Noninvasive prenatal testing_for_fetal_aneuploidy

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Noninvasive prenatal testing_for_fetal_aneuploidy

  1. 1. Noninvasive Prenatal Testing for Fetal Aneuploidy Clinical Assessment and a Plea for Restraint Mary E. Norton, MD, Nancy C. Rose, MD, and Peter Benn, PhD The recent introduction of clinical tests to detect fetal aneuploidy by analysis of cell-free DNA in maternal plasma represents a tremendous advance in prenatal diagnosis and the culmination of many years of effort by researchers in the field. The development of noninvasive prenatal testing for clinical application by commercial industry has allowed much faster introduction into clinical care, yet also presents some challenges regarding education of patients and health care providers strug- gling to keep up with developments in this rapidly evolving area. It is important that health care providers recognize that the test is not diagnostic; rather, it represents a highly sensitive and specific screening test that should be expected to result in some false-positive and false-negative diagnoses. Although currently being integrated in some settings as a primary screening test for women at high risk of fetal aneuploidy, from a population perspective, a better option for noninvasive prenatal testing may be as a second-tier test for those patients who screen positive by conventional aneuploidy screening. How noninvasive prenatal testing will ulti- mately fit with the current prenatal testing algorithms remains to be determined. True cost–utility analyses will be needed to determine the actual clinical efficacy of this approach in the general prenatal population. (Obstet Gynecol 2013;121:847–50) DOI: http://10.1097/AOG.0b013e31828642c6 The potential to obtain and analyze fetal genetic material from maternal plasma has stimulated vig- orous research for more than three decades. In October 2011, these efforts resulted in the first commercially available test to detect fetal aneuploidy by analysis of cell-free DNA in maternal plasma. Over time, this technology is likely to be applied to the prenatal detec- tion of an ever-increasing range of genetic disorders. This commentary presents an overview of the devel- opment, clinical application, and limitations of nonin- vasive prenatal testing as currently available in clinical practice. DEVELOPMENT OF NONINVASIVE PRENATAL TESTING The development of cell-free DNA testing differs in important ways from that of other methods of prenatal diagnosis and screening. Amniocentesis, chorionic villous sampling, and serum screening were largely developed by academic investigators who were sup- ported by public funding. After the conduct of independent clinical trials, with results presented at scientific meetings and published in peer-reviewed journals, clinical tests were introduced and supported by national committee guidelines. This process was slow but relied on the unbiased external review of data before widespread introduction of tests and changes in the standards of clinical care. The techni- ques to analyze cell-free DNA in maternal plasma were also originally developed in academic settings but were rapidly licensed to commercial companies typically supported by venture capital or other private funding. The tests that were developed are now publicized through marketing directly to the clinician, From the Department of Obstetrics and Gynecology, Stanford University School of Medicine/Lucile Packard Children’s Hospital, Stanford, California; Inter- mountain Healthcare, University of Utah School of Medicine, Intermountain Medical Center, Maternal Fetal Medicine, Salt Lake City, Utah; and the Depart- ment of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut. Corresponding author: Mary E. Norton, MD, 300 Pasteur Drive, HH333, Stanford University/Lucile Packard Children’s Hospital, Stanford, CA 94305; e-mail: menorton@stanford.edu. Financial Disclosure Dr. Norton is a coprincipal investigator on clinical trial NCT0145167 sponsored by Ariosa Diagnostics. The other authors did not report any potential conflicts of interest. © 2013 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/13 VOL. 121, NO. 4, APRIL 2013 OBSTETRICS & GYNECOLOGY 847
  2. 2. and scientific presentations at times appear geared toward a specific product. Although such commercial development may allow for faster introduction into clinical practice, to some degree, it bypasses some components of a rigorous, unbiased vetting process, which helps to provide quality assurance. The cell-free DNA field is still evolving, and the clinical tests have limitations that have not been highlighted in the rush to capture market share. Clearly, the sensitivity and specificity are very high, and this is likely to result in less patient anxiety as a result of false-positive results and a decrease in invasive procedures. However, both false-positive and false-negative results do occur, and, therefore, these should be considered screening tests. The positive predictive value varies substantially with other risk factors and is relatively low in low-risk patients. For example, assuming a detection rate of 99% and a 0.5% false-positive rate, in a woman with a prior risk of one in 1,000 for Down syndrome, the