Current Commentary
Look Before You Leap Genomic Screening in Obstetrics and Gynecology Michael C. Adams,
MS,
Jonathan S. Berg,
MD, PhD,
There are a number of new genetic tests and a variety of recommendations for obstetrician–gynecologists. In recent years, screening of low-risk pregnant women with noninvasive prenatal testing has been proposed as well as universal BRCA1 and BRCA2 screening of all women regardless of risk status. Both proposed genetic screening tests raise complicated issues relating to predictive value, cost, and consequences after screening to both the health care system as a whole as well as serious potential adverse consequences for the patient. In addition, there are significant barriers relating to clinician education in proper use of these genetic tests as well as logistic issues of performing adequate genetic counseling in a busy general practice. We recommend that pregnant women offered noninvasive prenatal testing be informed of its advantages and disadvantages compared with standard screening with the caveat that positive noninvasive prenatal tests must be confirmed with further, invasive testing. We recommend against population genetic screening of all women for BRCA1 and BRCA2 mutations until there are comprehensive data regarding harms and benefits as well as cost-effectiveness. Finally, we recommend that new educational models for genetics be developed for obstetrics and gynecology residency training so that future health care providers will be prepared for the opportunities and challenges that genetic testing creates. (Obstet Gynecol 2015;125:1299–305) DOI: 10.1097/AOG.0000000000000871
From the Department of Genetics and the Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and the Department of Obstetrics, Gynecology, and Surgery, University of Michigan, Ann Arbor, Michigan. Corresponding author: Neeta L. Vora, MD, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, 3010 Old Clinic Building, CB# 7516, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
VOL. 125, NO. 6, JUNE 2015
Mark D. Pearlman,
MD,
and Neeta L. Vora,
MD
R
ecent advances in genomics have led to a number of new genetic tests and a variety of recommendations for providers. The American College of Obstetricians and Gynecologists (the College) released prenatal cystic fibrosis screening recommendations in 2001 followed by recommendations for hemoglobinopathy screening in 2007, BRCA1 and BRCA2 testing in 2009, carrier screening of individuals of Ashkenazi Jewish descent in 2009, screening for Fragile X in 2010, and noninvasive prenatal testing recommendations for high-risk women in 2012. In the past year, universal BRCA1 and BRCA2 screening of all women regardless of risk status has been proposed.1 New data regarding noninvasive prenatal testing have also been published.2,3 Because so many of these recommendations affect the practices of obstetrician–gynecologists (ob-gyns), we believe that ob-gyns should have a firm understanding of the implications of genomics and genetic testing, including the potential benefits, limitations, and costs. The proposed noninvasive prenatal testing and BRCA1 and BRCA2 screening programs would affect millions of patients. However, are ob-gyns adequately prepared to guide and counsel patients on the use of such testing? A survey of 250 ob-gyns found that 62% had ordered BRCA1 and BRCA2 testing in the past year. However, only 19% of physicians overall correctly distinguished between low-risk and high-risk scenarios for familial breast and ovarian cancer.4 A lack of effective genetics training in residency and beyond5 as well as the inherent logistic issues of performing adequate genetic counseling in a busy general practice creates challenges for the practicing ob-gyn and could create misunderstandings about the limitations of genetic screening that adversely affect patient welfare. BRCA1 and BRCA2 mutations are estimated to account for between 5% and 15% of all breast and ovarian cancers.6 The original data for BRCA1 and BRCA2 were derived from high-risk populations based on family history of breast and ovarian cancer,
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1299
age of onset of cancer, or tumor characteristics. A recent study addressed genetic screening of the Ashkenazi Jewish population for three specific BRCA1 and BRCA2 gene mutations.7 These patients were not selected for having any other high-risk characteristics besides their baseline population risk. This study found that the risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers (the “penetrance,” or the proportion of mutation carriers who have the disease) with no substantial family or personal history of cancer was comparable to those mutation carriers with significant cancer family history. There are more than 1,000 known pathogenic mutations in BRCA1 and BRCA2, but the penetrance of many of these has likely been overestimated for individuals with no family history. Because of these recent data confirming the high cancer risks of specific gene mutations even in seemingly low-risk patients, and the existence of new genomic sequencing technologies that may substantially decrease the upfront cost of screening, King et al have suggested that all women including those of non-Ashkenazi descent be screened for mutations in BRCA1 and BRCA2.1 Equally controversial as BRCA1 and BRCA2 screening is the premise of offering noninvasive prenatal testing in low-risk pregnancies. Recent data comparing noninvasive prenatal testing with traditional first- and second-trimester screening in low-risk women shows that noninvasive prenatal testing can be a more predictive test for specific common chromosomal abnormalities. However, concerns about cost8 and sensitivity remain. A positive standard serum screening result that is confirmed with invasive testing offers the ability to detect a wider variety of chromosomal abnormalities than noninvasive prenatal testing, which only tests for the most common.3 Because circulating cell-free DNA is placental, not fetal, false-positive results from placental mosaicism may occur; thus, positive noninvasive prenatal test results should be confirmed by diagnostic testing. A recent study found that 6.2% of women receiving a positive noninvasive prenatal test proceeded with pregnancy termination directly rather than receiving confirmatory testing first,9 indicating the importance of clarifying the role of noninvasive prenatal testing as a screening, not a diagnostic test.
