosis of genome-wide microdeletions and microduplications as well as point mutations within single genes and later fetal exome sequencing. The greatest challenges are no longer circumscribed by technology but are now bridled more by society’s desire to invest in this technology and integrate it into clinical care.
DISCLOSURE STATEMENT M.E.N. has received research support from Ariosa Diagnostics, CellScape Corporation, and Natera. S.J.G. became the chief medical officer of Natera on December 9, 2013; this position did not influence the content of this review, which was submitted on that same day. The other authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS This review was prepared with the administrative assistance of Marsha Harben and Heather Ellis, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, Florida. www.annualreviews.org • Noninvasive Prenatal Screening and NGS
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LITERATURE CITED
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45. Faas BH, de Ligt J, Janssen I, Eggink AJ, Wijnberger LD, et al. 2012. Non-invasive prenatal diagnosis of fetal aneuploidies using massively parallel sequencing-by-ligation and evidence that cell-free fetal DNA in the maternal plasma originates from cytotrophoblastic cells. Expert Opin. Biol. Ther. 12(Suppl. 1):S19–26 46. Fairbrother G, Johnson S, Musci TJ, Song K. 2013. Clinical experience of noninvasive prenatal testing with cell-free DNA for fetal trisomies 21, 18, and 13, in a general screening population. Prenat. Diagn. 33:580–83 47. Fan HC, Blumenfeld YJ, Chitkara U, Hudgins L, Quake SR. 2008. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc. Natl. Acad. Sci. USA 105:16266–71 48. Fan HC, Gu W, Wang J, Blumenfeld YJ, El-Sayed YY, Quake SR. 2012. Non-invasive prenatal measurement of the fetal genome. Nature 487:320–24 49. Fan HC, Quake SR. 2010. Sensitivity of noninvasive prenatal detection of fetal aneuploidy from maternal plasma using shotgun sequencing is limited only by counting statistics. PLoS ONE 5:e10439 50. Forabosco A, Percesepe A, Santucci S. 2009. Incidence of non-age-dependent chromosomal abnormalities: a population-based study on 88965 amniocenteses. Eur. J. Hum. Genet. 17:897–903 51. Gao Y, Stejskal D, Jiang F, Wang W. 2014. False-negative trisomy 18 non-invasive prenatal test result due to 48,XXX,+18 placental mosaicism. Ultrasound Obstet. Gynecol. 43:477–78 52. Garfield SS, Armstrong SO. 2012. Clinical and cost consequences of incorporating a novel noninvasive prenatal test into the diagnostic pathway for fetal trisomies. J. Manag. Care Med. 15:34–41 53. Gil MM, Quezada MS, Bregant B, Syngelaki A, Nicolaides KH. 2014. Cell-free DNA analysis for trisomy risk assessment in first-trimester twin pregnancies. Fetal Diagn. Ther. 35:151–68 54. Goodspeed TA, Allyse M, Sayres LC, Norton ME, Cho MK. 2012. Translating cell-free fetal DNA technology: structural lessons from non-invasive RhD blood typing. Trends Biotechnol. 31:7–9 55. Grande M, Ordonez ˜ E, Cirigliano V, Cid J, Grau E, et al. 2013. Clinical application of midtrimester non-invasive fetal RHD genotyping and identification of RHD variants in a mixed-ethnic population. Prenat. Diagn. 33:173–78 56. Grati FR, Barlocco A, Grimi B, Milani S, Frascoli G, et al. 2010. Chromosome abnormalities investigated by non-invasive prenatal testing account for approximately 50% of fetal unbalances associated with relevant clinical phenotypes. Am. J. Med. Genet. A 152A:1434–42 57. Gregg AR, Gross SJ, Best RG, Monaghan KG, Bajaj K, et al. 2013. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet. Med. 15:395–98 58. Guetta E, Simchen MJ, Mammon-Daviko K, Gordon D, Aviram-Goldring A, et al. 2004. Analysis of fetal blood cells in the maternal circulation: challenges, ongoing efforts, and potential solutions. Stem Cells Dev. 13:93–99 59. Hahn S, Sant R, Holzgreve W. 1998. Fetal cells in maternal blood: current and future perspectives. Mol. Hum. Reprod. 