likelihood that a positive result is a true-positive is only approxi- mately one in six. Even for a higher risk woman with a prior risk of one in 100, the chance of Down syndrome with a positive result is two in three; one third of positive results will be false positives. Online conversations among patients, health care providers, and even geneticists regarding false-positive results and other test characteristics demonstrate a lack of understanding of some of these features of current cell-free DNA tests. Further education is critically important to assure appropriate interpretation of positive test results. The three clinically available tests offered by Sequenom, Inc., Verinata Health, Inc., and Ariosa Diagnostics, Inc. have quite different characteristics in terms of how the sequencing data are analyzed and results are reported. Sequenom presents results as dichotomous outcomes, in which they indicate that increased chromosome 21 material is either present or not, implying to some health care providers (although not explicitly stating) diagnostic accuracy. Ariosa provides results as a risk, more typical of a screening test. Verinata reports three categories of results, includ- ing “aneuploidy detected,” “aneuploidy suspected,” or “no aneuploidy detected.” Another approach that pro- vides a case-specific estimate of risk is being developed by Natera Inc. This heterogeneity in approach contrasts with current serum screening tests, whose reporting and laboratory standardization are much more consistent between laboratories. The ease of obtaining blood samples for cell-free DNA testing, together with the promise of early and accurate clinical information and the intense marketing, make it tempting to use these tests even in the absence of comprehensive validation or understanding. From a clinical provider’s standpoint, it is difficult and time- consuming enough to review standard information in established prenatal care without also having to explain to patients the limitations of these screening tests and the differences between clinical validity and clinical use. However, given that pregnancy termination is a potential result of a positive test, and that cell-free DNA tests will now be provided through general pre- natal practices rather than specialized prenatal diagno- sis centers, obstetric providers will absorb more of the burden of discussing these complex results. QUALITY CONTROL AND REGULATION OF GENETIC TESTING Unlike many European countries, the United States has limited direct regulation of genetic testing. As a result, large professional societies, private medical insurers, and for-profit companies largely govern the uptake and integration of new technologies into prenatal practice, and there is currently no legal obligation to demon- strate safety and effectiveness of cell-free DNA tests. As laboratory-developed tests, there is no requirement for premarket approval by the U.S. Food and Drug Administration.1 Although the laboratories providing noninvasive prenatal testing in the United States are compliant with the Clinical Laboratory Improvement Amendments of 1988, Clinical Laboratory Improve- ment Amendments regulations are designed to oversee compliance at a laboratory operational level and do not extend to validation of specific tests. The absence of guidelines for quality control and quality assurance for the laboratory testing is a signif- icant concern. The methodologies are highly complex and the testing is subject to intense commercial competitive pressures. Such competition has led to a series of patent infringement lawsuits between the different companies; how these legal challenges will be decided, and whether they will affect access to tests and viability of some of the companies, remains uncertain. The Secretary’s Advisory Committee on Genet- ics, Health and Society has noted gaps in five main areas of oversight that directly affect optimal use of genetic testing, including clinical laboratory quality assurance, transparency of genetic testing, oversight of clinical validity of genetic tests, level of knowledge regarding clinical use of genetic tests, and meeting the informational needs of health professionals, the public health community, patients, and consumers. This group has noted that “.the growing use of genetic testing will require significant investment in evidence- based assessments to understand the validity and 848 Norton et al Noninvasive Prenatal Testing for Aneuploidy OBSTETRICS & GYNECOLOGY
