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2020_12_11 Vortrag Holzgreve-Bonn AScharf FTS - NIPT-04 final

Comparison of performance metrics of FTS and NIPT in prenatal screening

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2020_12_11 Vortrag Holzgreve-Bonn AScharf FTS - NIPT-04 final

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  1. First Trimester Screening (FTS) by biochemical markers and ultrasound (= NT-Screening, combined test) in relation to NIPT Prof. Dr. Alexander Scharf Praxis für Pränatalmedizin Mainz

  2. FTS (combined NT test) in relation to NIPT What is our turf? • Interdisciplinary setting (Prenatal diagnostician - Geneticist - Pediatrician - Laboratory Specialist) -> conversation across disciplinary boundaries • Multidisciplinary approach • Translate subject-specific terms and concepts • Clear, unambiguous interdisciplinary terminology • Clear, unambiguous concept of postnatal (pediatrics, clinical genetics) vs. fetal health (prenatal medicine) • Clear, unambiguous knowledge of postnatal vs. prenatal health epidemiology (conceptuality of disease, e.g. „birth defects“ or „congenital anomaly“)

  3. Birth defects (congenital anomalies) • Worldwide: 6% of all births (130 Mio/yr) -> 7,8 Mio/ yr • 3,2 Mio disabled for life • Over 3.3 million children under age five die annually from birth defects (Thong 2014) • US: 3% prevalence at birth (1 in 33) = 1.3 Mio /yr

  4. Birth defects (congenital anomalies) Unknown,Embryology(most structural defects) EnvironmentalTeratogenic(mat. age, toxic, infectious, substance deficiency, diabetic) Genetic (Chromosome abnormalities, single gene defects) Origin(cause, reason)

  5. Angeborene Fehlbildungen (Birth defects = congenital anomalies) Environmental Primary,Embryology Origin(cause, reason) Genetic Multifactorial

  6. Angeborene Fehlbildungen (Birth defects = congenital anomalies) Environmental Origin(cause, reason) Unknown,Embryology Genetic Effect Functional disorders (problems exist with how a body part works) Structural disorders (problems with shape of body part)

  7. Angeborene Fehlbildungen (Birth defects = congenital anomalies) Environmental Origin(cause, reason) Unknown,Embryology Genetic Structural disorders Functional disorders Effect Consequence Physical disabilities Intellectualdisabilities Developmentaldisabilities

  8. Angeborene Fehlbildungen (Birth defects = congenital anomalies) Environmental Origin(cause, reason) Unknown,Embryology Genetic Structural disorders Functional disorders Effect Intellectualdisabilities Physical disabilities Consequence Developmentaldisabilities

  9. Prenatal perspective Environmental Origin(cause, reason) Unknown,Embryology Genetic Structural disorders Functional disorders Effect Intellectualdisabilities Physical disabilities Consequence Developmentaldisabilities

  10. Prenatal perspective Single Gene disorders (Molecular Genetics) (1%) IUGR (3% - 5%) Environmental (Infection, TORCH, GDM, Placentation) Chromosomes (Cytogenetics, Array-CGH) (0,4%) Origin(cause, reason) Primary(Embryology) US Genetic Fetal malformation (3%) • 3 main groups of fetal disorders: Structure, growth, genetics • Broad biological overlap (prenatal triangle of health) • Structural defects 10x more frequent than chromosome disorders • Quality (diagnostic precision): 1st commandment: No genetics w/o fetal US!

  11. Prenatal genetic screening:FTS in relation to NIPTyr 2000: Introduction of FTS (Combined (NT-)Test) • 1998 NT-Screening • 2000 NT plus biochemistry (Papp-A, fßHCG) • Primary aim: Chromosomes (T21-T18-T13) • High Sensitivity > 90% • Beyond expectation: Broad genetic coverage (AUC) Sensitivity 100% Fetal malformations (3%) 60-80% Sensitivity Sensitivity 100% 20% Rare (inter alia CNV, e.g. Microdel.) Sensi-tivity 0% Sensitivity 0% 50% Trisomy 21 10% SCA (XY-Pathologies) 90% Sensitivity 95% Sensitivity 20% Trisomy 18/13 Chromosomal disorders 0,4% = Germany 2800 cases (700000 births/yr) = US 16000 (4 Mio births/yr)