4:515–21 60. Hahn S, Zhong XY, Holzgreve W. 2008. Recent progress in non-invasive prenatal diagnosis. Semin. Fetal Neonatal Med. 13:57–62 61. Hall AL, Drendel HM, Verbrugge JL, Reese AM, Schumacher KL, et al. 2013. Positive cell-free fetal DNA testing for trisomy 13 reveals confined placental mosaicism. Genet. Med. 15:729–32 62. Hui L, Bianchi DW. 2013. Recent advances in the prenatal interrogation of the human fetal genome. Trends Genet. 29:84–91 63. Kitzman JO, Snyder MW, Ventura M, Lewis AP, Qiu R, et al. 2012. Noninvasive whole-genome sequencing of a human fetus. Sci. Transl. Med. 4:137ra76 64. Lau TK, Chen F, Pan X, Pooh RK, Jiang F, et al. 2012. Noninvasive prenatal diagnosis of common fetal chromosomal aneuploidies by maternal plasma DNA sequencing. J. Matern. Fetal Neonatal Med. 25:1370–74 65. Lau TK, Jiang FM, Chan MK, Zhang H, Lo PS, Wang W. 2013. Non-invasive prenatal screening of fetal Down syndrome by maternal plasma DNA sequencing in twin pregnancies. J. Matern. Fetal Neonatal Med. 26:434–37 66. Lau TK, Jiang FM, Stevenson RJ, Lo TK, Chan LW, et al. 2013. Secondary findings from non-invasive prenatal testing for common fetal aneuploidies by whole genome sequencing as a clinical service. Prenat. Diagn. 33:602–8
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67. Liang D, Lv W, Wang H, Xu L, Liu J, et al. 2013. Non-invasive prenatal testing of fetal whole chromosome aneuploidy by massively parallel sequencing. Prenat. Diagn. 33:409–15 68. Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, et al. 1997. Presence of fetal DNA in maternal plasma and serum. Lancet 350:485–87 69. Lo YM, Hjelm NM, Fidler C, Sargent IL, Murphy MF, et al. 1998. Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma. N. Engl. J. Med. 339:1734–38 70. Lo YM, Lun FM, Chan KC, Tsui NB, Chong KC, et al. 2007. Digital PCR for the molecular detection of fetal chromosomal aneuploidy. Proc. Natl. Acad. Sci. USA 104:13116–21 71. Lo YM, Tsui NB, Chiu RW, Lau TK, Leung TN, et al. 2007. Plasma placental RNA allelic ratio permits noninvasive prenatal chromosomal aneuploidy detection. Nat. Med. 13:218–23 72. Lun FM, Chiu RW, Chan KC, Leung TY, Lau TK, Lo YM. 2008. Microfluidics digital PCR reveals a higher than expected fraction of fetal DNA in maternal plasma. Clin. Chem. 54:1664–72 73. Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, et al. 2005. First-trimester or secondtrimester screening, or both, for Down’s syndrome. N. Engl. J. Med. 353:2001–11 74. Mennuti MT, Cherry AM, Morrissette JJ, Dugoff L. 2013. Is it time to sound an alarm about false-positive cell-free DNA testing for fetal aneuploidy? Am. J. Obstet. Gynecol. 209:415–19 75. Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. 1984. An association between low maternal serum α-fetoprotein and fetal chromosomal abnormalities. Am. J. Obstet. Gynecol. 148:886–94 76. Miltenyi S, Muller W, Weichel W, Radbruch A. 1990. High gradient magnetic cell separation with ¨ MACS. Cytometry 11:231–38 77. Moise KJ Jr, Boring NH, O’Shaughnessy R, Simpson LL, Wolfe HM, et al. 2013. Circulating cell-free fetal DNA for the detection of RHD status and sex using reflex fetal identifiers. Prenat. Diagn. 33:95–101 78. Morain S, Greene MF, Mello MM. 2013. A new era in noninvasive prenatal testing. N. Engl. J. Med. 369:499–501 79. Natl. Inst. Health. 2013. New NIH awards focus on nanopore technology for DNA sequencing. News Release, Sept. 6, Natl. Inst. Health, Bethesda, MD. http://www.nih.gov/news/health/sep2013/nhgri-06a.htm 80. Nicolaides KH, Syngelaki A, Ashoor G, Birdir C, Touzet G. 2012. Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population. Am. J. Obstet. Gynecol. 207:374–76 81. Nicolaides KH, Syngelaki A, Gil M, Atanasova V, Markova D. 2013. Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y. Prenat. Diagn. 33:575–79 82. Nicolaides KH, Syngelaki A, Gil MM, Quezada MS, Zinevich Y. 2014. Prenatal detection of fetal triploidy from cell-free DNA testing in maternal blood. Fetal Diagn. Ther. 35:207–12 83. Norton ME, Brar H, Weiss J, Karimi A, Laurent LC, et al. 2012. 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. 207:137–38 84. Norton ME, Rose NC, Benn P. 2013. Noninvasive prenatal testing for fetal aneuploidy: clinical assessment and a plea for restraint. Obstet. Gynecol. 