10/15/2015 Prenatal Aneuploidy Screening Disclosures Using cell Free DNA o Research support from Natera and Ariosa o No lucrative personal financial contracts Mary E. Norton MD Professor, Obstetrics, Gynecology and Reproductive Sciences University of California, San Francisco What Does the Evidence Tell Us? Oct 2015 Detection rate of prenatal screening for The questions being debated: Down syndrome has improved over time o Is cfDNA screening the best option for low risk 120 Detection Rate (%) 100 patients? 80 60 o Is cfDNA screening the best choice for primary 40 20 screening for any or all patients? 0 1
10/15/2015 Professional Society Opinions: ACOG; ACMG; Rumsfeld on current status of NIPT? International Society of Prenatal Diagnosis; National Society of Genetic Counselors “There are known knowns. There are things we know, we know. We Common themes (2012): also know there are known There are recognized benefits, but… o Not diagnostic unknowns. That is to say, we know • Needs confirmation there are some things we do not o Only detects common trisomies know. But there are also unknown o Requires comprehensive genetic counseling unknowns. The ones we don’t o Should only be used in validated groups (eg high risk) know we don’t know.” o Need a low risk study before introducing into general -Donald Rumsfeld, 2002 population screening Cell free fetal DNA Cell free DNA results from apoptosis o Short segments of fetal DNA (<200 base pairs) circulate in maternal plasma o Origin is primarily placenta Maternal DNA Fetal DNA 2
10/15/2015 Trisomy 21 performance cfDNA testing: meta-analysis ( Gil et al, Ultrasound Obstet Gynecol, 2015) Analysis of cell free DNA Trisomy 21 Non-Trisomy 21 DR: 99.2% (98.5 - 99.6)FPR: 0.09% (0.05 - 0.13) Zhong, X, Holzgreve, W, Glob. libr. women's med 2009 Cell free DNA: Biologic Challenges False positive cfDNA results and cancer False positives: o Unrecognized or vanishing twin o Placental mosaicism o Maternal genetic variation o Maternal malignancy False negatives: o Low level of fetal DNA o Placental mosaicism o Maternal genetic variation Failed results: o Increased BMI o Low level of fetal DNA o Fetal aneuploidy 3
10/15/2015 What percentage of chromosome Issues with cfDNA for primary screening abnormalities will be detected by cfDNA screening? 1. Not all abnormalities are detectable • Down syndrome comprises ~50% of aneuploidies A. 99% 41% 2. The PPV (chance that a positive is a TRUE B. 75% 28% POSITIVE) depends on maternal age C. 50% • This is often misunderstood 17% D. 12% 13% 3. Some tests fail to provide a result • These patients are at HIGH RISK of aneuploidy • Importance of “fetal fraction” % % % % 9 5 0 2 9 7 5 1 4
10/15/2015 Spectrum of Genetic Disease Spectrum of Genetic Disease Autosomal recessive Autosomal recessive Autosomal dominant Autosomal dominant CNV (microarray) CNV (microarray) X-linked X-linked Chromosomal/ Chromosomal/ karyotype karyotype Structural Malformations Structural Malformations Aneuploidies Present in HIGH RISK Women Aneuploidies Present in LOW RISK Women *Not detected by cfDNA *Not detected by cfDNA Other* Other* 16.9% 20.8% Tri 21: 53.2% Tri 21: 49.2% Sex chromosomal: 8.2% Sex chromosomal: 9.9% Tri 13: 4.6% Tri 13: 5.5% Tri 18: 17.0% Tri 18:12.9% Norton et al, SMFM, 2014 Norton et al, SMFM, 2015 5
10/15/2015 Rate of abnormalities by maternal age cfDNA Detection Rate n=452,901 patients screened in California Total Cases with Aneuploidy (n=2575) cfDNA Not Detectable Not Detected No Result Detectable (False negative+ Non-detectable) N=1841 N=105 N=69+560 (71.4%) (4.1%) (24.5%) In low-risk patients, this is a very accurate test for a rare event. 6
10/15/2015 NIPT and diagnostic testing with NIPT and diagnostic testing with chromosomal microarray (CMA) chromosomal microarray (CMA) Microarray detects an abnormality in 1.7% of cases (about 1/60) Microarray detects an abnormality in 1.7% of cases (about 1/60) AND: AND: NIPT detects T13,18, 21 – about 1/500 pregnancies NIPT detects T13,18, 21 – about 1/500 pregnancies THEN: THEN: � If NIPT is the routine screening test, it will detect about 12% of � If NIPT is the routine screening test, it will detect about 12% of diagnosable chromosomal abnormalities diagnosable chromosomal abnormalities NIPT and diagnostic testing with Your 25 yo patient has cfDNA screening and the chromosomal microarray (CMA) result is positive for trisomy 13. What is the chance that the fetus actually has trisomy 13? Microarray detects an abnormality in 1.7% of cases (about 1/60) A. >99% 34% AND: 28% B. 75% NIPT detects T13,18, 21 – about 1/500 pregnancies 21% C. 50% 17% THEN: D. <10% � If NIPT is the routine screening test, it will detect about 12% of diagnosable chromosomal abnormalities % % % % 9 0 5 0 9 7 5 1 > < 7
