Noninvasive Prenatal Cell-Free Fetal DNA Based Screening for Aneuploidies Other Than Trisomy 21
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Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 EXECUTIVE SUMMARY Background Fetal chromosomal abnormalities occur in approximately 1 in 160 live births. The majority of fetal chromosomal abnormalities are autosomal aneuploidies, defined as an abnormal number of autosomes. The trisomy syndromes are aneuploidies involving 3 copies of 1 chromosome. Trisomy 21 (T21; Down syndrome) is the most common fetal aneuploidy that is associated with survival to birth and beyond. Trisomy 18 (T18; Edwards syndrome) and trisomy 13 (T13; Patau syndrome) are the next most common fetal aneuploidy syndromes associated with survival to birth, although the percentage of cases surviving to birth is low and survival beyond birth is limited. Maternal age is the most important risk factor for T21, T18, and T13, with an approximate risk of 1:1600 at age 15 and1:28 by age 45. Sex chromosome aneuploidies (SCA; eg, 45, X; 47, XXY; 47, XYY) may occur in 1 of 400 live births, which makes them more common than individual autosomal aneuploidies. Turner syndrome (45, X) is a relatively common SCA that may be suspected prenatally based on fetal ultrasound findings, which may include nuchal translucency, and cardiac abnormalities plus abnormal serum biomarker levels (elevated human chorionic gonadotropin and inhibin, decreased alpha-fetoprotein, and unconjugated estriol levels). However, well-defined maternal serum biomarkers and algorithms for a prenatal screen for specific SCA, as for T21 or other autosomal aneuploidies, are not reported. SCA are usually diagnosed postnatally, in association with specific health problems, including diminished fertility or infertility. They also may be detected by karyotyping fetal cells obtained via amniocentesis or chorionic villus sampling (CVS) in pregnant women. However, the clinical significance of diagnosing an SCA is not entirely clear. Current guidelines recommend that all pregnant women be offered screening for T21 before 20 weeks of gestation, regardless of age. Screening programs may also detect T18 or T13. Noninvasive screening typically involves combinations of maternal serum markers and fetal ultrasound at various stages of pregnancy, but a standard approach is not defined. The detection rate for T21 using various combinations of noninvasive tests ranges from 60% to 96% when the false-positive rate is set at 5%, although the false- positive rate may be set lower for the rarer aneuploidies. Currently, noninvasive screening tests are not sufficiently specific to diagnose a trisomy syndrome, so confirmatory karyotyping is required. Given the low prevalence of trisomy syndromes, most patients who are recommended for confirmatory, invasive prenatal diagnostic procedures (eg, amniocentesis and CVS) have normal results. Direct karyotyping of fetal tissue obtained by amniocentesis (second trimester) or CVS (first trimester) is required to confirm the diagnosis of trisomy. Both amniocentesis and CVS are invasive procedures and have a small risk of miscarriage. A screening strategy minimizing amniocentesis and CVS procedures (and thus associated miscarriage) and increasing detection of aneuploidies has potential to improve outcomes. Volume 29, No. 7 Publication Date: December 2014 Page: 1 http://www.bcbs.com/blueresources/tec/vols/ Notice of Purpose: TEC Assessments and Special Reports are scientific opinions, provided solely for informational purposes. TEC Assessments and Special Reports should not be construed to suggest that Blue Cross Blue Shield Association or the TEC Program recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service; any particular course of treatment, procedure, or service; or the payment or nonpayment of the technology or technologies evaluated. Blue Cross Blue Shield Association is an association of independent Blue Cross and Blue Shield companies. © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 As early as 8 to 10 weeks of gestation, cell-free fetal DNA fragments (derived from the cytotrophoblastic cell layer of the placenta) may comprise 6% to 10% or more of the total cell-free DNA in a maternal plasma sample. As detailed in a 2012 TEC Assessment, DNA sequencing, particularly massively parallel sequencing (MPS; also known as next-generation or “next-gen” sequencing) is highly accurate for prenatal detection of T21. The methods used to screen for T21 using MPS have been extended to other less common aneuploidies (primarily T13 and T18), as well as the most common SCA (45, X; 47, XXY; 47, XYY). Objective To determine whether DNA sequencingbased testing for T13, T18, and SCA using cell-free fetal DNA improves net health outcomes compared with a traditional combined serum- and ultrasound-based screening strategy. In the analysis, we presume that a decision to screen for fetal aneuploidy would initially focus on T21 and that downstream events related to T21 screening will hold for screening for T13, T18, or SCA. Search Strategy PubMed and EMBASE databases were searched for articles published between January 1, 2009, and June 23, 2014, limited to English-language publication in human populations. Several search terms were combined, such as “trisomy,” “aneuploidy,” “sequencing,” “prenatal diagnosis,” “chromosome 18 or 13,” and “cell-free DNA.” Selection Criteria Included studies had the following characteristics: (1) performed maternal cell-free fetal DNA testing of pregnant women being screened for T18, T13, and SCA; (2) used a sequencing assay that is clinically available or applied clinical laboratory quality control measures; (3) compared the results of cell-free fetal DNA testing with the results of karyotype analysis (or fluorescence in situ hybridization if karyotype is not possible in individual cases), or with phenotype at birth; and (4) reported information on sensitivity and specificity, or provided sufficient information to calculate these parameters. Main Results We sought to determine the analytical and clinical validity and clinical utility of cell-free fetal DNAbased screening for fetal aneuploidies T13, T18, and SCA. We identified 29 published articles that described results of cell-free fetal DNA sequencingbased screening using one of several tests. Studies reported results for T13 (N=16,927 patients screened), T18 (N=32,554 patients screened), monosomy X (N=8994 patients screened), and other SCA (N=6449 patients screened) in high-risk (age >35) and average-risk (pregnant women who elect screening) cohorts. Maternal study populations were described or we inferred them to be: high risk for fetal aneuploidies in 21 of 29 (72%) studies; average risk in 6 (21%); mixed risk in 1 (3.5%); and not reported in 1 (3.5%). Among studies of T13 screening, 15 reported results in women deemed high risk for fetal aneuploidy (n=13,680) and 3 reported results in average-risk women (n=2144). For T18, 16 studies included women at high risk (n=16,694), and 6 included average-risk women (n=14,757). After assessing the quality of individual published studies using the QUADAS-2 tool, we pooled sensitivity and specificity estimates of fetal DNA‒based testing (all tests compiled), stratified according to maternal risk level (high or average). To address statistical issues in pooling studies with 1 or just a few cases, we pooled studies that included 5 or more cases (see Table A). The approach removed most studies in the average-risk population; however, it had little effect on the overall pooled estimates. The detection rates for T13 ranged from 76% to 92%; for T18, they ranged from 91% to 97%. The pooled specificity for either T13 or T18 was nearly 100%. The detection rates for the SCA ranged from 77% to 91%, with specificity nearly 100%. Volume 29, No. 7 Publication Date: December 2014 Page: 2 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 Table A. Meta-Analysis Results of Cell-Free Fetal DNA‒Based Test Screen Performance Sensitivity Specificity Pooled Estimate Normal Pooled Estimate 2 2 Aneuploidy Studies Cases FN (95% CI) I,% (N) FP (95% CI) I,% T13 7 95 8 0.86 (0.76 to 0.92) 0 8724 20 0.99 (0.99 to 1.00) 0 T18 15 392 10 0.95 (0.91 to 0.97) 0 22,754 15 1.00 (0.99 to 1.00) 68 Monosomy X 14 137 14 0.86 (0.79 to 0.92) 0 5286 15 1.00 (0.99 to 1.00) 0 Other SCA 5 37 1 0.91 (0.77 to 0.97) 0 4643 3 1.00 (0.99 to 1.00) 39 2 CI: confidence interval; FN: false negatives; FP: false positives; I : measure of statistical heterogeneity; SCA: sex chromosome aneuploidies. Table B shows posttest probabilities calculated for cell-free fetal DNA‒based testing for T13 and T18. These calculations show that a screen-positive result will require karyotype analysis to confirm or rule out the presence of T13 or T18. A negative finding reflects an exceedingly low probability for the presence of aneuploidy, sufficient to preclude the need for a diagnostic karyotype. Table B. Posttest Probabilities of Aneuploidy Following Cell-Free Fetal DNA‒Based Screening Test Prevalence/ Prevalence Positive Probability After Negative Probability After Risk Per 100,000 Likelihood Ratio Positive Test Likelihood Ratio Negative Test High T13 60 86 0.049 0.14 0.00008 T18 170 95 0.14 0.05 0.00009 Average T13 13 86 0.011 0.14 0.00002 T18 40 95 0.037 0.05 0.00002 We constructed a simple decision model to assess cell-free fetal DNA‒based screening compared with a standard integrated screen for T13 and T18. The model presumes that screening for T21 is performed concurrently and that amniocentesis or CVS with karyotype analysis subsequent to non-sequencing- based screening is prompted by the desire to detect T21. This model assumes that invasive procedures of amniocentesis or CVS and any resulting miscarriages are not a consequence of T13 or T18 screening. We did not model case detection rates for SCA owing to difficulty defining health outcomes for SCA identification. The strategies examined in the model include: a. a traditional integrated screen (first plus second trimester serum testing and nuchal translucency ultrasound) test followed, if positive, with an invasive procedure (CVS in the first trimester or amniocentesis in the second trimester) for confirmatory karyotyping; and b. cell-free fetal DNAbased testing in place of traditional serum screening; if positive, confirm with invasive procedure and karyotyping. The outcomes of interest are the number of cases of T13 or T18 correctly identified and the number of cases missed. The results were calculated for a high-risk population of women age 35 or older, and for an average-risk population including women of all ages electing an initial screen. For women who tested positive on initial screen and were offered an invasive confirmatory procedure, we assumed 75% of high- risk and 50% of average-risk women would proceed to an invasive test after a positive screen. We varied sensitivities and specificities for both standard and cell-free fetal DNA‒based screening tests to represent a plausible range of possible values. For either high- or average-risk women, our results suggest that a strategy of screening by sequencing- based assay followed by confirmatory diagnostic karyotype testing generally detects at least the same if Volume 29, No. 7 Publication Date: December 2014 Page: 3 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 not more T13 and T18 cases and misses fewer than does a traditional integrated screen followed by a diagnostic invasive karyotype analysis. This relationship held whether we obtained estimates using pooled sequencing performance parameters specific to T13 and T18 or performance parameters similar to the more prevalent T21 (not shown). Although fewer T13 and T18 cases are detected than T21 because prevalences of the former are lower than T21, base case estimates show detection of high proportions of cases for both populations (98%, respectively) using the sequencing to invasive testing strategy. In high-risk women, eg, for T13, T18, and T21 combined, the number of cases missed with integrated screening followed by invasive testing and karyotyping (40/884 [4.5%] maximum cases) falls to 19 of 884 (2.1%) (see Table 6 in the body of the Assessment). It follows that the number of invasive procedures needed and the number of total miscarriages after an invasive confirmatory karyotype procedure in this population would be reduced commensurately. The numbers derived for the average-risk population would be expected to be consistent in direction and magnitude of change with those for high-risk women. Author Conclusions and Comment This Assessment addressed the analytic and clinical validity and clinical utility of cell-free fetal DNA-based testing for T13, T18, and SCA compared with traditional screening procedures. Little direct evidence exists on analytic validity. The commercially available tests are offered as laboratory-developed tests subject to laboratory operational oversight under the Clinical Laboratory Improvement Act (CLIA). In recent years, recommendations for good laboratory practices for ensuring the quality of molecular genetic testing for heritable diseases and conditions under CLIA have been published. However, next-generation sequencing technology is becoming more common in the clinical laboratory, and regulatory and professional organizations are addressing important issues of methods standardization. Numerous studies of cell-free fetal DNA‒based assay performance relative to the reference standard of karyotyping in high- and average-risk populations are available. Some are multisite studies that have incorporated specimen collection, transport, and evaluation under conditions simulating real-world clinical testing. Our assessment of overall study quality indicated a low risk of bias, except in the domain