121:847–50 85. Ohno M, Caughey A. 2013. The role of noninvasive prenatal testing as a diagnostic versus a screening tool—a cost-effectiveness analysis. Prenat. Diagn. 33:630–35 86. Osborne CM, Hardisty E, Devers P, Kaiser-Rogers K, Hayden MA, et al. 2013. Discordant noninvasive prenatal testing results in a patient subsequently diagnosed with metastatic disease. Prenat. Diagn. 33:609– 11 87. Palomaki GE, Deciu C, Kloza EM, Lambert-Messerlian GM, Haddow JE, et al. 2012. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet. Med. 14:296–305 88. Palomaki GE, Haddow JE. 1987. Maternal serum α-fetoprotein, age, and Down syndrome risk. Am. J. Obstet. Gynecol. 156:460–63 89. Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, et al. 2011. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet. Med. 13:913–20 www.annualreviews.org • Noninvasive Prenatal Screening and NGS
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90. Pan M, Li FT, Li Y, Jiang FM, Li DZ, et al. 2013. Discordant results between fetal karyotyping and non-invasive prenatal testing by maternal plasma sequencing in a case of uniparental disomy 21 due to trisomic rescue. Prenat. Diagn. 33:598–601 91. Papageorgiou EA, Patsalis PC. 2012. Non-invasive prenatal diagnosis of aneuploidies: new technologies and clinical applications. Genome Med. 4:46 92. Poon LL, Leung TN, Lau TK, Chow KC, Lo YM. 2002. Differential DNA methylation between fetus and mother as a strategy for detecting fetal DNA in maternal plasma. Clin. Chem. 48:35–41 93. Rava RP, Srinivasan A, Sehnert AJ, Bianchi DW. 2014. Circulating fetal cell-free DNA fractions differ in autosomal aneuploidies and monosomy X. Clin. Chem. 60:243–50 94. Samango-Sprouse C, Banjevic M, Ryan A, Sigurjonsson S, Zimmermann B, et al. 2013. SNP-based non-invasive prenatal testing detects sex chromosome aneuploidies with high accuracy. Prenat. Diagn. 33:643–49 95. Schaffer A. 2012. Nanopore sequencing. MIT Technol. Rev., May/June. http://www2.technologyreview. com/article/427677/nanopore-sequencing 96. Schindler AM, Martin-du-Pan R. 1972. Prenatal diagnosis of fetal lymphocytes in the maternal blood. Obstet. Gynecol. 40:340–46 97. Sehnert AJ, Rhees B, Comstock D, de Feo E, Heilek G, et al. 2011. Optimal detection of fetal chromosomal abnormalities by massively parallel DNA sequencing of cell-free fetal DNA from maternal blood. Clin. Chem. 57:1042–49 98. Simpson JL. 2005. Choosing the best prenatal screening protocol. N. Engl. J. Med. 353:2068–70 99. Simpson JL, Elias S. 2003. Genetics in Obstetrics and Gynecology. Philadelphia: Saunders. 3rd ed. 100. Song K, Musci TJ, Caughey AB. 2013. Clinical utility and cost of non-invasive prenatal testing with cfDNA analysis in high-risk women based on a US population. J. Matern. Fetal Neonatal Med. 26:1180– 85 101. Song Y, Liu C, Qi H, Zhang Y, Bian X, Liu J. 2013. Noninvasive prenatal testing of fetal aneuploidies by massively parallel sequencing in a prospective Chinese population. Prenat. Diagn. 33:700–6 102. Sparks AB, Struble CA, Wang ET, Song K, Oliphant A. 2012. Noninvasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. Am. J. Obstet. Gynecol. 206:319 103. Sparks AB, Wang ET, Struble CA, Barrett W, Stokowski R, et al. 2012. Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenat. Diagn. 32:3–9 104. Srinivasan A, Bianchi DW, Huang H, Sehnert AJ, Rava RP. 2013. Noninvasive detection of fetal subchromosome abnormalities via deep sequencing of maternal plasma. Am. J. Hum. Genet. 92:167–76 105. Srinivasan P, Westover MB, Bianchi MT. 2012. Propagation of uncertainty in Bayesian diagnostic test interpretation. South. Med. J. 105:452–59 106. Swennenhuis JF, Reumers J, Thys K, Aerssens J, Terstappen LW. 2013. Efficiency of whole genome amplification of single circulating tumor cells enriched by CellSearch and sorted by FACS. Genome Med. 5:106 107. van den Heuvel A, Chitty LS, Dormandy E, Newson A, Deans Z, et al. 2010. Will the introduction of non-invasive prenatal diagnostic testing erode informed choices? An experimental study of health care professionals. Patient Educ. Couns. 