SCREENING FUNDAMENTALS Any screening test should satisfy several strict criteria to provide a net benefit to patients. Before considering the routine inclusion of a new screening test: 1) the screening test must be valid, 2) the disease must be an important health problem, 3) the disease must be treatable, 4) the disease must have a latent stage such
1300
Adams et al
Look Before You Leap
that identifying and treating it early may reduce morbidity and mortality, 5) the screening test must be acceptable to patients and not impose undue harm, and 6) the screening program must be cost-effective.10 We judge the validity of a screening test by evaluating the sensitivity (ability to detect people with the disease) and specificity (ability to correctly identify people without the disease) of the test. Although the sensitivity and specificity of a given test may be high, the predictive value of a test result is dependent directly on the prevalence of the disease in a population. The positive predictive value (PPV) is defined as the probability that a person actually has disease given a positive test result, and the negative predictive value is the probability that a person does not have disease given a negative test result. The prevalence of the condition in the population influences the predictive values of any test. In screening, this directly corresponds to the pretest probability of a given patient having the condition. We can consider some real examples that illustrate these points: 1) a 39-year-old primigravid woman considering noninvasive prenatal testing for chromosomal abnormalities; 2) an 18-year-old woman considering the same test; she has had no prior testing and has no family history of birth defects; 3) a 40-year-old woman with a strong family history of breast cancer, considering BRCA1 and BRCA2 testing; her predicted risk of a BRCA1 or BRCA2 mutation is 10%; and 4) a 35-year-old woman seen as part of a well-woman visit with no personal or family history of cancer. Because of our patient’s age in example 1, her pretest probability of having a fetus with Down syndrome (most often, trisomy 21) is the prevalence of the condition, approximately 11 per 1,000. An noninvasive prenatal test with a sensitivity of 99.9% and specificity of 99.7% for Down syndrome2 has a PPV of 79%. However, in example 2, the pretest probability of the fetus having Down syndrome is only approximately one per 1,000, resulting in a PPV of 25%, meaning that in three of four cases, a positive test is wrong. Figure 1 illustrates this effect, showing the difference in accuracy of noninvasive prenatal testing when screening 1,000 high-risk women as in example 1 and screening 1,000 low-risk women like in example 2. This effect of the prior prevalence of disease on a screening test is also true in BRCA1 and BRCA2 testing. It is difficult to accurately quantify the clinical sensitivity and specificity of BRCA1 and BRCA2 testing because of the varying clinical effect that a “likely pathogenic” mutation will have given the patient’s
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Down syndrome
Down syndrome
Absent
11
3
11 ——— 11+3
͌ 0.79
Negative predictive value: 0
986
986 ——— =1.00 986+0
A
Negative
Positive predictive value:
Positive
Present Noninvasive prenatal testing
Positive Negative
Noninvasive prenatal testing
Present
Absent Positive predictive value:
1
3
1 ——— =0.25 1+3
Negative predictive value: 0
996
996 ——— =1.00 996+0
B
Fig. 1. In this example, a noninvasive prenatal test is applied to two populations: high-risk women (A) and low-risk women (B). Despite the high sensitivity and specificity of the test, most positive test results in the low-risk population are incorrect. A. High-risk women (prevalence 1.1%). Assume 99.9% sensitivity, 99.7% specificity, screening 1,000 women. Positive predictive value 79.0%. Positive test was correct in four of five cases. B. Low-risk women (prevalence 0.1%). Assume 99.9% sensitivity, 99.7% specificity, screening 1,000 women. Positive predictive value 25.0%. Positive test was incorrect in three of four cases. Adams. Look Before You Leap. Obstet Gynecol 2015.
family history and potential other genetic modifiers. However, assuming a test with 95% sensitivity and 95% specificity, the PPV of diagnostic testing in example 3 is 68%. In case 4, the PPV drops to only 16% because the general population prevalence is less than 1%. Thus, in this case, more than four of five women who screened positive would receive an incorrect, yet potentially devastating, diagnosis.
FLAWS OF GENETIC TESTING There are several reasons why noninvasive prenatal testing, BRCA1 and BRCA2 testing, or any genetic testing may have less than 100% specificity. In the case of noninvasive prenatal testing, major limitations include the source of the DNA material that is sequenced—the DNA comes from both maternal and placental cells and is not actually fetal DNA. There are also limitations of the analysis method, where cases of maternal aneuploidy, multiple gestations, vanishing twins, or maternal cancer may cause falsepositive results. In BRCA1 and BRCA2 testing, both genes are sequenced and examined for potentially pathogenic mutations. However, in all humans, both of these genes will contain a substantial number of genetic mutations or variants, only a fraction of which will cause disease. A molecular geneticist will determine the pathogenicity of variants, typically using five categories: “known pathogenic,” “likely pathogenic,” “variant of uncertain significance,” “likely benign,” or “known benign.”11 Most often, “known pathogenic” and “likely pathogenic” variants are treated as disease-causing. This
VOL. 125, NO. 6, JUNE 2015
classification incorporates multiple factors, including previous reports about the variant or data from internal or external databases.12,13 Because many variants are novel and have never been reported in the medical literature and because of limitations of the existing literature, classifying genetic variants as disease-causing is subject to uncertainty and possible misclassification.14 Differences in the available knowledge base can lead to interlaboratory discrepancies. Thus, although very difficult to quantify, imperfect specificity is inherent to genetic tests. In addition, as discussed previously, some genetic variants that are considered pathogenic in individuals with a substantial cancer family history may have reduced penetrance in individuals without a cancer family history as a result of other genetic modifiers.15 Finally, “variants of uncertain significance” are reported in approximately 10% of BRCA1 and BRCA2 tests,16 in which case it is impossible to determine with a high degree of confidence whether the variant is causally implicated in predisposition to breast and ovarian cancer. Despite this uncertainty, patients and physicians may opt to institute aggressive screening or risk-reducing surgery in patients with “variant of uncertain significance” results,16 yet by their nature, “variants of uncertain significance” are unlikely to be causative of disease and expert recommendations suggest that they should not be acted on.17
CONSEQUENCES In addition to understanding the test performance of widespread screening tests, the additional tests and
Adams et al
Look Before You Leap
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1301
consequences after a positive screening result must also be considered.