of patient selection. In general, assays from all companies currently offering fetal trisomy screening by sequencing cell-free fetal DNA in maternal plasma show high sensitivity and specificity for T13, T18, and SCA. False-positive rates were relatively consistent across the prevalence rates for the aneuploidies. Calculated posttest probabilities for a negative T13 or T18 test were exceedingly small. Thus, the clinical validity of sequencing-based cell-free fetal DNA screening appears to be well defined for T13, T18, and SCA. To examine clinical utility requires a comparison with current screening practices and evaluation of the impact of screening on health outcomes. We did not identify direct comparative evidence of outcomes, so we performed a decision analysis model exercise to estimate the number of cases detected and cases missed using prevalence data from the literature; summarized data on cell-free fetal DNA assay performance for T13 and T18; and published data on traditional screening performance and patient uptake of confirmatory test procedures. Our findings indicate that for pregnant women undergoing aneuploidy screening, a strategy of using a cell-free fetal DNA‒based screening test followed by confirmation of positive test results with an invasive procedure (amniocentesis or CVS) to determine fetal karyotype detected an equivalent or larger proportion of fetal T13 or T18 and missed fewer cases than a strategy employing the traditional integrated screen followed by amniocentesis or CVS diagnosis. Given that T13 and T18 cell-free fetal DNA‒based tests will be performed along with T21 testing, the number of invasive procedures and miscarriages secondary to an invasive diagnostic procedure will be reduced with the cell-free fetal DNA‒based strategy (based on the conclusions of the 2012 TEC Assessment examining T21). The nearly null posttest Volume 29, No. 7 Publication Date: December 2014 Page: 4 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 probability of a negative sequencing-based screen T18 and T13 provides assurance to pregnant women in any risk category that a negative screen minimizes any need (except as indicated by abnormal ultrasound—eg, nuchal cord translucency, cystic hygroma) for a subsequent invasive diagnostic karyotype test and negates accompanying risks for fetal loss. Cell-free fetal DNA‒based testing without confirmatory karyotype analysis carries a risk of misidentifying normal pregnancies as positive for a trisomy syndrome due to the small false-positive rate together with the low baseline prevalence of T13, T18, and SCA in all populations. The false-positive rates of sequencing-based tests appear lower than those of traditional serum- and ultrasound-based screening tests. However, cell-free fetal DNA‒based testing does not eliminate the necessity of ultrasound studies. The first trimester ultrasound scan is required to confirm gestational age and to determine whether the pregnancy is multiple, findings that provide necessary information for sequencing-based testing of cell- free fetal DNA. Ultrasound examination that details fetal anatomy in the second trimester is important for fetal risk assessment, and may provide indications of chromosomal abnormalities not currently detected by cell-free fetal DNA sequencingbased tests. Cell-free fetal DNAbased testing is also not a replacement for second trimester maternal screening for risk of neural tube defects. Finally, we did not compare all potential screening strategies such as serum screening and ultrasound followed by cell-free fetal DNA or cell-free fetal DNA plus subsequent serum screening and ultrasound to examine which might be optimal. SUMMARY OF APPLICATION OF THE TECHNOLOGY EVALUATION CRITERIA Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel (MAP) made the following judgments about whether DNA sequencingbased testing of cell-free fetal DNA meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria to screen expecting women for fetal trisomy syndromes 13 (T13), 18 (T18), and sex chromosome aneuploidies (SCA). 1. The technology must have final approval from the appropriate governmental regulatory bodies. None of the commercially available sequencing assays for T13, T18, or SCA has been submitted to or reviewed by the U.S. Food and Drug Administration (FDA). Clinical laboratories may develop and validate tests in-house (laboratory-developed tests [LDTs]; previously called “home-brew”) and market them as a laboratory service; LDTs must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Laboratories offering LDTs must be licensed by CLIA for high-complexity testing. 2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes. Although we identified no direct evidence for the analytical validity of the massively parallel cell-free fetal DNA sequencing assays that are commercially available, they are subject to laboratory operational oversight under CLIA. Recommendations for good laboratory practices to ensure the quality of molecular genetic testing for heritable diseases and conditions under CLIA have been published. Furthermore, next- generation sequencing technology is becoming more common in the clinical laboratory, and regulatory and professional organizations are addressing important issues of methods to standardize the use of this technology. Therefore we have reason to conclude the analytical validity is sufficient to support use of the available tests for the purposes described in this Assessment. A body of 29 individual publications provides sufficient evidence to establish the clinical validity (sensitivity and specificity vs criterion reference of karyotype analysis) of the available screening tests for T13, T18, Volume 29, No. 7 Publication Date: December 2014 Page: 5 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 and SCA. Among studies of T13 screening, 15 reported results in women deemed high risk (age >35) for fetal aneuploidy (n=13,680) and 3 reported results in average-risk (pregnant women who elect screening) (n=2144) populations. For T18, 16 studies included women at high risk (n=16,694), and 6 included average-risk women (n=14,757). We identified no direct comparative evidence that use of any of the cell-free fetal DNA‒based tests alters clinical management compared with other screening strategies. To address clinical utility, we conducted a decision-modeling exercise to compare T13 and T18 case detection rates using either a cell-free fetal DNA‒based screen followed by invasive diagnostic karyotype confirmation of screen-positives or a traditional integrated maternal serum- and ultrasound-based screen followed by the same invasive diagnostic karyotype analysis. The decision model showed that the cell-free fetal DNA‒based strategy was at least equivalent, but generally superior to, a traditional screening strategy, using 2 different sets of cell-free fetal DNA test sensitivity and specificity estimates, thus indirectly supporting the clinical utility of the tests for T13 and T18. We did not model SCA in our analysis because the balance of benefits and harms of a positive cell-free fetal DNA‒based prenatal screen and subsequent karyotype diagnosis of an SCA—each of which has variable and uncertain prognosis and management—is unclear. Although evidence supports the accuracy of cell-free fetal DNA‒based test performance for SCA, we could not determine an effect of cell-free fetal DNA‒based screening on net health outcomes. Therefore, evidence on clinical utility is insufficient to draw conclusions for these aneuploidies. 