78:24–28 108. Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty LS, Mackinson AM. 2003. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol. Assess. 7(11):1–77 109. Walknowska J, Conte FA, Grumbach MM. 1969. Practical and theoretical implications of fetal-maternal lymphocyte transfer. Lancet 293:1119–22 110. Wang E, Batey A, Struble C, Musci T, Song K, Oliphant A. 2013. Gestational age and maternal weight effects on fetal cell-free DNA in maternal plasma. Prenat. Diagn. 33:662–66 111. Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, et al. 2012. Chromosomal microarray versus karyotyping for prenatal diagnosis. N. Engl. J. Med. 367:2175–84 112. White HE, Dent CL, Hall VJ, Crolla JA, Chitty LS. 2012. Evaluation of a novel assay for detection of the fetal marker RASSF1A: facilitating improved diagnostic reliability of noninvasive prenatal diagnosis. PLoS ONE 7:e45073
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113. Wilson KL, Czerwinski JL, Hoskovec JM, Noblin SJ, Sullivan CM, et al. 2013. NSGC practice guideline: prenatal screening and diagnostic testing options for chromosome aneuploidy. J. Genet. Couns. 22:4–15 114. Woyke T, Tighe D, Mavromatis K, Clum A, Copeland A, et al. 2010. One bacterial cell, one complete genome. PLoS ONE 5:e10314 115. Wright A, Zhou Y, Weier JF, Caceres E, Kapidzic M, et al. 2004. Trisomy 21 is associated with variable defects in cytotrophoblast differentiation along the invasive pathway. Am. J. Med. Genet. A 130A:354–64 116. Wright CF, Burton H. 2009. The use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal diagnosis. Hum. Reprod. Update. 15:139–51 117. Zimmermann B, Hill M, Gemelos G, Demko Z, Banjevic M, et al. 2012. Noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X, and Y, using targeted sequencing of polymorphic loci. Prenat. Diagn. 32:1233–41
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Noninvasive Prenatal Screening by Next-Generation Sequencing Anthony R. Gregg,1 Ignatia B. Van den Veyver,2 Susan J. Gross,3 Rajeevi Madankumar,4 Britton D. Rink,5 and Mary E. Norton6 1
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, Florida 32610; email: greggar@ufl.edu
2
Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas 77030; email: [email protected]
3
Department of Obstetrics and Gynecology and Women’s Health, Albert Einstein College of Medicine, Yeshiva University, New York, NY 10461; email: [email protected]
4
Division of Maternal Fetal Medicine, Long Island Jewish Medical Center, New Hyde Park, New York 11040; email: [email protected]
5
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine, Ohio State University, Columbus, Ohio 43210; email: [email protected]
6
Department of Obstetrics, Gynecology, and Reproductive Sciences, Institute of Human Genetics, University of California, San Francisco, California 94143; email: [email protected]
Annu. Rev. Genomics Hum. Genet. 2014. 15:11.1–11.21 The Annual Review of Genomics and Human Genetics is online at genom.annualreviews.org This article’s doi: 10.1146/annurev-genom-090413-025341 c 2014 by Annual Reviews. Copyright All rights reserved
Keywords fetal aneuploidy, noninvasive prenatal testing, noninvasive prenatal screening, cell-free fetal DNA
Abstract Noninvasive prenatal screening (NIPS) has emerged as a highly accurate method of screening for fetal Down syndrome, with a detection rate and specificity approaching 100%. Challenging the widespread use of this technology are cost and the paradigm shift in counseling that accompanies any emerging technology. The expense of the test is expected to decrease with increased utilization, and well beyond the current NIPS technology, its components (fetal genome isolation, sequencing technology, and bioinformatics) will be utilized alone or in combinations to interrogate the fetal genome. The end goal is simple: to offer patients information early in pregnancy about fetal genomes without incurring procedural risks. This will allow patients an opportunity to make informed reproductive decisions based on precise fetal genomic information.