10/15/2015 cfDNA vs Standard Screening Bianchi et al, NEJM, 2014 FPR PPV cfDNA 0.3% 45.5% p<.001 Standard 3.6% 4.2% o N=1914 women undergoing standard screening o Only 8 aneuploidy cases in the cohort (5: T21, 2: o Mean maternal age = 29.6 yrs o Primary outcome = false positive rates for T18 and T21 T18, and 1: T13) o All were detected “NEXT” study: 15,841 average risk women Cell free First DNA trimester screening screening Detection rate 38/38 30/38 (79%) P=0.008 (100%) o 15,841 women had cfDNA and first trimester False positive 0.06% 5.4% P<0.0001 rate screening Positive 81% 3.4% P<0.0001 o Mean maternal age = 30.7 yrs predictive value Norton et al, NEJM, 2015 8
10/15/2015 Wang et al, Genetics in Medicine, 2014 Aneuploidy No. of positives No (%) confirmed T21 41 38/41 (93%) T18 25 16/25 (64%) T13 16 7/16 (44%) 45X 16 6/16 (38%) Total 98 67 (67%) o 6.2% had termination without karyotype confirmation o Disconcerting if only 67% are true positives 9
10/15/2015 Consequences of false positive results Consequences of false positive results NIPT NIPT Serum Screening N=100,000 N=100,000 N=100,000 1% false positives 1% false positives 5% false positives 1000 abnormal results 1000 abnormal results 5000 abnormal results 6.2% TAB w/o 6.2% TAB w/o confirmation confirmation 0.2% loss rate 62 TAB 62 TAB (amnio) 67% PPV 67% PPV 42 TP 21 FP 42 TP 21 FP 10 losses of normal fetuses 21 TAB of normal fetuses 21 TAB of normal fetuses If your patient has a positive result: www.perinatalquality.org 10
10/15/2015 The poorly understood PPV Your patient has cfDNA screening, and the lab calls to tell you the test failed to provide a result. What are possible reasons for this? 71% A. Maternal obesity B. The fetus has a chromosome abnormality 16% 12% C. The blood was drawn too early 1% D. All of the above y e t v i . s . . . o e . t b o n b a o m w e o a l h a r r n h d t f r c s o e t a a w l l a s A M a d h o s o u l t b e e f e h h T T 11
10/15/2015 Published Trials of NIPT: failure rates Fetal fraction of DNA and test failure Trial Failure rate 3-5% of samples do not provide a result Chiu et al (2011) 11/764 (1.4%) Ehrich et al. (2011) 18/467 (3.8%) • Low fraction fetal DNA, failed sequencing, high variability Palomaki et al. (2011) 13/1696 (0.8%) Bianchi et al. (2012) 30/532 (3.0%) in counts Norton et al (2012) 148/3228 (4.6%) • Some association with gestational age (<10 wks) Zimmermann et al (2012) 21/166 (12.6%) • Low fetal fraction associated with maternal BMI Pergament et al (2014) 85/1051 (8%) - 20% at >250 lbs Norton et al (2015) 488/16,329 (3.0%) - 50% at >350 lbs All 729/23,182 (3.1%) � Low fetal fraction is associated with aneuploidy � Repeating test will provide a result in SOME cases Pergament et al, 2014 Obesity in US Adults o N=1051 samples were analyzed o N=85/1051 (8%) samples failed to obtain a result o 20/85 (22%) were aneuploid � “No call” cases represent a very high risk group Obstet Gynecol 2014 12
10/15/2015 Kaiser cfDNA Experience: No Results Cases Kaiser cfDNA Experience: No Results Cases Total Pregnancies Sampled Total Pregnancies Sampled N = 4446 N = 4446 Low Risk High Risk No Results Low Risk High Risk No Results N = 4187 N = 157 N = 102 N = 4187 N = 157 N = 102 (94.2%) (3.5%) (2.3%) (94.2%) (3.5%) (2.3%) Redrawn Redrawn Redraw Declined Redraw Declined N = 63 N = 63 N=39 N=39 Low Risk Low Risk High Risk No Result High Risk No Result N=32 (50.8%) N=32 (50.8%) N=5 (7.9%) N=26(41.3%) N=5 (7.9%) N=26(41.3%) NO FINAL RESULT NO FINAL RESULT N = 65 (1.5%) N = 65 (1.5%) Kaiser cfDNA Experience: No Results Cases Kaiser cfDNA: No Results Total Pregnancies Sampled N = 4446 KPNC 10/29/12 – 6/30/14 Total pregnancies sampled = 4446 Low Risk High Risk No Results NO FINAL RESULT N = 4187 N = 157 N = 102 N = 65 (1.5%) (94.2%) (3.5%) (2.3%) Redrawn Redraw Declined N = 63 N=39 Chromosomes not done Normal chromosomes Abnormal chromosomes Low Risk High Risk No Result 43/65 (66%) 13/65 (20%) 9/65 (14%) N=32 (50.8%) N=5 (7.9%) N=26(41.3%) NO FINAL RESULT N = 65 (1.5%) 13
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