3. The technology must improve the net health outcome. Noninvasive cell-free fetal DNA sequencing‒based screening for T13 or T18 will improve the net health outcome when used in a strategy that includes a sequencing-based screen followed by invasive diagnostic karyotype analysis in those who are screen-positive. Thus, compared with a standard integrated screening strategy, the number of invasive procedures, possible miscarriages secondary to an invasive diagnostic procedure, and the number of affected births will be reduced with the cell-free fetal DNA‒based strategy for T13 and T18. Furthermore, the nearly null posttest probability of a negative cell- free fetal DNA‒based screening test result provides assurance to pregnant women, in any risk category, that a negative screen obviates the need for a subsequent invasive diagnostic test and negates associated downstream risks. We did not include SCA in the decision analysis, because the implications of a screen-positive finding and diagnostic confirmation differ significantly from those of T13 and T18. The balance of benefits and harms of a positive cell-free fetal DNA‒based prenatal screen and subsequent diagnosis of SCA, each of which has variable and uncertain prognosis, is unclear. 4. The technology must be as beneficial as any established alternatives. A decision model showed that the use of sequencing-based cell-free fetal DNA screening increased the number of detected cases of T13 and T18, with commensurate reduction of missed cases, compared with standard integrated screening procedures for those parameters, in high- and average-risk (general obstetric) populations of pregnant women. Evidence is insufficient to determine the clinical benefit of cell-free fetal DNA‒based screening for SCA compared with traditional tests. 5. The improvement must be attainable outside the investigational settings. A number of studies were conducted by third-party investigators at multiple clinical locations (13-60 sites) in the United States and other countries; all companies’ assays were represented and samples were sent Volume 29, No. 7 Publication Date: December 2014 Page: 6 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 to company laboratories for cell-free fetal DNA testing, as would occur for routine clinical test orders. Thus, the test performance leading to improved overall screening outcomes should be attainable outside the investigational settings. Based on the above, Sequencing-based analysis of cell-free fetal DNA obtained from maternal plasma to screen for the presence of fetal T13 or T18—followed by diagnostic karyotype analysis of screen-positive results—in either high-risk or average-risk pregnant women being screened for fetal autosomal aneuploidies meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria. Sequencing-based analysis of cell-free fetal DNA obtained from maternal plasma to screen for the presence of fetal sex chromosome aneuploidies in pregnant women being screened for fetal aneuploidies does not meet the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria. Volume 29, No. 7 Publication Date: December 2014 Page: 7 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 AUTHORS, STAFF, AND MEDICAL ADVISORY PANEL TEC Staff Contributors Lead Author: Thomas A. Ratko, Ph.D.; Co-Author: Ryan D. Chopra, M.P.H. Executive Director, Center for Clinical Effectiveness: Suzanne E. Belinson, Ph.D., M.P.H. Executive Director, Clinical Evaluation, Innovation, and Policy: Naomi Aronson, Ph.D. Director, Technology Assessment: Mark D. Grant, M.D., Ph.D. Research/Editorial Staff: Claudia Bonnell, R.N., M.L.S., Kimberly Hines, M.S., Michael Vasko, M.A. Blue Cross Blue Shield Association Medical Advisory Panel Chair Trent T. Haywood, M.D., J.D., Senior Vice President, Clinical Affairs/Medical Director, Blue Cross Blue Shield Association Vice Chair Suzanne E. Belinson, Ph.D., M.P.H., Executive Director, Center for Clinical Effectiveness, Blue Cross Blue Shield Association Scientific Advisors Steven N. Goodman, M.D., M.H.S., Ph.D., Dean for Clinical and Translational Research, Stanford University School of Medicine, and Professor, Departments of Medicine, Health Research and Policy Mark A. Hlatky, M.D., Professor of Health Research and Policy and of Medicine (Cardiovascular Medicine), Stanford University School of Medicine; American College of Cardiology Appointee Panel Members Peter C. Albertsen, M.D., Professor, Chief of Urology, and Residency Program Director, University of Connecticut Health Center Ann Boynton, Deputy Executive Officer, Benefits Programs Policy and Planning, CalPERS Virginia Calega, M.D., M.B.A., F.A.C.P., Vice President, Medical Management and Policy, Highmark Inc. Sarah T. Corley, M.D., F.A.C.P., Chief Medical Officer, NextGen Healthcare Information Systems Inc.; American College of Physicians Appointee Helen Darling, M.A., Strategic Advisor, National Business Group on Health Josef E. Fischer, M.D., F.A.C.S., William V. McDermott Professor of Surgery, Harvard Medical School; American College of Surgeons Appointee Lee A. Fleisher, M.D., Professor and Chair, Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Senior Fellow, Leonard Davis Institute of Health Economics I. Craig Henderson, M.D., Adjunct Professor of Medicine, University of California, San Francisco Jo Carol Hiatt, M.D., M.B.A., F.A.C.S., Chair, Inter-Regional New Technology Committee, Kaiser Permanente Saira A. Jan, M.S., Pharm.D., Associate Clinical Professor, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Residency Director and Director of Clinical Programs Pharmacy Management, Horizon Blue Cross and Blue Shield of New Jersey Lawrence Hong Lee, M.D., M.B.A., F.A.C.P., Vice President and Executive Medical Director for Quality and Provider relations, Blue Cross and Blue Shield of Minnesota Bernard Lo, M.D., President, The Greenwall Foundation Randall E. Marcus, M.D., Charles H. Herndon Professor and Chairman, Department of Orthopaedics, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio Barbara J. McNeil, M.D., Ph.D., Ridley Watts Professor and Head, Department of Health Care Policy, Harvard Medical School; Professor of Radiology, Brigham and Women's Hospital William R. Phillips, M.D., M.P.H., T.J. Phillips Endowed Professor in Family Medicine, University