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OVERVIEW
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The identification of reduced α-fetoprotein (AFP) levels in maternal circulation in Down syndrome pregnancies in the mid-1980s (75) began an era of biomarker discovery in which researchers searched for the best approaches to prenatal Down syndrome risk assessment and diagnosis. Noninvasive testing using maternal serum has expanded, and improvements have been made in invasive diagnostic testing using chorionic villus sampling (CVS) and/or amniocentesis. Invasive tests entail procedure-related pregnancy loss; however, to date, only these types of tests are diagnostic, a major distinction from noninvasive screening tests (e.g., those relying on blood drawing and/or ultrasound). The goal continues to be a noninvasive diagnostic test for a range of significant fetal abnormalities that would be without risk of procedure-related pregnancy loss and appropriate for all pregnant patients at early gestational ages. CVS is performed at between 10 and 13 weeks’ gestation and carries an associated risk of miscarriage of approximately 0.2% (23). Amniocentesis, when performed for aneuploidy detection, is typically offered at 15 and 20 weeks’ gestation and carries an associated risk of miscarriage that has improved from 0.5% in the 1980s to 0.06% in the present (23, 41, 99). Relatively low risks aside, invasive (i.e., diagnostic) procedures are avoided by some because they are considered a prelude to pregnancy termination. Down syndrome screening based on age (≥35 years old at delivery) has a sensitivity (detection rate) of approximately 25–30% (98). Incorporation of maternal serum AFP as a screening tool for women 10)
High risk (retrospective) (8–34)
High risk (prospective) (9–18)
5.4
12.6
3
4.6
1
0
4
0.8
DR (%)
Spec (%)
T21: 100 T18: 100 T13: 100
T21: 100 T18: 100 T13: 100
T21: 100 T18: 97.2 T13: 78.6
T21: 100 T18: 97.4
T21: 100 T18: 100 T13: 100
T21: 100 T18: 100 T13: 100
T21: 100 T18: 100 T13: 100
T21: 100 T18: 93.3
T21: 100 T18: 100
T21: >99 T18: >99
T21: >99 T18: >99 T21: 100 T18: 98
T21: 99.8
T21: 99.7
T21: 100
T21: 98.6
PPV (%)
T21: 100 T18: 100 T13: 100
NA
T21: 100 T18: 100 T13: 100
T21: 98.8 T18: 94.8
NA
NA
T21: 97.5
T21: 98.6
FP (%)
T21: 0 T18: 0 T13: 0
NA
T21: 0 T18: 0 T13: 0
T21: 0.03 T18: 0.07
NA
NA
T21: 0.2
T21: 0.2
NPV (%)
T21: 100 T18: 100 T13: 100
NA
T21: 100 T18: 99.8 T13: 99.4
T21: 100 T18: 96.6
NA
NA
T21: 100
T21: 99.8
FN (%)
T21: 0 T18: 0 T13: 0
NA
T21: 0 T18: 2.8 T13: 21.4
T21: 0 T18: 2.6
NA
NA
T21: 0
T21: 1.4
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Abbreviations: DANSR, Digital Analysis of Selected Regions; DR, detection rate; Eup, euploidy; FN, false negative; FORTE, Fetal-Fraction Optimized Risk of Trisomy Evaluation; FP, false positive; MPS, massively parallel sequencing; NA, not applicable; NATUS/PS, Next-Generation Aneuploidy Testing Using SNPs/Parental Support; NPV, negative predictive value; PPV, positive predictive value; Spec, specificity; T, trisomy. a Cell-free fetal DNA fraction not reported (reported by all others).