Chromosomal Abnormality Screening in Pregnant Women In low-risk women, the College recommends traditional screening (first-trimester screen or the quad screen) for genetic abnormalities in addition to offering invasive diagnostic testing. The National Society of Genetic Counselors agrees and states that they do not recommend noninvasive prenatal testing as a first-line test in low-risk women. The American College of Medical Genetics and Genomics recommendations on noninvasive prenatal testing do not specifically address which group may be offered noninvasive prenatal testing as first-line screening. All guidelines as well as recent research emphasize the role of pre- and posttest genetic counseling.18 A positive screening test would indicate referral to a genetic counselor, maternal-fetal medicine specialist, or both and diagnostic testing would be offered with amniocentesis or chorionic villus sampling. Another option is noninvasive prenatal testing and offering diagnostic invasive testing after a positive noninvasive prenatal testing result. In high-risk women, the College states that traditional screening or noninvasive prenatal testing may be considered as first-line screening tests. Alternatively, noninvasive prenatal testing may be considered after a positive traditional screening result. Because of this variety of tests, it can be difficult to determine the appropriate algorithm for an individual patient. Figure 2 outlines some potential aneuploidy screening algorithms for women who desire screening (not immediate diagnostic testing) and highlights some of the considerations and concerns that have been raised with each screening technology. Noninvasive prenatal testing is costly, which is a significant economic barrier to widespread use.8 Noninvasive prenatal testing does have superior PPV than traditional screening for the most common chromosomal abnormalities, but it may not detect a variety of other kinds of genetic abnormalities that invasive testing can (eg, duplications or deletions of genetic material in the chromosome, rare trisomies3,19). A key consideration when the predictive value of screening can be low is the existence of a gold standard test that can rule in or rule out the condition. Although the gold standard test in this case (amniocentesis or chorionic villous sampling) is an invasive procedure that has risks (albeit small, with an iatrogenic miscarriage rate of less than two per 1,000) and costs, this can serve to avert the larger harm of parents being provided incorrect results.
1302
Adams et al
Look Before You Leap
BRCA1 and BRCA2 Screening The consequences of BRCA1 and BRCA2 screening are very different. A deleterious mutation in either of these genes potentially corresponds to a 45–84% lifetime risk of breast cancer and a 11–62% lifetime risk of ovarian cancer.6 Therefore, positive results of BRCA1 and BRCA2 testing indicate referral to a specialist, frequently to a comprehensive cancer center. The follow-up recommendations are for intensive surveillance consisting of frequent clinical breast examinations, annual breast MRI and mammograms, transvaginal ultrasound scans and CA-125 testing, possible risk-reducing double mastectomy, and bilateral salpingo-oophorectomy. Chemoprevention with oral contraceptives or tamoxifen may also be offered. The costs of screening a large fraction of the U.S. female population for BRCA1 and BRCA2 mutations are staggering. Even assuming the cost of the genetic sequencing itself could be substantially reduced (current costs are approximately $2,000–$4,000), the costs of breast and ovarian cancer surveillance with the associated callbacks, needle biopsies or laparoscopies, and other physician visits could cost billions of dollars a year given the size of the proposed screening program (potentially 80,000,000 women or more), the number of women who could screen positive (including approximately 4,000,000 false-positive results if “likely pathogenic” variants are reported), and costs of these procedures. Because of the relatively small number of women that could benefit from this approach (the combined general population prevalence of pathogenic BRCA1 and BRCA2 mutations is under 1%), any false-positive results will reduce potential cost-savings of averting cancer morbidity and mortality. Beyond the costs to society in screening every woman for BRCA1 and BRCA2 gene mutations, we must consider the individual patient. Here, incorrect positive results can be devastating. Positive results can have implications in almost every area of a woman’s life with particular effect on reproductive decisions including salpingo-oophorectomy. If a woman is considering using assistive reproductive technologies including in vitro fertilization or oocyte cryopreservation, decisions must be made about whether to have preimplantation genetic diagnosis of embryos for the same BRCA1 and BRCA2 mutation with transfer of only unaffected embryos. A woman may also face genetic discrimination. Although the U.S. Genetic Information Non Discrimination Act protects against genetic discrimination in health insurance and many places of employment, the law does not protect
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Fig. 2. Potential screening algorithms for women who desire aneuploidy screening. The American College of Obstetricians and Gynecologists (the College) does not recommend noninvasive prenatal testing as first-line screening in low-risk women, but those who test positive with traditional screening become high risk, and the high-risk algorithms should be evaluated. Noninvasive prenatal tests are evolving, but current costs and inability to detect as wide a variety of chromosomal abnormalities as invasive testing should be considered. Red dashed arrows indicate a possible course of action. *First-trimester combined screening, second-trimester maternal serum screening, or a combination. †Positive predictive value of traditional screening is often less than 5%. ‡Noninvasive prenatal testing is more costly than traditional screening. §Ultrasonography for structural anomaly, nuchal translucency, cystic hygroma, or multiple gestation. Adams. Look Before You Leap. Obstet Gynecol 2015.
against discrimination in life, long-term care, or disability insurance. Importantly, there is no gold standard confirmatory test for BRCA1 and BRCA2 mutations. In the case of chromosomal abnormality testing with noninvasive prenatal testing, we can avert substantial negative downstream consequences of a false-positive screening test result with an invasive test; this is not possible with BRCA1 and BRCA2 screening. Unnecessary aggressive surveillance or surgical intervention will likely grow substantially if lowrisk women are screened.