of Washington; American Academy of Family Physicians Appointee Rita F. Redberg, M.D., M.Sc., F.A.C.C., Professor of Medicine and Director, Women's Cardiovascular Services, University of California San Francisco Maren T. Scheuner, M.D., M.P.H., F.A.C.M.G., Chief, Medical Genetics, VA Greater Los Angeles Healthcare System; Professor, Department of Medicine, David Geffen School of Medicine at UCLA, Affiliate Natural Scientist, RAND Corporation; American College of Medical Genetics and Genomics Appointee Leslie Robert Schlaegel, M.S., Associate Vice President of Human Resources, Stanford University J. Sanford Schwartz, M.D., F.A.C.P., Leon Hess Professor of Medicine and Health Management & Economics, School of Medicine and The Wharton School, University of Pennsylvania John B. Watkins, Pharm.D., M.P.H., B.C.P.S., Pharmacy Manager, Formulary Development, Premera Blue Cross Volume 29, No. 7 Publication Date: December 2014 Page: 8 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 ASSESSMENT OBJECTIVE The overall objective of this Assessment is to determine whether DNA sequencingbased testing to screen for trisomy 13 (T13), trisomy 18 (T18), and sex chromosome aneuploidies (SCA) using cell-free fetal DNA improves net health outcomes compared with a traditional serum- and ultrasound-based integrated screening strategy. Commercial, noninvasive, cell-free fetal DNA‒based testing of maternal plasma for T13, T18, and SCA has recently become available and has the potential to substantially alter screening strategies for these anomalies. Current noninvasive testing strategies have suboptimal accuracy and imperfect specificity, the latter of which results in low positive predictive values. As a result, many invasive procedures are required to identify a small number of pregnancies with T13, T18, and SCA. More accurate screening tests could improve the efficiency and accuracy of screening and reduce unnecessary invasive procedures. In this Assessment, cell-free fetal DNA‒based testing for T13 and T18 is compared with a current integrated strategy for screening, which comprises noninvasive maternal serum biomarkers and fetal ultrasound examination. We assumed that screening for trisomy 21 (T21) is performed as the priority and that amniocentesis or chorionic villous sampling (CVS) subsequent to non-sequencing-based screening is performed to detect T21. Based on these assumptions, we did not consider amniocentesis or CVS and any resulting miscarriages to be a consequence of T13 or T18 screening. Relevant clinical outcomes will include detection rates for T13 or T18, and number of cases missed using each strategy. To estimate these rates, we estimated test sensitivity and specificity using meta-analysis and the reference standard of invasive tissue sampling and karyotyping. The sensitivity and specificity will be used in a decision model incorporating existing data to estimate rates of detected and missed cases. BACKGROUND Fetal Trisomy Syndromes Fetal chromosomal abnormalities occur in approximately 1 in 160 live births. A majority of fetal chromosomal abnormalities are aneuploidies, defined as an abnormal number of chromosomes a (autosomes or sex chromosomes). Trisomy syndromes are autosomal aneuploidies involving 3 copies of 1 chromosome. T21 (Down syndrome) is the most common form of fetal aneuploidy associated with survival to birth and beyond. T18 (Edwards syndrome) and T13 (Patau syndrome) are the next most common fetal aneuploidy syndromes associated with survival to birth, although the percentage of cases 1 surviving to birth is low and survival beyond birth is limited. Trisomy may result from failure of chromosomal pairs to separate during meiosis (“nondisjunction”) or less b often from a Robertsonian translocation either way. The result is 3 copies of a chromosome rather than 2 a A euploid individual or cell has the normal number of chromosomes for that species. Humans have 46 chromosomes, 2 copies of each of 23 chromosomes, except for unfertilized egg and sperm cells, which have only 23 chromosomes or 1 copy of each. b A Robertsonian translocation is a type of nonreciprocal translocation that can occur in one of the acrocentric chromosomes, including chromosomes 13 and 21. During a Robertsonian translocation, the participating chromosomes break at their centromeres and the long arms fuse to form a single chromosome with a single centromere. The short arms may also fuse but are usually lost in subsequent cell divisions. A carrier of a Robertsonian translocation involving chromosome 13 or 21 is phenotypically normal, but the carrier’s progeny may Volume 29, No. 7 Publication Date: December 2014 Page: 9 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 after fertilization. Mosaic forms of trisomy may also occur, in which only some cells show trisomy and other cells are normal. The severity of the mosaic trisomy phenotype depends on the type and number of cells that have the extra chromosome. Maternal age is the most important risk factor for a trisomy syndrome. The proportion of pregnancies that occur with “advanced maternal age” has tripled over the last 30 years, to 14% of all pregnancies in the 2 United States. Prenatal screening for an autosomal trisomy began in the 1970s, when amniocentesis was first used to obtain fetal tissue for karyotyping from the amniotic fluid of mothers determined to be at high risk for T21 based on maternal age. Sex Chromosome Aneuploidy Trisomy of sex chromosomes also occurs; eg, 46 XXY (2 X plus 1 Y chromosomes) results in Klinefelter syndrome. SCA (eg, 45, X; 47, XXY; 47, XYY) may occur in 1 of 400 live births, which make them more common than individual autosomal aneuploidies. Turner syndrome (45, X) is a relatively common SCA that may be suspected prenatally based on fetal ultrasound findings, which may include nuchal translucency, cystic hygroma, and cardiac abnormalities, plus abnormal serum biomarker levels (elevated human chorionic gonadotropin and inhibin, decreased 3,4 alpha-fetoprotein and unconjugated estriol levels). However, well-defined algorithms screening for other specific SCA, as for T21 or other autosomal aneuploidies, are not reported. Because no maternal biomarkers exist to screen for specific SCA, they are usually diagnosed postnatally, in association with 4,5 specific health problems including diminished fertility or infertility. When SCA are diagnosed prenatally, they are often found incidentally, during invasive karyotype testing of pregnant women who are deemed at high risk for an autosomal aneuploidy. Because most women are screened and tested to exclude fetal T21-associated Down syndrome, diagnosis of an incidental SCA in an otherwise karyotypically normal fetus may present unanticipated findings to parents This is a key consideration because the clinical significance of an SCA may be unclear and ill-defined; many affected individuals in the end may not exhibit