DANSR, FORTE
Ariosa Diagnostics
MPS
Failure (%)
ARI
Sequenom
N
Company
Reference
Study population (weeks of gestation)
Method
Selected validation studies for noninvasive prenatal screening
Table 3
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literacy coupled with the rapid pace at which these technologies advance, thus leading to gaps in the provision of care (14). All of the professional organizations acknowledge that pre- and posttest counseling are fundamental to the provision of noninvasive prenatal testing, and many of them also recognize the lack of resources and training to meet this need (3, 40, 57). Several aspects of NIPS suggest that it is different from other currently available screening tests—for example, in its superior sensitivity and specificity for aneuploidy detection but lack of information on other conditions (e.g., adverse pregnancy outcomes, structural birth defects, and rare aneuploidies). In the current model of prenatal risk assessment, owing to cost and feasibility, many women who undergo prenatal screening do not have detailed genetic counseling (13). When Bangsgaard & Tabor (10) studied informed choice in the setting of first-trimester risk assessment for Down syndrome, they found that 20% of patients were not given information about the test prior to testing. There are empirical data to suggest that health care providers regard informed consent as less important for NIPS than for invasive testing (107). Although noninvasive testing removes the need to discuss procedure-related risk, it does not alter the potential significance of the information patients receive. Further, patients must understand that noninvasive testing is not diagnostic and must consider the alternative testing strategies, including invasive testing if the screening test indicates an increased risk for aneuploidy. The widespread direct-to-consumer and direct-to-practitioner marketing of NIPS along with patient demand could lead to the routinization of prenatal testing and erosion of informed decision-making opportunities. Providers of genetic services may need to explore alternative ways to educate patients, including written information and online resources, to complement direct provider encounters. Depending on the complexity of the results, more in-depth posttest counseling may be indicated. Uninformative or inconclusive results should prompt a review of alternative testing strategies. The issue of pregnancy termination associated with increased uptake of prenatal screening for aneuploidy is debated in the medical literature and will become more relevant with NIPS (13). Future studies will be necessary to elucidate how women understand and react to complex genetic results.
INTEGRATION INTO CLINICAL CARE Challenging the Current Paradigm The role of NIPS in aneuploidy screening and prenatal diagnosis is evolving. This test has been called disruptive, a term used to describe innovations that displace existing technologies with something generally more efficient and worthwhile (31). In many ways, NIPS fits that description: It is a far more effective screening test for Down syndrome than current multiple-marker screening with serum analytes and nuchal translucency ultrasound (7, 17, 27, 35, 54, 83, 89, 102). However, it also cannot provide information about the range of possible conditions based on multiple-marker screening (e.g., adverse pregnancy outcomes) (11), and it is much more expensive than current screening. No screening modality detects as many chromosomal abnormalities as invasive diagnostic testing, especially if a chromosomal microarray is used (111). NIPS has been proposed as a firsttier screening test, a second-tier screening test, and a replacement for diagnostic testing. Each of these approaches has benefits and costs, and the test is currently being utilized in all three contexts. Using NIPS as a first-tier, universal screening test entails performing NIPS instead of (or in addition to) multiple-marker screening on all pregnant women. Using NIPS as a secondtier approach entails offering NIPS to high-risk patients (Table 1) as an alternative to invasive testing or other screening. It has also been suggested that NIPS—which, as described above, www.annualreviews.org • Noninvasive Prenatal Screening and NGS
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was initially referred to as noninvasive prenatal diagnosis—is a reasonable alternative to invasive diagnostic testing. In fact, many of the cost-effectiveness analyses that have been reported, much of the ethical discussion that has occurred, and most of what is written in the lay press focus on the benefits of NIPS over amniocentesis, implying, if not explicitly stating, that noninvasive prenatal testing is a diagnostic test.
Noninvasive Prenatal Screening as a First-Tier Test
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If NIPS were offered to all pregnant women as a first-tier screening test, the rate of detection of fetal trisomies 21, 18, and 13 would be very high. But the proportion of patients that attempt NIPS and do not obtain a result owing to inadequate fetal DNA, failed sequencing, or other problems with the test has been reported to be as low as 0.8% and as high as 12.6%, depending on the specific platform (Table 3). Failed results are more common in overweight and obese women, although the precise rate of failed testing and the likelihood of success on a redraw are unknown. At what body mass index cutoff the test is no longer worth attempting and in what circumstances a repeat attempt is worthwhile are also unknown. First-trimester screening or integrated screening approaches that include nuchal translucency and maternal serum screening may identify aneuploidies beyond those currently detectable with NIPS. A retrospective review of all karyotypes detected in response to first-trimester screening found that one-third of chromosomal abnormalities were abnormalities other than trisomy 21, 18, or 13 (2). Overall, approximately 16% of chromosomal abnormalities detected by invasive testing following abnormal first-trimester screening would not be detected by NIPS. In another recent publication on NIPS in a population of women of all ages undergoing first-trimester screening, NIPS detected 55% of the total chromosomal abnormalities (8 of 8 cases of trisomy 21 and 2 of 3 cases of trisomy 18, but no other abnormalities), whereas first-trimester screening detected 100% (all trisomy 21 and trisomy 18 cases as well as 7 other deletions, duplications, and other abnormalities) (80). In addition, screening for neural tube and ventral wall defects is an important component of current screening protocols that must be considered. Recommendations that a maternal serum AFP test or detailed ultrasound be performed in patients that undergo primary NIPS for aneuploidy screening are important to assure that patients continue to have risk assessment for neural tube and ventral wall defects.