  12. Prenatal genetic screening: FTS in relation to NIPTyr 2012: Introduction of NIPT - Comparison of coverage and sensitivity 2012 NIPT 2000 NT -> 2010 NT 20% Rare (inter alia CNV, e.g. Microdel.) Sensitivity= 99% 10% SCA (XY-Pathologies) 10% SCA (XY-Pathologies) Sensitivity 0% 50% Trisomy 21 50% Trisomie 21 Sensitivity= 95 - 97% 95% Sensitivity 90% Sensitivity 20% Trisomy 18/13 20% Trisomy 18/13 95% Sensitivity • Less coverage (AUC) • Improved selective sensitivity at T21 (90/95% -> 99%) • Clinicial point of view: Giant leap? • More of a nice, selective hop! • AUC: Sideways trend

  13. Prenatal genetic screening: FTS in relation to NIPTyr 2012: Introduction of NIPT - Comparison of FPR/specificity 2000 NT -> 2010 NT NIPT 20% Rare (inter alia CNV, e.g. Microdel.) • Improved accuracy (TP+TN) • Less type 1 and type 2 errors • Markedly improved PPV 10% SCA (XY-Pathologies) 10% SCA (XY-Pathologies) 50% Trisomy 21 50% Trisomy 21 20% Trisomy 18/13 20% Trisomy 18/13

  14. Prenatal genetic screening: FTS in relation to NIPTyr 2015: Introduction of NIPT - Additional spectrum: Microdeletions NIPT 2015 NIPT 2012 Microdel. (DiG, PW/Ang., WHS, CDS, 1p36) 10% SCA (XY-Pathologies) 10% SCA (XY-Pathologies) 50% Trisomie 21 50% Trisomie 21 20% Trisomy 18/13 20% Trisomy 18/13 • Microdeletions: • Sens DiG 75%, remainder > 90% • Apart from DiGeorge (1:4000 - 1:1000): Low disease prevalence (Cri du chat, Wolf-Hirschhorn, 1p36, Prader-Willi/Angelman) • Translates into rel. high FPR, low PPV (10-15%) • NIPT @ CNV: Scientifically effective, but practically not efficient (cost-benefit-ratio) • Primary screening: Dead end

  15. Prenatal genetic screening: FTS in relation to NIPTNIPT - Comparison of FPR/specificity high risk vs. primary screening NIPT Ger 2021statutory health insurance NIPT 2012 Sensitivity= 99% • Communication / Marketing: Test performance mainly from high risk-studies • No call (1% @MPS - 5% @SNP): Signif. increase of FPR • Marked decrease of PPV to < 10% • Transformation (Calc) to low risk population, allowance for no call (Meta-analysis Taylor-Philips, 2016): • Drop of sensitivity to 96% (T21), 87% (T18), 77% (T13) • Slight increase of FN 10% SCA (XY-Pathologies) T13 50% Trisomie 21 Sensitivity= 95 - 97% Sensitivity= 77% T21 20% Trisomy 18/13 T18 144/187discov. rate Sensitivity= 86% Sensitivity= 96% 321/373 discov. rate 1344/1400 discov. rate

  16. Prenatal genetic screening: FTS in relation to NIPT NT • Sensitivity: In experienced hands (mind US!) modest difference • Specificity: NIPT T21 -> Practical gain/advance • Summary: In practical prenatal medicine within certain boundaries (cost, funding, maternal expectations) combined Test and NIPT valuable, alternative approaches in the same field Chromosomal disorders 0,4% Fetal malformations (3%) NIPT

  17. Risiken AC -CVS • Vergl. BVNP - Dossiers • Abortrisiko AC 1: 1000 (nicht 1:100) • Abortrisiko CVS 1: unendlich = faktisch NULL • - CVS - Vorteile: Früher -sicher - Ergebnis Folgetag

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