any relevant symptoms or will have only mild symptoms, including infertility, whereas others will be 5-7 affected to a greater, unpredictable extent. Unlike prenatal diagnosis of T13 or T18, prenatal diagnosis of an SCA may offer opportunity for early prevention and management of SCA-related disease, psychological issues, and fertility problems in the live-born child. Given that fetuses that carry an SCA typically survive to term—unlike those with T13 or T18—the considerations for use of sequencing-based prenatal screening findings are not necessarily the same. Screening for Autosomal Trisomies Other Than T21 Guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommend that all 8 pregnant women should be offered noninvasive screening for aneuploidies, particularly T21. Traditional noninvasive screening has involved combinations of maternal serum markers and fetal ultrasound performed at various stages of pregnancy, but a standard approach has not been defined. The most common serum T21 screening test consists of a panel of maternal markers. Maternal serum markers include alpha-fetoprotein, the free beta subunit of human chorionic gonadotropin (hCG), unconjugated estriol, and inhibin A (not used in the risk calculation for T18). Some screening strategies employ 3 of these markers (“triple screen,” not including inhibin A) while others incorporate all 4 (“quad screen”). These marker combinations are used for screening during the second trimester, in part, because first trimester screening became available after second trimester screening became common. inherit an unbalanced trisomy 13 or trisomy 21. Inherited translocations result in genetic counseling that is different from typical de novo cases of Down syndrome. Robertsonian translocations can also occur de novo and in total account for about 4% of all Down syndrome cases. Volume 29, No. 7 Publication Date: December 2014 Page: 10 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 Fetal ultrasound measures (nuchal cord translucency) are used to supplement the traditional maternal serum markers and to increase the performance characteristics of the screening test panels. However, specialized training is required to accurately determine nuchal translucency, and, as a result, the performance of this screening technique may vary. Review of observational studies, evaluating nuchal translucency screening in the general population, has revealed variation in reported Down syndrome 9 detection rates ranging from 29% to 91%. Other investigators have suggested that studies may be limited because scans were often carried by sonographers who were either inadequately trained or not 10 sufficiently motivated to measure nuchal translucency. This wide rate detection variation emphasizes the importance of training, measurement standardization, and ongoing quality control in screening programs. 11 Contemporary T21 screening programs may also be used to detect T13, T18, and SCA. In a large (N=36,171) study (FASTER), first trimester screening by cystic hygroma (present in ≥40% of fetuses with T13 and T18) or combined screening had a 78% detection rate for all non-Down syndrome aneuploidies, 11 with an overall false-positive rate of 6.0%. In the same study, the second trimester quadruple screen identified 69% of non-Down syndrome aneuploidies, at a false-positive rate of 8.9%. With the combined screen, the use of T18 risk factors did not detect any additional non-Down syndrome aneuploidies compared with the Down syndrome risk alone. In a position statement from the International Society for Prenatal Diagnosis (ISPD), the detection rate for various combinations of these measures for T13 and 12 T18 ranges from 60% to 96% in various studies when the false-positive rate is set at 5%. The sensitivity is highest when testing involves a “sequential” or “integrated” approach. Although noninvasive tests have improved since they first became available, they are not sufficiently sensitive or specific to diagnose any trisomy syndromes. Direct karyotyping of fetal tissue obtained by amniocentesis or CVS is required to confirm that a chromosomal abnormality is present. Karyotyping is the microscopic analysis of chromosomes prepared from cultured fetal cells at a stage when chromosomes are highly condensed. Large gains, losses, or exchanges (translocations) of chromosomal material can be detected. Both amniocentesis and CVS are invasive and have an associated risk of miscarriage. Amniocentesis is safest when performed between 15 and 20 weeks of gestation. The risk of pregnancy loss after mid-term amniocentesis is less than 1%, and has been estimated to be in the range 13 of 1 in 300 to 500 procedures at experienced centers. Other complications of amniocentesis include vaginal spotting with or without chorioamniotic leakage in 1% to 2% of cases and chorioamnionitis in 13 0.1% of cases. CVS can be performed earlier in pregnancy, most commonly at 10 to 12 weeks of gestation. This advantage of CVS may be offset by a higher rate of adverse events. The rate of pregnancy loss due to CVS is in the range of that for mid-term amniocentesis, though some estimates put the rate slightly 13 higher. An increased rate of limb defects may exist after CVS, but this association is controversial. Vaginal spotting or bleeding is common after the procedure, occurring in up to a third of cases. Amniotic fluid leakage with or without chorioamnionitis occur at a rate of less than 0.5%. The choice of screening strategy depends on factors such as maternal age, gestational age at first prenatal visit, previous obstetrical history, family history, availability of fetal ultrasound, parents’ risk 13 tolerance, and desire to undergo pregnancy termination if a trisomy syndrome is detected. A majority of women elect to have noninvasive testing performed, with a decision for invasive testing based on 1 screening test results. Some women who are at particularly high risk due to factors outlined above, or who want to rule out chromosomal abnormalities with certainty, may proceed directly to invasive testing. Other women decline testing for trisomy altogether if they want to avoid the risks of invasive testing (see following), or are certain that they would not alter decisions regarding their pregnancy based on results. Clinicians disagree as to the specific screening strategy that is preferred. Current screening strategies have a number of limitations. Foremost, current testing strategies have a low positive predictive value due to the suboptimal specificity and low prevalence of trisomy syndromes. As a Volume 29, No. 7 Publication Date: December 2014 Page: 11 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 result, a majority of fetuses that are diagnosed using an invasive procedure are not found to have a trisomy syndrome. The largest potential benefit of a sequencing-based screening strategy would therefore be reducing amniocentesis