DISCUSSION No medical test is perfect, and genetic tests are no exception. Even the high specificity associated with genetic tests does not overcome the problem of
VOL. 125, NO. 6, JUNE 2015
screening for uncommon conditions. Positive results must be interpreted cautiously. We suggest that counseling for patients considering noninvasive prenatal testing include: • Noninvasive prenatal testing is a screening test for the most common chromosomal abnormalities (trisomies 21, 13, 18), but not all chromosomal abnormalities; • Noninvasive prenatal testing is a screening test only, and any positive results must be confirmed by a definitive test (eg, amniocentesis or chorionic villus sampling); and • Standard screening for chromosomal abnormalities is much less expensive than noninvasive prenatal testing. If a positive test is confirmed with invasive testing, a wider variety of genetic conditions
Adams et al
Look Before You Leap
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1303
including rare trisomies and deletions and duplications might be found compared with noninvasive prenatal testing. However, standard screening is much more likely to produce false-positive results. We suggest that counseling for patients regarding BRCA1 and BRCA2 testing include: • BRCA1 and BRCA2 are genes that, when deleterious mutations are present, substantially increase the risk of both breast and ovarian cancer as well as other cancers. Standard management exists that can substantially reduce the risk of disease-specific morbidity and mortality through enhanced surveillance or risk reduction surgery; • A family history of cancer should be taken on every patient. If this cancer history includes a patterns suggestive of substantial family cancer history,6 then referral to a clinical geneticist and genetic counselor is indicated. Diagnostic testing should be ordered by health care providers with specific expertise in risk assessment; and • Testing of BRCA1 and BRCA2 or larger breast cancer panels in the absence of family or personal history is not recommended, because there is substantial increased risk of false-positive results, increased cost and intervention, and there are no data currently available demonstrating that the benefit of routine testing in low-risk population exceeds the risks. If ob-gyns are going to successfully incorporate additional genetic screening into their practices, they must be adequately trained. We believe that increased obstetrics and gynecology residency training in genetics will assist future health care providers to both counsel their patients appropriately and improve the lives of the patients and families for whom they provide care. This training should cover the applications and limitations of genetic tests. Innovative, sustainable educational methods in genetics training for all clinical providers are needed. The Council on Resident Education in Obstetrics and Gynecology should consider using models in medical education that other fields have used. The Surgical Council on Resident Education curriculum (www.surgicalcore.org) used in general surgery residencies is a leading alternative model. This is an online education portal in which residents watch videos, read prepared chapters, and answer questions to test their knowledge. Another potential model is the obstetrics and gynecology–specific PearlCasts found on YouTube for medical student education. Creation of a standardized, online curriculum for genetics education in obstetrics and gynecology residency could occur by partnering the College, the Association of
1304
Adams et al
Look Before You Leap
Professors of Gynecology and Obstetrics, and the American College of Medical Genetics to develop specific genetics modules. Support for such efforts could potentially be found through partnering with a variety of genetics advocacy organizations and nonprofit foundations already working in obstetrics and gynecology. To maintain this base of genetics knowledge, the American Board of Obstetrics and Gynecology could include a more robust genetics component in the Maintenance of Certification required of its diplomats. Proposed noninvasive prenatal testing and BRCA1 and BRCA2 universal screening programs are just two examples of potential genetic screening tests. If these or others are to become widespread, we must do more to ensure that every ob-gyn is prepared to appropriately navigate the complex situations genetic screening creates. REFERENCES 1. King M, Levy-Lahad E, Lahad A. Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award. JAMA 2014;312: 1091–2. 2. Bianchi DW, Parker RL, Wentworth J, Madankumar R, Saffer C, Das AF, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014;370:799–808. 3. Norton ME, Jelliffe-Pawlowski LL, Currier RJ. Chromosome abnormalities detected by current prenatal screening and noninvasive prenatal testing. Obstet Gynecol 2014;124:979–86. 4. Bellcross CA, Kolor K, Goddard KAB, Coates RJ, Reyes M, Khoury MJ. Awareness and utilization of BRCA1/2 testing among U.S. primary care physicians. Am J Prev Med 2011; 40:61–6. 5. Cleary-Goldman J, Morgan MA, Malone FD, Robinson JN, D’Alton ME, Schulkin J. Screening for Down syndrome: practice patterns and knowledge of obstetricians and gynecologists. Obstet Gynecol 2006;107:11–7. 6. Daly MB, Pilarski R, Axilbund JE, Buys SS, Crawford B, Friedman S, et al. Genetic/familial high-risk assessment: breast and ovarian, version 1.2014. J Natl Compr Cancer Netw 2014; 12:1326–38. 7. Gabai-Kapara E, Lahad A, Kaufman B, Friedman E, Segev S, Renbaum P, et al. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci 2014;111:14205–10. 8. Ayres AC, Whitty JA, Ellwood DA. A cost-effectiveness analysis comparing different strategies to implement noninvasive prenatal testing into a Down syndrome screening program. Aust N Z J Obstet Gynaecol 2014;54:412–7. 9. Dar P, Curnow KJ, Gross SJ, Hall MP, Stosic M, Demko Z, et al. Clinical experience and follow-up with large scale singlenucleotide polymorphism-based noninvasive prenatal aneuploidy testing. Am J Obstet Gynecol 2014;211:527.e1–17. 10. Wilson JMG, Jungner G; World Health Organization. Principles and practice of screening for disease. 1968. Available at: http://apps.who.int//iris/handle/10665/37650. Retrieved February 21, 2015. 11. Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, et al. ACMG recommendations for standards for
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10:294–300. 12. Pruss D, Morris B, Hughes E, Eggington JM, Esterling L, Robinson BS, et al. Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. Breast Cancer Res Treat 2014;147: 119–32. 13. Tavtigian SV, Greenblatt MS, Goldgar DE, Boffetta P; IARC Unclassified Genetic Variants Working Group. Assessing pathogenicity: overview of results from the IARC Unclassified Genetic Variants Working Group. Hum Mutat 2008;29:1261–4. 14. Rahman N. Realizing the promise of cancer predisposition genes. Nature 2014;505:302–8. 15. Couch FJ, Wang X, McGuffog L, Lee A, Olswold C, Kuchenbaecker KB, et al. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet 2013;9:e1003212.
16. Murray ML, Cerrato F, Bennett RL, Jarvik GP. Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: variant reclassification and surgical decisions. Genet Med 2011;13:998–1005. 17. Lindor NM, Goldgar DE, Tavtigian SV, Plon SE, Couch FJ. BRCA1/2 sequence variants of uncertain significance: a primer for providers to assist in discussions and in medical management. Oncologist 2013;18:518–24. 18. Kuppermann M, Pena S, Bishop JT, Nakagawa S, Gregorich SE, Sit A, et al. Effect of enhanced information, values clarification, and removal of financial barriers on use of prenatal genetic testing: a randomized clinical trial. JAMA 2014;312:1210–7. 19. Grati FR, Barlocco A, Grimi B, Milani S, Frascoli G, Di Meco AM, 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 A 2010;152A:1434–42.