Noninvasive Prenatal Screening as a Second-Tier Test Professional practice guidelines suggest that NIPS is an option for high-risk patients (Table 1). The justification for this limitation is that the test has not been validated in low- or averagerisk women. Prior ACOG guidelines, in contrast, have recognized that all prenatal tests should be available to all women regardless of maternal age (4, 5), and this contradiction in the NIPS recommendations has been discussed (84). Offering NIPS to all pregnant women eliminates the difficulties associated with offering the test to only selected groups but comes at considerable financial cost. A strategy of concurrently ordering both NIPS and first- and second-trimester screening (alone or in combination) together has become the default in many practices because of confusion about the appropriate role of this test. However, such a strategy will greatly increase costs without current evidence of incremental benefit.
Cost Considerations Several cost-effectiveness analyses of NIPS have been performed (17, 52, 85, 100). The assumptions and comparisons vary between the analyses, and therefore the conclusions are somewhat 11.14
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different. One analysis compared use of NIPS in women aged 35 and older as a diagnostic as opposed to a screening tool (85). The authors compared the costs and outcomes when amniocentesis confirmation was performed with those when the NIPS was assumed to be diagnostic without a need for confirmation. Assuming published rates of invasive testing uptake and termination for trisomy 21, they estimated that confirmatory amniocentesis would be required in 5,780 patients overall and that this would lead to 29 procedure-related miscarriages; in cases where amniocentesis confirmation was not required, they estimated that there would be 2,424 terminations of normal fetuses based on false-positive results. Therefore, although there are costs associated with the confirmatory amniocentesis, the number of false-positive terminations far outweighs the number of procedure-related losses in this model. Another analysis evaluated the costs of avoiding a Down syndrome birth using different approaches to NIPS compared with conventional screening (52). The authors found that the most cost-effective approach was a contingent policy in which all women undergo conventional screening and the 10–20% at highest risk are then offered NIPS. Offering NIPS to all women as a first-tier test would result in marginal costs of $1.4–$8.0 million per affected fetus detected, depending on the NIPS cost (varying between $500 and $2,000 per test). Economic analyses sponsored by Sequenom and Verinata found that the use of NIPS in high-risk women could be justified based on cost savings if the unit cost of NIPS was less than 96% of invasive testing (17) or less than $1,200 (100). An analysis from Ariosa Diagnostics considered a risk-based model in which women over 35 years old and women with positive results from conventional screening are offered NIPS as a follow-up test (85). This approach was also found to be cost effective when compared with conventional screening (52).
SUMMARY NIPS is and will continue to challenge the landscape of prenatal screening. Its components— isolation of cffDNA, novel PCR applications, next-generation sequencing bioinformatics, and proprietary statistical analyses—culminate in a future that has potential that goes beyond the noninvasive identification of Down syndrome. Potential future directions include the prenatal diagnosis of genome-wide microdeletions and microduplications as well as point mutations within single genes and later fetal exome sequencing. The greatest challenges are no longer circumscribed by technology but are now bridled more by society’s desire to invest in this technology and integrate it into clinical care.
DISCLOSURE STATEMENT M.E.N. has received research support from Ariosa Diagnostics, CellScape Corporation, and Natera. S.J.G. became the chief medical officer of Natera on December 9, 2013; this position did not influence the content of this review, which was submitted on that same day. The other authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS This review was prepared with the administrative assistance of Marsha Harben and Heather Ellis, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, Florida. www.annualreviews.org • Noninvasive Prenatal Screening and NGS
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