and CVS procedures and their associated risks including fetal loss. The sensitivity of noninvasive screening strategies is also imperfect, and some trisomies are not detected. A noninvasive test with improved sensitivity would therefore reduce the number of cases that are missed. Another limitation of current testing is the narrow gestational window of applicability and a need to combine multiple markers, sometimes at different time points, to arrive at a clinically useful sensitivity and specificity profile. For example, one of the best-case standard screening scenarios, called “integrated” screening, combines results from first trimester nuchal translucency and PAPP-A test results with second trimester quad screen results for an overall interpretation of risk. Sensitivity for T21 integrated screening 8 is 94% to 96% when specificity is 5%. Alternative screening methods would offer the opportunity for improved efficiency. Sequencing-Based Testing of Cell-Free Fetal DNA to Screen for Aneuploidies 14 In 1997, Lo et al reported that fetal cell-free DNA could be detected in the plasma of pregnant women, and that this fetal DNA comprised approximately 3% to 6% of total cell-free DNA in a maternal blood 15 sample. The cytotrophoblastic cell layer of the placenta is the source of the fetal DNA rather than 16 circulating fetal cells. Fetal DNA is entirely present in short fragments, with a majority less than 200 17,18 17 base pairs (bp). Maternal DNA may have a broader fragment size distribution (majority
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 syndromes 1p36 deletion Panorama (Natera) ● ● ● ● ● Verifi (Verinata Health) ● ● ● ● ● ● ● T: trisomy. Statements From Professional Societies ISPD published a rapid response statement (http://www.ispdhome.org) on noninvasive tests based on the presence of cell-free fetal nucleic acids in maternal plasma. ISPD considers these tests to be advanced screening tests, requiring confirmation through invasive testing. They further suggest that studies are needed in average-risk populations and in subpopulations such as twin pregnancies and in vitro fertilization donor pregnancies. The National Society of Genetic Counselors (NSGC) published a position statement on its website (http://nsgc.org/p/bl/et/blogid=47&blogaid=33). NSGC currently supports noninvasive prenatal testing/noninvasive prenatal diagnosis (NIPT/NIPD) as an option for patients whose pregnancies are considered at an increased risk for certain chromosome abnormalities. NSGC recommends that NIPT/NIPD only be offered after informed consent, education, and counseling by a qualified provider (eg, a certified genetic counselor). Patients whose NIPT/NIPD results are abnormal, or who have other factors suggestive of a chromosome abnormality, should receive genetic counseling and be given the option of standard confirmatory diagnostic testing. The ACOG Committee on Genetics and the Society for Maternal-Fetal Medicine’s Publications Committee 21 published a Committee Opinion on noninvasive prenatal testing for fetal aneuploidy. The Opinion states that pregnant women at increased risk of aneuploidy, but not those at average risk, can be offered sequencing-based cell-free fetal DNA screen testing after pretest counseling. The Opinion further states that women with positive screen test results should be offered counseling and invasive prenatal diagnosis for confirmatory testing, noting that cell-free fetal DNA testing is not a replacement for invasive prenatal diagnosis. The American College of Medical Genetics and Genomics (ACMG) has recently published a statement on 22 noninvasive prenatal screening for aneuploidy. The statement supports a conclusion that cell-free fetal DNA‒based tests to screen for aneuploidy have high sensitivity and specificity, but ACMG highlighted several limitations of the testing strategy, including: Approximately 50% of cytogenic abnormalities identified by amniocentesis will not be detected Chromosomal abnormalities such as unbalanced translocations, deletions, or duplications will not be detected Cell-free fetal DNA‒based tests cannot distinguish between specific types of aneuploidy (eg, an extra copy of chromosome 21, a Robertsonian translocation of chromosome 21, high-level mosasicim) No screening for single-gene mutations Delayed diagnosis if insufficient cell-free fetal DNA is isolated Longer turn-around time for cell-free fetal DNA sequencing than for maternal serum testing No testing for open neural tube defects Limited data on nonsingleton pregnancies No role in predicting late-pregnancy complications. ACMG recommends that before a mother undergoes cell-free fetal DNA‒based testing for aneuploidy, she should receive information on the purpose of the testing, advantages and disadvantages compared with standard screening, testing limitations, and considerations for posttest counselling in the event of a positive test. Volume 29, No. 7 Publication Date: December 2014 Page: 13 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 FDA Status None of the commercially available sequencing assays for trisomy syndromes has been reviewed by the Food and Drug Administration (FDA). Clinical laboratories may develop and validate tests in-house (laboratory-developed tests [LDTs]; previously called “home-brew”) and market them as a laboratory service; LDTs must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Laboratories offering LDTs must be licensed by CLIA for high-complexity testing. METHODS Search Strategy We searched the National Library of Medicine PubMed and EMBASE biomedical literature databases in April 2014, updated June 23 2014, after the MAP review, and show the search strategies and results in Appendix Table 2. Study Selection The following selection criteria were applied to select studies for inclusion: 1. Performed maternal plasma cell-free fetal DNA testing of pregnant women being screened for T13, T18, and SCA. 2. Used a sequencing assay that is clinically available and has reported application of clinical laboratory quality control measures. 3. Compared the results of plasma cell-free fetal DNA testing with the results of karyotype analysis (or fluorescence in situ hybridization [FISH] if karyotype not possible in individual cases), or with phenotype at birth. 