Author Instructions on Editorial ManagerTM Visit http://ong.editorialmanager.com for answers to your submission questions
Documents available online include: s)NSTRUCTIONSFOR!UTHORS s3UBMISSION#HECKLISTAND!UTHOR!GREEMENT sGuide to Writing for Obstetrics & Gynecology sh3UBMISSION'UIDELINES!T ! 'LANCEv s2EFERENCEFORMATTINGINSTRUCTIONS s3AMPLEPATIENTCONSENTFORM sh7HATTO%XPECT!FTER3UBMISSIONv 1UESTIONS #ALLTHE%DITORIAL/FlCEAT
VOL. 125, NO. 6, JUNE 2015
Adams et al
rev 11/2014
Look Before You Leap
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1305
Look Before You Leap Genomic Screening in Obstetrics and Gynecology Michael C. Adams,
MS,
Jonathan S. Berg,
MD, PhD,
There are a number of new genetic tests and a variety of recommendations for obstetrician–gynecologists. In recent years, screening of low-risk pregnant women with noninvasive prenatal testing has been proposed as well as universal BRCA1 and BRCA2 screening of all women regardless of risk status. Both proposed genetic screening tests raise complicated issues relating to predictive value, cost, and consequences after screening to both the health care system as a whole as well as serious potential adverse consequences for the patient. In addition, there are significant barriers relating to clinician education in proper use of these genetic tests as well as logistic issues of performing adequate genetic counseling in a busy general practice. We recommend that pregnant women offered noninvasive prenatal testing be informed of its advantages and disadvantages compared with standard screening with the caveat that positive noninvasive prenatal tests must be confirmed with further, invasive testing. We recommend against population genetic screening of all women for BRCA1 and BRCA2 mutations until there are comprehensive data regarding harms and benefits as well as cost-effectiveness. Finally, we recommend that new educational models for genetics be developed for obstetrics and gynecology residency training so that future health care providers will be prepared for the opportunities and challenges that genetic testing creates. (Obstet Gynecol 2015;125:1299–305) DOI: 10.1097/AOG.0000000000000871
From the Department of Genetics and the Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and the Department of Obstetrics, Gynecology, and Surgery, University of Michigan, Ann Arbor, Michigan. Corresponding author: Neeta L. Vora, MD, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, 3010 Old Clinic Building, CB# 7516, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
VOL. 125, NO. 6, JUNE 2015
Mark D. Pearlman,
MD,
and Neeta L. Vora,
MD
R
ecent advances in genomics have led to a number of new genetic tests and a variety of recommendations for providers. The American College of Obstetricians and Gynecologists (the College) released prenatal cystic fibrosis screening recommendations in 2001 followed by recommendations for hemoglobinopathy screening in 2007, BRCA1 and BRCA2 testing in 2009, carrier screening of individuals of Ashkenazi Jewish descent in 2009, screening for Fragile X in 2010, and noninvasive prenatal testing recommendations for high-risk women in 2012. In the past year, universal BRCA1 and BRCA2 screening of all women regardless of risk status has been proposed.1 New data regarding noninvasive prenatal testing have also been published.2,3 Because so many of these recommendations affect the practices of obstetrician–gynecologists (ob-gyns), we believe that ob-gyns should have a firm understanding of the implications of genomics and genetic testing, including the potential benefits, limitations, and costs. The proposed noninvasive prenatal testing and BRCA1 and BRCA2 screening programs would affect millions of patients. However, are ob-gyns adequately prepared to guide and counsel patients on the use of such testing? A survey of 250 ob-gyns found that 62% had ordered BRCA1 and BRCA2 testing in the past year. However, only 19% of physicians overall correctly distinguished between low-risk and high-risk scenarios for familial breast and ovarian cancer.4 A lack of effective genetics training in residency and beyond5 as well as the inherent logistic issues of performing adequate genetic counseling in a busy general practice creates challenges for the practicing ob-gyn and could create misunderstandings about the limitations of genetic screening that adversely affect patient welfare. BRCA1 and BRCA2 mutations are estimated to account for between 5% and 15% of all breast and ovarian cancers.6 The original data for BRCA1 and BRCA2 were derived from high-risk populations based on family history of breast and ovarian cancer,
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1299
age of onset of cancer, or tumor characteristics. A recent study addressed genetic screening of the Ashkenazi Jewish population for three specific BRCA1 and BRCA2 gene mutations.7 These patients were not selected for having any other high-risk characteristics besides their baseline population risk. This study found that the risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers (the “penetrance,” or the proportion of mutation carriers who have the disease) with no substantial family or personal history of cancer was comparable to those mutation carriers with significant cancer family history. There are more than 1,000 known pathogenic mutations in BRCA1 and BRCA2, but the penetrance of many of these has likely been overestimated for individuals with no family history. Because of these recent data confirming the high cancer risks of specific gene mutations even in seemingly low-risk patients, and the existence of new genomic sequencing technologies that may substantially decrease the upfront cost of screening, King et al have suggested that all women including those of non-Ashkenazi descent be screened for mutations in BRCA1 and BRCA2.1 Equally controversial as BRCA1 and BRCA2 screening is the premise of offering noninvasive prenatal testing in low-risk pregnancies. Recent data comparing noninvasive prenatal testing with traditional first- and second-trimester screening in low-risk women shows that noninvasive prenatal testing can be a more predictive test for specific common chromosomal abnormalities. However, concerns about cost8 and sensitivity remain. A positive standard serum screening result that is confirmed with invasive testing offers the ability to detect a wider variety of chromosomal abnormalities than noninvasive prenatal testing, which only tests for the most common.3 Because circulating cell-free DNA is placental, not fetal, false-positive results from placental mosaicism may occur; thus, positive noninvasive prenatal test results should be confirmed by diagnostic testing. A recent study found that 6.2% of women receiving a positive noninvasive prenatal test proceeded with pregnancy termination directly rather than receiving confirmatory testing first,9 indicating the importance of clarifying the role of noninvasive prenatal testing as a screening, not a diagnostic test.