  3. 3. utility of these tests in clinical and personal decision- making.”1 In the absence of direct regulation, other options have been suggested for oversight of these, and other, genetic tests. Professional societies could encourage voluntary registration of new prenatal tests with the National Institute of Health’s Genetic Test Registry, which would promote the documentation of clinical and analytic validity of new tests before active use. A model that could be useful to evaluate new prenatal genetic testing is one similar to the Secretary’s Advi- sory Committee for Heritable Diseases in Newborns and Children. Chartered in 2003, this multidisciplinary working group is designed to report to the Secretary of Health and Human Services on “.the most appropri- ate application of universal newborn screening tests, technologies, policies, guidelines and standards” to effectively reduce morbidity and mortality in newborns and children having, or at risk for, heritable disorders.2 A similar multidisciplinary committee to oversee pre- natal genetic testing, which is likely to increase greatly in scope and complexity in coming years, could be an appropriate venue for test evaluation and consider- ation. In the meantime, the Secretary’s Advisory Com- mittee for Heritable Diseases in Newborns and Children suggests that professional societies should issue guidelines that encourage physicians to review validity data before ordering tests and likewise should recommend minimum levels of clinical use.1 APPROPRIATE CLINICAL APPLICATION Despite the complex background of cell-free DNA testing, benefits for implementation into patient care clearly exist. However, the aggressive advertising, high visibility in the press, and the initial introduction of these tests before publication of professional society guidelines has left the general obstetrician with some confusion on how to best incorporate this new tool into clinical practice. To critically review the scientific publications and noninvasive prenatal testing clinical trial reports requires an in-depth understanding of genetics, molecular biology, and statistics. Moreover, there are limited data on how well the tests will perform in actual clinical practice, particularly for specific subgroups of women in which noninvasive prenatal testing has not been adequately validated. The tests have primarily been validated on archived samples in carefully selected groups of high-risk women; such studies do not answer the question of clinical use in the general population. Nevertheless, obstetricians may be concerned about their liability if they do not offer cell-free DNA tests as an available option. Conversely, given that pregnancy termination is a potential result of cell-free DNA testing, the obstetrician bears the burden for accurate counseling and interpretation of test results. Current American College of Obstetricians and Gynecologists guidelines recognize that prenatal diag- nosis should be available to all women regardless of maternal age3 and that prenatal screening tests can help women decide whether to accept or reject inva- sive testing.4 First-trimester screening with nuchal translucency and maternal serum screening carries added benefits, including identification of aneuploidies beyond those currently detectable with noninvasive prenatal testing.5 In a recent publication on noninva- sive prenatal testing in an average risk population of women undergoing first-trimester screening, noninva- sive prenatal testing detected 55% of the total chromo- somal abnormalities (eight of eight cases of trisomy 21 and two of three cases of trisomy 18), whereas first- trimester screening detected 100% (all T21 and T18 as well as seven other deletions, duplications, and other abnormalities).6 In addition, screening for neural tube and ventral wall defects is an important component of current screening protocols. Optimal introduction of noninvasive prenatal testing would preserve the prin- ciple of providing prenatal screening and diagnosis in a way that maximizes women’s reproductive choice and, in addition, ensure that noninvasive prenatal test- ing is not performed on women who are unaware of the purpose and scope of the test.7 Not surprisingly, the major companies providing this testing in the United States are targeting large groups of women for testing. Sequenom and Verinata advocate testing on all high-risk women, which includes all women of advanced maternal age. However, many older women undergo other screening tests and most are determined to be lower risk; currently available and recommended serum and ultrasonographic protocols are better at identifying high-risk women than just age alone.8 In gen- eral, the concept of “advanced maternal age” as a screen- ing test is now considered arbitrary and outdated. Offering noninvasive prenatal testing to all preg- nant women eliminates the difficulties associated with offering the test to only selected groups but at consider- able financial cost. Ariosa recommends screening women of all ages and a complete replacement for all existing aneuploidy screening but makes this recom- mendation in the absence of published in-depth research with regard to efficacy. They have carried out limited studies on low-risk women and demon- strated that the test failure rate appears to be no higher and the false-positive rate comparable with that in high-risk women. Before concluding that conventional screening could be replaced by noninvasive prenatal VOL. 121, NO. 4, APRIL 2013 Norton et al Noninvasive Prenatal Testing for Aneuploidy 849