4. Reported information on sensitivity and specificity, or provided sufficient information to calculate these parameters. Data Abstraction Data were abstracted from each study including the following elements: Study/authors/year Manufacturer of test Number of participants and selection process for testing Stage of pregnancy Maternal risk for aneuploidy Rates of indeterminate tests Sensitivity, specificity Because reported sensitivity and specificity results were not always accompanied by 95% confidence intervals (CIs), and any reported CIs may not have been calculated by the same method, we (re-) calculated all CIs using the exact method. Study Quality Assessment We used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)‒2 instrument to perform a 23 formal quality assessment for individual studies. This instrument includes questions within 4 domains on the risk of bias, and 3 questions on the applicability of the studies with respect to the specific Assessment key questions. The domain summary questions and the applicability questions are each assigned a rating of average risk, high risk, or unclear. Volume 29, No. 7 Publication Date: December 2014 Page: 14 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 Meta-Analysis We conducted a meta-analysis of the sensitivity and specificity of studies reporting cell-free fetal DNA analysis for T18, T13, monosomy X (Turner syndrome), and other SCA. In the main analysis, studies with fewer than 5 cases were excluded due to unreliability of the estimates. A pooled summary estimate was calculated using a random-effects (DerSimonian-Laird) model. Due to the small number of studies in “average-risk” mothers and small numbers of cases, a subgroup analysis of “average-risk” and “high-risk” populations was undertaken, was deemed relatively unreliable, and is reported in Appendix Table 9. All analyses were obtained using Open Meta Analyst (Center for Evidence-Based Medicine, Brown University). Decision Analysis We constructed 2 prenatal screening and confirmatory strategies for comparing detected and missed cases for T13 and T18 in average-risk and high-risk populations. Medical Advisory Panel Review The Blue Cross and Blue Shield Association Medical Advisory Panel (MAP) reviewed this assessment on June 10, 2014. To maintain the timeliness of the scientific information in this Assessment, we performed literature search updates subsequent to the Panel's review (see Search Strategy section above). If we identified any additional studies that met the criteria for detailed review, we included those results in the tables and text where appropriate. No additional studies were identified that would change the conclusions of this Assessment. MAP reviewed a previous TEC Assessment on cell-free fetal DNAbased tests for T21 in December 2012. At that review, the MAP found that the evidence for noninvasive, cell-free fetal DNA‒based testing to screen for T21 met TEC criteria compared with standard noninvasive screening methods in both high- and average-risk pregnant women. MAP deemed the screening evidence for T13 and T18 insufficient to draw conclusions. FORMULATION OF THE ASSESSMENT Patient Indications The patient indications are pregnant women who are being screened for T13, T18, and SCA. Specific subgroups of interest include: pregnant women at high risk; and pregnant women at average risk. We did not discern women in the first or second trimester because the sequencing-based evidence was not necessarily specific to the trimester. Technologies to Be Evaluated and Compared The technologies for comparison are the current traditional screening and confirmatory tests for T13, T18, and SCA: Noninvasive traditional testing o First trimester Maternal serum screening for free beta hCG and PAPP-A Ultrasound: specific measures of nuchal translucency and nasal bone o Second trimester Maternal serum screening for alpha-fetoprotein, unconjugated estriol, free beta hCG, and inhibin A Volume 29, No. 7 Publication Date: December 2014 Page: 15 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
TEC ASSESSMENT Noninvasive Prenatal Cell-Free Fetal DNABased Screening for Aneuploidies Other Than Trisomy 21 Ultrasound: basic fetal anatomy survey Invasive testing (confirmatory testing after a positive screen, or primary testing when risk is already known to be very high) to determine karyotype (or conduct FISH analysis) o First trimester CVS o Second trimester Amniocentesis In the first trimester, use of free beta hCG, PAPP-A, and nuchal translucency together may be referred to as the “combined screen.” In the second trimester, a number of the available tests may be combined as a screen, and may also include the results of first trimester testing in order to improve risk estimates. Rather 8 than explore all second trimester screens in this Assessment, we used the “integrated screen” (one of the best-case scenario screens) as our comparator. Health Outcomes We evaluated cell-free fetal DNA‒based assay performance characteristics for T13, T18, and SCA prediction. Next, we estimated correctly identified trisomy cases (true positive rate) and number of cases of trisomy cases missed (false negative rate). We did not carry the analysis further based on the rationale that prenatal screening would include T21. In the previous TEC Assessment, we determined the impact of T21 cell-free fetal DNA‒based screening on the numbers of invasive procedures performed and avoided, and the numbers of miscarriages averted by avoiding an invasive diagnostic procedure triggered by a false-positive initial screen. For this Assessment, we assumed that decisions and actions after a positive T13 or T18 result with a cell-free fetal DNA‒based test would be identical to those for T21. Thus, downstream events would be the same for T13 or T18 as for T21. The implications of an SCA-positive initial screen may differ substantially from those of the autosomal aneuploidies and so the former were not assessed using a similar methodology. However, because most available cell-free fetal DNA screening tests can identify common SCA, if an identified SCA would impact decisions, logic similar to that of the autosomal conditions would apply. Analytic Framework See Figure 1 (below) for a decision tree comparing screening. Specific Assessment Questions 1. What is the analytic validity of cell-free fetal DNA sequencingbased screening tests for T13, T18, and SCA? 2. What is the clinical validity of cell-free fetal DNA sequencingbased screening tests for T13, T18, and SCA as measured by sensitivity, specificity, and predictive value? 3. What is the clinical utility of cell-free fetal DNA sequencingbased screening tests for T13, T18, and SCA (detected and missed cases) for: a. a positive standard integrated noninvasive screen followed by diagnostic invasive karyotype analysis; and b. a positive cell-free fetal DNA‒based screen followed by diagnostic invasive karyotype analysis. REVIEW OF EVIDENCE Overview of Included Evidence We identified 29 original publications that met the inclusion criteria for this Assessment, which included 9 from the 2012 TEC Assessment. As shown in Table 2, 17 of 29 publications (59%) were described as prospective cohort studies; 10 (34%) were case-control studies; and 2 (7%) were retrospective cohort Volume 29, No. 7 Publication Date: December 2014 Page: 16 http://www.bcbs.com/blueresources/tec/vols/ © 2014 Blue Cross Blue Shield Association. Reproduction without prior authorization is prohibited.
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