SCREENING FUNDAMENTALS Any screening test should satisfy several strict criteria to provide a net benefit to patients. Before considering the routine inclusion of a new screening test: 1) the screening test must be valid, 2) the disease must be an important health problem, 3) the disease must be treatable, 4) the disease must have a latent stage such
1300
Adams et al
Look Before You Leap
that identifying and treating it early may reduce morbidity and mortality, 5) the screening test must be acceptable to patients and not impose undue harm, and 6) the screening program must be cost-effective.10 We judge the validity of a screening test by evaluating the sensitivity (ability to detect people with the disease) and specificity (ability to correctly identify people without the disease) of the test. Although the sensitivity and specificity of a given test may be high, the predictive value of a test result is dependent directly on the prevalence of the disease in a population. The positive predictive value (PPV) is defined as the probability that a person actually has disease given a positive test result, and the negative predictive value is the probability that a person does not have disease given a negative test result. The prevalence of the condition in the population influences the predictive values of any test. In screening, this directly corresponds to the pretest probability of a given patient having the condition. We can consider some real examples that illustrate these points: 1) a 39-year-old primigravid woman considering noninvasive prenatal testing for chromosomal abnormalities; 2) an 18-year-old woman considering the same test; she has had no prior testing and has no family history of birth defects; 3) a 40-year-old woman with a strong family history of breast cancer, considering BRCA1 and BRCA2 testing; her predicted risk of a BRCA1 or BRCA2 mutation is 10%; and 4) a 35-year-old woman seen as part of a well-woman visit with no personal or family history of cancer. Because of our patient’s age in example 1, her pretest probability of having a fetus with Down syndrome (most often, trisomy 21) is the prevalence of the condition, approximately 11 per 1,000. An noninvasive prenatal test with a sensitivity of 99.9% and specificity of 99.7% for Down syndrome2 has a PPV of 79%. However, in example 2, the pretest probability of the fetus having Down syndrome is only approximately one per 1,000, resulting in a PPV of 25%, meaning that in three of four cases, a positive test is wrong. Figure 1 illustrates this effect, showing the difference in accuracy of noninvasive prenatal testing when screening 1,000 high-risk women as in example 1 and screening 1,000 low-risk women like in example 2. This effect of the prior prevalence of disease on a screening test is also true in BRCA1 and BRCA2 testing. It is difficult to accurately quantify the clinical sensitivity and specificity of BRCA1 and BRCA2 testing because of the varying clinical effect that a “likely pathogenic” mutation will have given the patient’s
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Down syndrome
Down syndrome
Absent
11
3
11 ——— 11+3
͌ 0.79
Negative predictive value: 0
986
986 ——— =1.00 986+0
A
Negative
Positive predictive value:
Positive
Present Noninvasive prenatal testing
Positive Negative
Noninvasive prenatal testing
Present
Absent Positive predictive value:
1
3
1 ——— =0.25 1+3
Negative predictive value: 0
996
996 ——— =1.00 996+0
B
Fig. 1. In this example, a noninvasive prenatal test is applied to two populations: high-risk women (A) and low-risk women (B). Despite the high sensitivity and specificity of the test, most positive test results in the low-risk population are incorrect. A. High-risk women (prevalence 1.1%). Assume 99.9% sensitivity, 99.7% specificity, screening 1,000 women. Positive predictive value 79.0%. Positive test was correct in four of five cases. B. Low-risk women (prevalence 0.1%). Assume 99.9% sensitivity, 99.7% specificity, screening 1,000 women. Positive predictive value 25.0%. Positive test was incorrect in three of four cases. Adams. Look Before You Leap. Obstet Gynecol 2015.
family history and potential other genetic modifiers. However, assuming a test with 95% sensitivity and 95% specificity, the PPV of diagnostic testing in example 3 is 68%. In case 4, the PPV drops to only 16% because the general population prevalence is less than 1%. Thus, in this case, more than four of five women who screened positive would receive an incorrect, yet potentially devastating, diagnosis.
FLAWS OF GENETIC TESTING There are several reasons why noninvasive prenatal testing, BRCA1 and BRCA2 testing, or any genetic testing may have less than 100% specificity. In the case of noninvasive prenatal testing, major limitations include the source of the DNA material that is sequenced—the DNA comes from both maternal and placental cells and is not actually fetal DNA. There are also limitations of the analysis method, where cases of maternal aneuploidy, multiple gestations, vanishing twins, or maternal cancer may cause falsepositive results. In BRCA1 and BRCA2 testing, both genes are sequenced and examined for potentially pathogenic mutations. However, in all humans, both of these genes will contain a substantial number of genetic mutations or variants, only a fraction of which will cause disease. A molecular geneticist will determine the pathogenicity of variants, typically using five categories: “known pathogenic,” “likely pathogenic,” “variant of uncertain significance,” “likely benign,” or “known benign.”11 Most often, “known pathogenic” and “likely pathogenic” variants are treated as disease-causing. This
VOL. 125, NO. 6, JUNE 2015
classification incorporates multiple factors, including previous reports about the variant or data from internal or external databases.12,13 Because many variants are novel and have never been reported in the medical literature and because of limitations of the existing literature, classifying genetic variants as disease-causing is subject to uncertainty and possible misclassification.14 Differences in the available knowledge base can lead to interlaboratory discrepancies. Thus, although very difficult to quantify, imperfect specificity is inherent to genetic tests. In addition, as discussed previously, some genetic variants that are considered pathogenic in individuals with a substantial cancer family history may have reduced penetrance in individuals without a cancer family history as a result of other genetic modifiers.15 Finally, “variants of uncertain significance” are reported in approximately 10% of BRCA1 and BRCA2 tests,16 in which case it is impossible to determine with a high degree of confidence whether the variant is causally implicated in predisposition to breast and ovarian cancer. Despite this uncertainty, patients and physicians may opt to institute aggressive screening or risk-reducing surgery in patients with “variant of uncertain significance” results,16 yet by their nature, “variants of uncertain significance” are unlikely to be causative of disease and expert recommendations suggest that they should not be acted on.17
CONSEQUENCES In addition to understanding the test performance of widespread screening tests, the additional tests and
Adams et al
Look Before You Leap
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1301
consequences after a positive screening result must also be considered.