  4. 4. testing, a detailed comparison of all costs and benefits, both direct and indirect, needs to be carried out. RECOMMENDATIONS AND CONSIDERATIONS So what is the general obstetric provider to do at this point in time? The American College of Obstetricians and Gynecologists recent published guidelines indi- cating that cell-free DNA testing is of benefit in high- risk women.9 However, they caution that such testing should not be part of routine care but should only be provided after pretest counseling. Furthermore, they note that the test has not yet been adequately evalu- ated in low-risk women, to whom it should not yet be offered. In addition, we would suggest considering the following: 1) Although noninvasive prenatal testing has high detection rates and low false-positive rates, it is a screening test and a positive noninvasive pre- natal testing result must be confirmed by invasive testing if pregnancy termination is being considered. 2) In high-risk women, particularly those identified as such through traditional screening, noninvasive pre- natal testing can be very useful but it should be made clear that it screens for limited fetal aneuploidies at this time (trisomies 21, 18, and 13). A diagnostic inva- sive test definitively identifies a much broader range of chromosome abnormalities (especially if microar- ray technology is used). 3) If patients are to undergo noninvasive prenatal testing, they need to understand the purpose and limitations of the test; this cannot be routinely added to standard prenatal laboratory test- ing without adequate counseling. 4) Current serum screening and ultrasonographic strategies that have been thoughtfully developed and evaluated and any replacement should be based on evidence of improved clinical use, including considerations of the range of abnormalities detected with each strategy. 5) A strategy of concurrently ordering both noninvasive prenatal testing and integrated screening cannot be advocated, because this seems likely to greatly increase costs with- out current evidence of incremental benefit. At this time, the most appropriate use of non- invasive prenatal testing may be as a second-tier test for those with screen-positive results from conventional aneuploidy screening. As noninvasive prenatal testing expands to screen for more disorders and there are more data available on its use, it may replace current screening methods. However, at the present time, it does not replace all forms of prenatal screening. Finally, the implications of failed tests need to be considered. Up to 5% of cases do not generate a result, often as a result of insufficient fetal cell-free DNA (especially for women with high body mass index).10 It is unknown at what body mass index cutoff the test is no longer worth attempting and in what circumstances a repeat attempt is worthwhile. Results of noninvasive prenatal testing can take 1–3 weeks, and the implica- tions of the turnaround time, especially if a test result is ultimately not provided, need to be considered, espe- cially for patients who are later in the second trimester, for whom it may be too late to pursue other screening or diagnostic testing options. In summary, noninvasive prenatal testing using cell-free DNA is an exciting new technology with tremendous potential to benefit pregnant women. Undoubtedly, cell-free DNA technology will expand over the next few years and dramatically advance the field of prenatal screening and diagnosis. Developing reasonable clinical management guidelines and edu- cation will be essential as the testing becomes more sophisticated. Like other new technologies, it should be carefully assessed in an unbiased fashion before it completely replaces our current standard of care and before we change prenatal practice for the four million pregnancies that occur in this country each year. REFERENCES 1. Ferreira-Gonzalez A, Teutsch S, Williams MS, Au SM, Fitzgerald KT, Miller PS, et al. US system of oversight for genetic testing: a report from the Secretary’s Advisory Commit- tee on Genetics, Health and Society. Per Med 2008;5:521–8. 2. Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children. Available at: http://www.hrsa.gov/ advisorycommittees/mchbadvisory/heritabledisorders/index.html. Retrieved October 23, 2012. 3. Screening for fetal chromosomal abnormalities. ACOG Prac- tice Bulletin No. 77. American College of Obstetricians and Gynecologists. Obstet Gynecol 2007;109:217–27. 4. Invasive prenatal testing for aneuploidy. ACOG Practice Bulle- tin No. 88, December 2007. American College of Obstetricians and Gynecologists. Obstet Gynecol 2007;110:1459–67. 5. Syngelaki A, Chelemen T, Dagklis T, Allan L, Nicolaides KH. Challenges in the diagnosis of fetal non-chromosomal abnor- malities at 11–13 weeks. Prenat Diagn 2011;31:90–102. 6. Nicolaides KH, Syngelaki A, Ashoor G, Birdir C, Touzet C. Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population. Am J Obstet Gynecol 2012; 207:374.e1–6. 7. Benn PA, Chapman AR. Ethical challenges in providing non- invasive prenatal diagnosis. Curr Opin Obstet Gynecol 2010; 22:128–34. 8. Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, et al. First-trimester or second-trimester screening, or both, for Down’s syndrome. N Engl J Med 2005;353:2001–11. 9. Noninvasive prenatal testing for fetal aneuploidy. Committee Opinion No. 545. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:1532–4. 10. Ashoor G, Poon L, Syngelaki A, Mosimann B, Nicolaides KH. Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks’ gestation: effect of maternal and fetal factors. Fetal Diagn Ther 2012;31:237–43. 850 Norton et al Noninvasive Prenatal Testing for Aneuploidy OBSTETRICS & GYNECOLOGY

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