6/9/2016 Prenatal Screening and Diagnostic Testing: Current Status Thanks Bill for 40 great years of AIM! Mary E. Norton MD University of California, San Francisco Maternal Fetal Medicine and Reproductive Genetics Detection rate of prenatal screening for Disclosures Down syndrome has improved over time o Principal Investigator of clinical trial on 120 cfDNA supported by Ariosa Diagnostics 100 o Research support from Natera Detection Rate (%) 80 o No personal financial disclosures 60 40 20 0 1
6/9/2016 Cell free DNA tests performed through 2014 Screening First trimester screen $ Sequential screen $ Quad screen $ Cell free DNA market Diagnosis CVS when avail Amnio $$ Amazing tests from the genome Pairings FISH $$ Microarray $$$ MSAFP $ Nuchal translucency $$ Future Offerings Whole exome $$$$$$ Title: Pregnancy: Prepare for unexpected prenatal test results. Source: Nature [0028-0836] Bianchi, Diana yr:2015 vol:522 iss:7554 pg:29 -30 cfDNA screening for T21: meta-analysis ( Gil et al, Ultrasound Obstet Gynecol, 2015) Traditional Serum Screening 1 st trimester biochemistry 2 nd trimester biochemistry Nuchal translucency 10-14 weeks 15-20 weeks DR: 99.2% (98.5 - 99.6) FPR: 0.09% (0.05 - 0.14) Down Syndrome: 93% detection, 4.5% screen positive rate 2
6/9/2016 cfDNA vs traditional screening cfDNA vs traditional screening Pros Pros Cons � Simpler protocol � Simpler protocol � Need for more complete pre-test consent ◦ Results more ◦ Results more straightforward straightforward ◦ Advantages of a two-step ◦ Not as gestational age ◦ Not as gestational age process dependent dependent � Fewer invasive tests = less � More accurate � More accurate expertise ◦ Fewer invasive tests ◦ Fewer invasive tests � 2-4% test failure � Potentially earlier results � Potentially earlier results � Expensive Disorder Prevalence What percentage of all chromosome Common trisomies 0.2% abnormalities will be detected by cfDNA (13,18,21) Causes of Birth screening? Other chromosome 0.2% abnormalities Defects and A. 99% Microdeletions and 1.5% Other Adverse 37% duplications Perinatal Outcomes: B. 75% Mendelian Genetic 0.4% It’s Not All Down C. 50% 23% Disorders 21% 19% Syndrome Congenital heart defects 0.8% D. 12% Other structural defects 3% Adverse OB outcomes 15-20% % % % % 9 5 0 2 9 7 5 1 Total ~25% 3
6/9/2016 Congenital disorders by maternal age Aneuploidies Present in LOW RISK Women *Not detected by cfDNA Other* 20.8% Tri 21: 49.2% Sex chromosomal: 9.9% Tri 13: 5.5% Tri 18:12.9% Norton et al, SMFM, 2015 Increasing maternal age � cfDNA is a very precise test for a rare condition cfDNA is more precise for T13, 18, 21 35 yo cfDNA Current NT + serum screen Increasing maternal age � 4
6/9/2016 cfDNA screening Traditional screening cfDNA is more precise for T13, 18, 21 � Trisomy 13, 18, 21 � Trisomy 18, 21, +/-13 � Sex chromosomes � Other chromosomal Other abnormalities � +/- microdeletions � Early dx fetal anomalies, esp cardiac (NT) � Spina bifida and ventral wall defects (MSAFP) � Adverse obstetric outcomes � Preeclampsia, preterm birth, fetal growth restriction cfDNA Current NT + serum screen Other aneuploidies The performance of cfDNA for other aneuploidies is NOT AS GOOD as for trisomy 21 Trisomy Detection Rate False Positive Rate Trisomy 21 99% 0.1% Trisomy 18 97% 0.3% Trisomy 13 87% 0.6% Sex chromosomes 86% 0.6% Total 1.6% 5
6/9/2016 Your 25 y.o. patient has cfDNA screening that Wang et al, Genetics in Medicine, 2014 returns positive for trisomy 13. What is the chance that this is a TRUE positive results? Aneuploidy No. of positives No (%) A. >99% 43% confirmed B. 75% T21 41 38/41 (93%) C. 50% 27% T18 25 16/25 (64%) D. <10% 17% T13 16 7/16 (44%) 13% 45X 16 6/16 (38%) Total 98 67 (67%) % % % % 9 5 0 0 9 7 5 1 > < PPV Calculator: www.perinatalquality.org 6
6/9/2016 Cell free DNA limitations Fraction of cfDNA that is fetal 1. Limited number of abnormalities (T13,18,21, sex chromosomes) • 75-80% of aneuploidies • Missed aneuploidies can be associated with intellectual and other disabilities • Important for patients who request screening 2. Test failure • 1-8% of tests fail to provide a result • This increases the risk for abnormality 7
6/9/2016 Failed testing increases aneuploidy risks Fetal fraction and maternal weight Author OR for aneuploidy Norton et al, 2015 6.2x Pergament et al, 2014 2.5x Turocy et al, 2015 5.7x o Primarily T13, 18, triploidy o These are essentially screen positive results Hudecova I et al, PLoS One, 2014 cfDNA vs Sequential Screening: Detection and False Positive Rates Cohort Detection False Positive Rate Rate Sequential 81.6% 4.5% screening If you consider detection of all chromosomal cfDNA if “no 77.1% 3.7% results” cases = high abnormalities, and consider all the failed tests risk as “screen positive”, what is the performance cfDNA if “no 70.7% 0.7% of traditional screening vs cfDNA screening? results” have no follow up 8
6/9/2016 ACOG/SMFM September 2015 o Conventional screening is most appropriate first line screen for most patients o Ethically any patient may choose cfDNA screening, but should be counseled regarding limitations and benefits o Diagnostic testing is required to confirm abnormal results before irreversible decisions Competency and training in invasive prenatal diagnosis: ‘the elephant in the room’ cfDNA FTS amnio � Amniocentesis loss rate now estimated CVS at 0.11% (1/900) Ultrasound in Obstetrics & Gynecology; 2016 9
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6/9/2016 Meschino et al, Prenatal Diagn, 2016 “…these products may have caused or have caused actual harm to patients.” 11
6/9/2016 Should all women be offered cfDNA screening? Should all women be offered cfDNA screening? Should all women be offered cfDNA screening? 12
6/9/2016 Should all women be offered cfDNA screening? Issues with cfDNA screening mean the clinical utility is lower than carefully curated data would lead you to believe gem.perinatalquality.org 13
6/9/2016 What is a provider to do? What is a provider to do? o Follow ACOG/SMFM guidelines o Use PPV calculator for any test positive cases o Explain to patients that cfDNA is NOT a “noninvasive amnio” o Counsel patients with failed tests o Know the performance characteristics of the lab that you use • Test failure rate • Incidental findings reporting Thank you!! 14
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