Chromosomal Abnormality Screening in Pregnant Women In low-risk women, the College recommends traditional screening (first-trimester screen or the quad screen) for genetic abnormalities in addition to offering invasive diagnostic testing. The National Society of Genetic Counselors agrees and states that they do not recommend noninvasive prenatal testing as a first-line test in low-risk women. The American College of Medical Genetics and Genomics recommendations on noninvasive prenatal testing do not specifically address which group may be offered noninvasive prenatal testing as first-line screening. All guidelines as well as recent research emphasize the role of pre- and posttest genetic counseling.18 A positive screening test would indicate referral to a genetic counselor, maternal-fetal medicine specialist, or both and diagnostic testing would be offered with amniocentesis or chorionic villus sampling. Another option is noninvasive prenatal testing and offering diagnostic invasive testing after a positive noninvasive prenatal testing result. In high-risk women, the College states that traditional screening or noninvasive prenatal testing may be considered as first-line screening tests. Alternatively, noninvasive prenatal testing may be considered after a positive traditional screening result. Because of this variety of tests, it can be difficult to determine the appropriate algorithm for an individual patient. Figure 2 outlines some potential aneuploidy screening algorithms for women who desire screening (not immediate diagnostic testing) and highlights some of the considerations and concerns that have been raised with each screening technology. Noninvasive prenatal testing is costly, which is a significant economic barrier to widespread use.8 Noninvasive prenatal testing does have superior PPV than traditional screening for the most common chromosomal abnormalities, but it may not detect a variety of other kinds of genetic abnormalities that invasive testing can (eg, duplications or deletions of genetic material in the chromosome, rare trisomies3,19). A key consideration when the predictive value of screening can be low is the existence of a gold standard test that can rule in or rule out the condition. Although the gold standard test in this case (amniocentesis or chorionic villous sampling) is an invasive procedure that has risks (albeit small, with an iatrogenic miscarriage rate of less than two per 1,000) and costs, this can serve to avert the larger harm of parents being provided incorrect results.
1302
Adams et al
Look Before You Leap
BRCA1 and BRCA2 Screening The consequences of BRCA1 and BRCA2 screening are very different. A deleterious mutation in either of these genes potentially corresponds to a 45–84% lifetime risk of breast cancer and a 11–62% lifetime risk of ovarian cancer.6 Therefore, positive results of BRCA1 and BRCA2 testing indicate referral to a specialist, frequently to a comprehensive cancer center. The follow-up recommendations are for intensive surveillance consisting of frequent clinical breast examinations, annual breast MRI and mammograms, transvaginal ultrasound scans and CA-125 testing, possible risk-reducing double mastectomy, and bilateral salpingo-oophorectomy. Chemoprevention with oral contraceptives or tamoxifen may also be offered. The costs of screening a large fraction of the U.S. female population for BRCA1 and BRCA2 mutations are staggering. Even assuming the cost of the genetic sequencing itself could be substantially reduced (current costs are approximately $2,000–$4,000), the costs of breast and ovarian cancer surveillance with the associated callbacks, needle biopsies or laparoscopies, and other physician visits could cost billions of dollars a year given the size of the proposed screening program (potentially 80,000,000 women or more), the number of women who could screen positive (including approximately 4,000,000 false-positive results if “likely pathogenic” variants are reported), and costs of these procedures. Because of the relatively small number of women that could benefit from this approach (the combined general population prevalence of pathogenic BRCA1 and BRCA2 mutations is under 1%), any false-positive results will reduce potential cost-savings of averting cancer morbidity and mortality. Beyond the costs to society in screening every woman for BRCA1 and BRCA2 gene mutations, we must consider the individual patient. Here, incorrect positive results can be devastating. Positive results can have implications in almost every area of a woman’s life with particular effect on reproductive decisions including salpingo-oophorectomy. If a woman is considering using assistive reproductive technologies including in vitro fertilization or oocyte cryopreservation, decisions must be made about whether to have preimplantation genetic diagnosis of embryos for the same BRCA1 and BRCA2 mutation with transfer of only unaffected embryos. A woman may also face genetic discrimination. Although the U.S. Genetic Information Non Discrimination Act protects against genetic discrimination in health insurance and many places of employment, the law does not protect
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Fig. 2. Potential screening algorithms for women who desire aneuploidy screening. The American College of Obstetricians and Gynecologists (the College) does not recommend noninvasive prenatal testing as first-line screening in low-risk women, but those who test positive with traditional screening become high risk, and the high-risk algorithms should be evaluated. Noninvasive prenatal tests are evolving, but current costs and inability to detect as wide a variety of chromosomal abnormalities as invasive testing should be considered. Red dashed arrows indicate a possible course of action. *First-trimester combined screening, second-trimester maternal serum screening, or a combination. †Positive predictive value of traditional screening is often less than 5%. ‡Noninvasive prenatal testing is more costly than traditional screening. §Ultrasonography for structural anomaly, nuchal translucency, cystic hygroma, or multiple gestation. Adams. Look Before You Leap. Obstet Gynecol 2015.
against discrimination in life, long-term care, or disability insurance. Importantly, there is no gold standard confirmatory test for BRCA1 and BRCA2 mutations. In the case of chromosomal abnormality testing with noninvasive prenatal testing, we can avert substantial negative downstream consequences of a false-positive screening test result with an invasive test; this is not possible with BRCA1 and BRCA2 screening. Unnecessary aggressive surveillance or surgical intervention will likely grow substantially if lowrisk women are screened.
