Growing Options in Prenatal Screening & Diagnosis

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1 Growing Options in Prenatal Screening & Diagnosis Joseph R. Biggio Jr., M.D. University of Alabama at Birmingham Disclosures Site Investigator at UAB for trials enrolling patients Natera Prenatus study Sequenom No personal support or other conflicts 1

2 CLINICAL MANAGEMENT GUIDELINES FOR OBSTETRICIAN GYNECOLOGISTS NUMBER 77, JANUARY 2007 Screening for Fetal Chromosomal Abnormalities ACOG Practice Bulletin #77 Maternal age should not be sole factor in offering diagnostic test Diagnostic testing should be an option for all women 2

3 ACOG Practice Bulletin #77 Screening tests should be offered to all women regardless of age Ideal screening test represents a combination of the best tests from the 1 st and 2 nd trimesters FASTER Trial 15 U.S. centers 38,189 singleton gestations 117 with trisomy 21 First and second trimester strategies compared Malone et al., NEJM, 2005; 353:

4 Integrated Screening A combination of 1 st and 2 nd trimester screening tests weeks: NT, PAPP A weeks: AFP, hcg, estriol, & inhibin Final result provided once Quad screen completed All testing combined into a SINGLE result FASTER Trial Detection Rate for 5% Screen Positive Rate Integrated tests NT Triple Quad NT + PAPPA + hcg PAPPA + Quad NT + PAPPA + Quad 4

5 Screening Tests Detection rates based on 5% screen positive rate First Trimester NT, PAPP A, hcg 82 87% Second Trimester AFP, estriol, hcg, inhibin A 81% First Plus Second Trimester Integrated 95% Serum Integrated 85 88% FASTER, Malone et al, NEJM, 2005; 303:2001 Non Invasive Prenatal Diagnosis 5

6 Cell free DNA in the Maternal Circulation Placenta Maternal plasma Maternal blood cells Cell-free fetal and cell-free maternal DNA circulate in maternal plasma as relatively short fragments ( base pairs) Fragments represent the entire genome Placenta Fetal DNA Blood cells Maternal DNA Fetal DNA: 5-25% (~10%) total cell-free DNA Lo, Lancet 1997;350: Relative amount of chromosome 21 Normal Mother Normal Fetus The Concept of Massively Parallel Shotgun Sequencing Normal Mother Down syndrome 18 copies + 2 copies 20 copies 18 copies + 3 copies 21 copies Need to distinguish 21 copies from 20 copies, a 5% difference. (assumes 10% of cfdna is fetal) 6

7 Schematic: Massively parallel genomic sequencing for fetal chromosomal aneuploidy Chiu R W K et al. PNAS 2008;105:20458 %chr21 = 1 / 51 = 2% 7

8 Data analysis 12 to 19 million sequences per sample matched (aligned) to the human genome Unique matches on the first bp Interpretation of results Express percent of chromosome 21 matches to all matches Express patient results in SD s above/below expected Percent unique reads and corresponding z score for chromosome 21 Higher proportion map to 21 with trisomy % of all unique reads Blue normal male Orange normal female Green T21 male Red T21 female Z score Normal range Chiu R W K et al. PNAS 2008;105:

9 Laboratory Developed Tests MPSS based tests Sequenom Center for Molecular Medicine Maternit21 PLUS Introduced Fall, 2011 Verinata Health Verifi March, 2012 Validation Studies:MaterniT21 Multicenter study 4,664 women Blinded nested case control study 212 Trisomy <15 wk; 107 >15 wk Seven euploid:each case 1,484 z score at or above 3 diagnostic of T21 Fetal fraction of cfdna: 13.4% mean Failure rate 0.8% Palomaki et al, Genetics in Medicine, 2011; 13:913 9

10 T21 Detection 209/ % (95% CI ) False Positive 3/1,4710.2% (95% CI < ) Failure and false negative associated with lower fetal fraction Palomaki et al, Genetics in Medicine, 2011; 13:913 Same population 62 Trisomy Trisomy 13 3 euploid controls matched z score at or above 3 diagnostic Failure rate 0.9% 3 failures T18 Validation Studies: MaterniT21 PLUS Palomaki et al, Genetics in Medicine, March (3):296 10

11 Trisomy 18 Detection 59/59 100% (95% CI ) Including failures 59/ % False positive 5/1, % (95% CI ) Trisomy 13 Detection 11/ % (95% CI 61 99) False positive 16/1, % (95% CI ) Validation Studies:Verifi Whole chromosome aneuploidy 2,882 women Nested case control study (1:4 ratio) 532 samples analyzed Normalized chromosome values > 4 affected <2.5 unaffected indeterminate Rava et al, SMFM abstract 837, AJOG Jan 2012 S367; Bianchi et al, Obstet Gynecol, 2012:119(5) 11

12 Verifi Performance Sensitivity 95% CI Specificity 95% CI Trisomy 21 (n=493) Trisomy 18 (n=496) Trisomy 13 (n=499) Female (n=433) Male (n=433) Monosomy X (n=433) 100 (89/89) (404/404) (35/36) (460/460) (11/14) (485/485) (232/233) 100 (184/184) (199/200) (249/249) (15/16) (416/417) Overall Performance: Verifi No false positives for autosomal aneuploidies Mosaicism for trisomy 21 and monosomy X detected Trisomy 20 and trisomy 16 detected Sex chromosome aneuploidies classified 12

13 LDT: Directed DNA Analysis Specific loci sequenced from chromosomes of interest Less variability when applied Increased accuracy, simple bioinformatics Quoted shorter TAT and lower cost Targeted DNA LDTs for NIPT Aria/Ariosa Harmony Introduced Summer 2012 Natera NATUS (next generation aneuploidy testing using SNPs) Panorama Launched end

14 Harmony Non Invasive Chromosomal Evaluation (NICE) Study Locus specific oligonucleotides serve as sequencing templates FORTE (Fetal fraction optimized Risk of Trisomy Evaluation) algorithm incorporates counts LR based on fetal fraction, maternal age, GA >1/100: High risk Ashoor et al, AJOG 2012; 206:322; Norton et al, AJOG 2012; 207:137 NICE Results: T21 and T18 T21 Sensitivity 100% False positive 0.03% T18 Sensitivity 97.4 % False positive 0.07% 14

15 Quantitative and Qualitative NIPT: Natera Panorama Fetal signal identified at polymorphic sites Ratio fetal:maternal SNPs at target and reference chromosomes Individualized trisomy risk assessment for each chromosome based on statistical genetics Zimmermann et al, Prenatal Diagnosis 2012; 32:1233: Result Comparisons Detection Rate False Positive Rate Sequenom Verinata Ariosa Natera Trisomy % 0.2% <99.9% 0.2% 100% 0.1% >99% 0.0% Trisomy % 0.3% 97.4% 0.4% 98% 0.1% >99% 0.0% Trisomy % 1.0% 87.5% 0.1% 80% 0.05% >99% 0.0% 45,X (Monosomy X) Not evaluated 95% 1.0% Not evaluated >99% 0.0% Based on available published data as of Feb

16 Fetal Fraction Key in Success Affected by: Gestational age 9 10 weeks Obesity Other??? Average 10 15% Equivocal or no call rate if <5% Application of NIPT Role in clinical practice Screening vs. diagnosis Applicable population Capacity/Infrastructure/TAT Insurance coverage 16

17 Reflex Test Modeling Using as MPSS secondary screening test vs invasive testing Reduce diagnostic testing by >90% Reduce fetal loss rate by 93 95% Improve trisomy detection 3 6% Palomaki et al, Genetics in Medicine, March (3):296 NOT for low-risk, general population women Appropriate Populations: AMA Prior affected Abnormal screen Ultrasound abnormality Robertsonian translocation involving 13 or 21 Pre- and post-test counseling on false positives and false negatives Need more information for multiples 17