DISCUSSION No medical test is perfect, and genetic tests are no exception. Even the high specificity associated with genetic tests does not overcome the problem of
VOL. 125, NO. 6, JUNE 2015
screening for uncommon conditions. Positive results must be interpreted cautiously. We suggest that counseling for patients considering noninvasive prenatal testing include: • Noninvasive prenatal testing is a screening test for the most common chromosomal abnormalities (trisomies 21, 13, 18), but not all chromosomal abnormalities; • Noninvasive prenatal testing is a screening test only, and any positive results must be confirmed by a definitive test (eg, amniocentesis or chorionic villus sampling); and • Standard screening for chromosomal abnormalities is much less expensive than noninvasive prenatal testing. If a positive test is confirmed with invasive testing, a wider variety of genetic conditions
Adams et al
Look Before You Leap
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1303
including rare trisomies and deletions and duplications might be found compared with noninvasive prenatal testing. However, standard screening is much more likely to produce false-positive results. We suggest that counseling for patients regarding BRCA1 and BRCA2 testing include: • BRCA1 and BRCA2 are genes that, when deleterious mutations are present, substantially increase the risk of both breast and ovarian cancer as well as other cancers. Standard management exists that can substantially reduce the risk of disease-specific morbidity and mortality through enhanced surveillance or risk reduction surgery; • A family history of cancer should be taken on every patient. If this cancer history includes a patterns suggestive of substantial family cancer history,6 then referral to a clinical geneticist and genetic counselor is indicated. Diagnostic testing should be ordered by health care providers with specific expertise in risk assessment; and • Testing of BRCA1 and BRCA2 or larger breast cancer panels in the absence of family or personal history is not recommended, because there is substantial increased risk of false-positive results, increased cost and intervention, and there are no data currently available demonstrating that the benefit of routine testing in low-risk population exceeds the risks. If ob-gyns are going to successfully incorporate additional genetic screening into their practices, they must be adequately trained. We believe that increased obstetrics and gynecology residency training in genetics will assist future health care providers to both counsel their patients appropriately and improve the lives of the patients and families for whom they provide care. This training should cover the applications and limitations of genetic tests. Innovative, sustainable educational methods in genetics training for all clinical providers are needed. The Council on Resident Education in Obstetrics and Gynecology should consider using models in medical education that other fields have used. The Surgical Council on Resident Education curriculum (www.surgicalcore.org) used in general surgery residencies is a leading alternative model. This is an online education portal in which residents watch videos, read prepared chapters, and answer questions to test their knowledge. Another potential model is the obstetrics and gynecology–specific PearlCasts found on YouTube for medical student education. Creation of a standardized, online curriculum for genetics education in obstetrics and gynecology residency could occur by partnering the College, the Association of
1304
Adams et al
Look Before You Leap
Professors of Gynecology and Obstetrics, and the American College of Medical Genetics to develop specific genetics modules. Support for such efforts could potentially be found through partnering with a variety of genetics advocacy organizations and nonprofit foundations already working in obstetrics and gynecology. To maintain this base of genetics knowledge, the American Board of Obstetrics and Gynecology could include a more robust genetics component in the Maintenance of Certification required of its diplomats. Proposed noninvasive prenatal testing and BRCA1 and BRCA2 universal screening programs are just two examples of potential genetic screening tests. If these or others are to become widespread, we must do more to ensure that every ob-gyn is prepared to appropriately navigate the complex situations genetic screening creates. REFERENCES 1. King M, Levy-Lahad E, Lahad A. Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award. JAMA 2014;312: 1091–2. 2. Bianchi DW, Parker RL, Wentworth J, Madankumar R, Saffer C, Das AF, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014;370:799–808. 3. Norton ME, Jelliffe-Pawlowski LL, Currier RJ. Chromosome abnormalities detected by current prenatal screening and noninvasive prenatal testing. Obstet Gynecol 2014;124:979–86. 4. Bellcross CA, Kolor K, Goddard KAB, Coates RJ, Reyes M, Khoury MJ. Awareness and utilization of BRCA1/2 testing among U.S. primary care physicians. Am J Prev Med 2011; 40:61–6. 5. Cleary-Goldman J, Morgan MA, Malone FD, Robinson JN, D’Alton ME, Schulkin J. Screening for Down syndrome: practice patterns and knowledge of obstetricians and gynecologists. Obstet Gynecol 2006;107:11–7. 6. Daly MB, Pilarski R, Axilbund JE, Buys SS, Crawford B, Friedman S, et al. Genetic/familial high-risk assessment: breast and ovarian, version 1.2014. J Natl Compr Cancer Netw 2014; 12:1326–38. 7. Gabai-Kapara E, Lahad A, Kaufman B, Friedman E, Segev S, Renbaum P, et al. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci 2014;111:14205–10. 8. Ayres AC, Whitty JA, Ellwood DA. A cost-effectiveness analysis comparing different strategies to implement noninvasive prenatal testing into a Down syndrome screening program. Aust N Z J Obstet Gynaecol 2014;54:412–7. 9. Dar P, Curnow KJ, Gross SJ, Hall MP, Stosic M, Demko Z, et al. Clinical experience and follow-up with large scale singlenucleotide polymorphism-based noninvasive prenatal aneuploidy testing. Am J Obstet Gynecol 2014;211:527.e1–17. 10. Wilson JMG, Jungner G; World Health Organization. Principles and practice of screening for disease. 1968. Available at: http://apps.who.int//iris/handle/10665/37650. Retrieved February 21, 2015. 11. Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, et al. ACMG recommendations for standards for
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10:294–300. 12. Pruss D, Morris B, Hughes E, Eggington JM, Esterling L, Robinson BS, et al. Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. Breast Cancer Res Treat 2014;147: 119–32. 13. Tavtigian SV, Greenblatt MS, Goldgar DE, Boffetta P; IARC Unclassified Genetic Variants Working Group. Assessing pathogenicity: overview of results from the IARC Unclassified Genetic Variants Working Group. Hum Mutat 2008;29:1261–4. 14. Rahman N. Realizing the promise of cancer predisposition genes. Nature 2014;505:302–8. 15. Couch FJ, Wang X, McGuffog L, Lee A, Olswold C, Kuchenbaecker KB, et al. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet 2013;9:e1003212.
16. Murray ML, Cerrato F, Bennett RL, Jarvik GP. Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: variant reclassification and surgical decisions. Genet Med 2011;13:998–1005. 17. Lindor NM, Goldgar DE, Tavtigian SV, Plon SE, Couch FJ. BRCA1/2 sequence variants of uncertain significance: a primer for providers to assist in discussions and in medical management. Oncologist 2013;18:518–24. 18. Kuppermann M, Pena S, Bishop JT, Nakagawa S, Gregorich SE, Sit A, et al. Effect of enhanced information, values clarification, and removal of financial barriers on use of prenatal genetic testing: a randomized clinical trial. JAMA 2014;312:1210–7. 19. Grati FR, Barlocco A, Grimi B, Milani S, Frascoli G, Di Meco AM, 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 A 2010;152A:1434–42.
Author Instructions on Editorial ManagerTM Visit http://ong.editorialmanager.com for answers to your submission questions
Documents available online include: s)NSTRUCTIONSFOR!UTHORS s3UBMISSION#HECKLISTAND!UTHOR!GREEMENT sGuide to Writing for Obstetrics & Gynecology sh3UBMISSION'UIDELINES!T ! 'LANCEv s2EFERENCEFORMATTINGINSTRUCTIONS s3AMPLEPATIENTCONSENTFORM sh7HATTO%XPECT!FTER3UBMISSIONv 1UESTIONS #ALLTHE%DITORIAL/FlCEAT
VOL. 125, NO. 6, JUNE 2015
Adams et al
rev 11/2014
Look Before You Leap
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1305