18 Diagnostic Testing Deletions& Duplications: Submicroscopic 18

19 FISH: Targeted for Microdeletion Syndromes Caused by deletion of submicroscopic amounts of DNA Involves multiple genes DiGeorge Syndrome 22q11 Williams Syndrome 7q11 Array Comparative Genomic Hybridization (CGH) 19

20 A Matter of Resolution: How close are we focused on changes? G band chromosomes 5 15 Mb level FISH 2 Mb level Advantages of Chromosomal Microarray Finer resolution 1 Mb, 100 Kb or lower Multiple areas simultaneously DNA based Living cells not required Albertson et al, Hum Mol Gen, 2003; Oostlander et al, Clin Gen,

21 Limitations of Chromosomal Microarray Cannot identify balanced translocations Potential to detect variants of unknown significance (VOUS) Microarray: Postnatal Genetic Diagnosis Developmental delay, autism spectrum, or multiple anomalies 3% abnormal G banded chromosomes 15 20% abnormal array ACMG: Array CGH first line for postnatal evaluation of DD, ASD, MCA Devries et al, 2005; Friedman et al, 2006; Menten et al, 2006; Miller et al, AJHG,

22 Indications: AMA Abnl screen US anomaly Prior history/anxiety Risks Study Procedures Possibility of findings of uncertain significance ID variants associated with adult onset disease 22

23 Outcomes Study Procedures Success rate of microarray Ability to ID common autosome and sex chromosome aneuploidies Prevalence of CNVs with normal karyotype Ability to ID uncommon cytogenetic abnormalities (markers, rearrangements, etc) Arrays covered: Study Procedures Regions of known disease loci Pericentromeric regions Subtelomeres Genomic backbone 75kb SNP based array used at some labs as well 23

24 Positive Results Study Procedures CNV in or overlapping a targeted region 1 Mb CNV in other region <1 Mb but includes a gene implicated in a chromosome disorder, AD condition, or X linked disorder Study Procedures Pathogenic well described phenotype Benign based on databases and publication Uncertain Significance Likely benign small size, gene content, normal US, negative family hx Uncertain subjected to adjudication 24

25 4,406 women enrolled Microarray result: 98.8% Results Detected all autosomal and sex chromosome aneuploidies Did not detect: Balanced rearrangements Triploidy 1 of 3 marker chromosomes 1399 CNVs identified 1234 (88%) common benign 35 (2.5%) known pathogenic 130 (9.8%) uncertain significance Results After adjudication, 61 felt to be significant enough to report 96 potential pathogenic (6.8%) 25

26 Frequency of Additional Information Indication N Pathogenic 95% CI Any % AMA % Abnormal Screen % Anomaly on US % Other % Microarray and Stillbirth 532 stillbirths Result: Microarray 87% vs karyotype 70% Aneuploidy and CNV 8.3% vs 5.8% With anomalies 30% vs 19% Microarray increased information in: 42% all stillbirths 35% antepartum stillbirths 54% stillbirths with anomalies Reddy et al, NEJM, December :

27 Role of Microarray Benefit of additional information Risk of additional information Insurance coverage Appropriate patients Anomalies Others? Summary NIPT is able to provide detection of common aneuploidies with high sensitivity and specificity CGH array can provide additional information beyond that of normal karyotype, especially in the setting of anomalies or stillbirth Pre and post test counseling regarding the limitations, benefits, and risks of each type of testing is vital 27

28 Questions? Improvements with recent advances 3.4% with normal karyotype CNVs with uncertain clinical significance Based on 2012 data, only 1.5% would remain of uncertain significance SNP arrays will detect triploidy 28

29 Landmark papers PNAS 2008;105:15255 PNAS 2008;105: (sd=0.02) ( ) Z = = Higher proportion of sequenced fragments map to Ch21 in setting of trisomy Higher z-score 29

30 Arrays in Prenatal Settings Schaeffer et al, AJHG, 2004 sab n=41 4 additional abnormalities Benkhalifa et al, Prenatal Dx, 2005 sab with failed culture n=26 15/26 with chromosome imbalances LeCaignec et al, J Med Gen, 2005 Fetuses with multiple malformation and normal karyotype n=49 10% with imbalance 30

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