!"#$%&'()(#*+,-##"("./ +010#/'2/03#/!-0/ Univ.-Doz. Dr. Elisabeth Krampl-Bettelheim

Transkript

1 !"#$%&'()(#*+,-##"("./ +010#/'2/03#/!-0/ Univ.-Doz. Dr. Elisabeth Krampl-Bettelheim

2 ///4,3/5(&&/666/!"#$$%&'!()$$!*%#&!+#&(!,%$-&(!#$.'!!%$!&#/0.!1%23#%2%&!!"#$$%&'!()$$!#/0!()$!4%$.%!,%.)&!0)5%6!

3 +,-##"("./1$2/789/ Detektionsrate in Prozent Falsch Positiv Rate > % < 0,1% % 3% % % 5%

4 !"5#")$"./,2/MK!/ C#)(".0#=/ +,-##"("./ S';L("#)/7#=0/BS7J/1&=/%-(;<-#=/+,-##"("./G#-213-#"/ NT > 3.5mm, Risiko > 1:10, Fehlbildung -> Invasive PND +/- Microarray anbieten :-(;<-#=/ +,-##"("./ I'&.#L#=$,3/8/?',3#"/=%<0#-/++?/98A/! C#=%-#,3$"./K4:7/C#2$")/! M$-,32N3-$"./K7/$")/2-N3#=/O-.1"=,-##"("./! K7/P/Q6R;;/')#-/I#3&L(&)$"./SG+/AT*/U(,-'1--1V/1"L(#0#"/ +%<0#=/ +,-##"("./ S';L("#)/7#=0/BS7J/]#-%1==0/31L#"/ K4:7/2N-/:1D#"D""#"/;(0/I#3&L(&)$".T3'3#;/W(=(X'/2N-/!"#$%&')(#/2N-/ )(#/#("/+,351".#-=,31^=1LL-$,3/"(,30/("/I-1.#/X';;0/ _$#&&#Y/U1`(;(&(1"/+,3;()/ 4

5 !"5#")$"./,2/MK!/ C#)(".0#=/ +,-##"("./ S';L("#)/7#=0/BS7J/1&=/%-(;<-#=/+,-##"("./G#-213-#"/ NT > 3.5mm, Risiko > 1:10, Fehlbildung -> Invasive PND +/- Microarray anbieten :-(;<-#=/ +,-##"("./ I'&.#L#=$,3/8/?',3#"/=%<0#-/++?/98A/! C#=%-#,3$"./K4:7/C#2$")/! M$-,32N3-$"./K7/$")/2-N3#=/O-.1"=,-##"("./! K7/P/Q6R;;/')#-/I#3&L(&)$"./SG+/AT*/U(,-'1--1V/1"L(#0#"/ +%<0#=/ +,-##"("./ S';L("#)/7#=0/BS7J/]#-%1==0/31L#"/ K4:7/2N-/:1D#"D""#"/;(0/I#3&L(&)$".T3'3#;/W(=(X'/2N-/!"#$%&')(#/2N-/ )(#/#("/+,351".#-=,31^=1LL-$,3/"(,30/("/I-1.#/X';;0/ _$#&&#Y/U1`(;(&(1"/+,3;()/ 5

6 M1=/!&0#-/)#-/+,351".#-#"/ Risiko % ! Trisomie 21 xxx/xxy/xyy! Trisomie 18! Trisomie 13 45x Jahren Triploidie M1=/W(=(X'/=0#(.0/;(0/)#;/!&0#-/)#-/U$a#-/

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8 S';L("#)/7#=0/*/O+S!W/ Alter Fetale NT Mütterliches hcg & PAPP-A Falsch positiv Rate 5%, Entdeckungsrate 90% 3

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10 I1&=,3*%'=(D]#/// Falsch positiv Rate 3%, Entdeckungsrate 95%

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13 :#-2'-;1",#/M<"#;1-X/ Teilnahme am Screening in Prozent Detektionsrate für Trisomie 21 in Prozent ,3 93,4 89,4 92,9 90,

14 :$"XD'"/ b! Schwangere Punktionen 200 Fehlgeburten

15 M(1."'=#/'3"#/W(=(X'c/ b! I-1.;#"0#/2#01&#-/MK!/(;/C&$0/)#-/U$a#-/ /d/,emk!/d/s#&&/2-##/2#01&/mk!/ b! U:+/f/;1==(]#&V/%1-1&&#&/=#g$#",("./ /d/"#`0/.#"#-1d'"/=#g$#",("./ /d/=3'0.$"/=#g$#",("./

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17 G#-2N.L1-/("/h=0#--#(,3/ PraenaTest 825 EUR 600 EUR NIPT 793 EUR 600 EUR Stand: Februar 2014

18 S#&&*2-##/B,2J/MK!/

19 +#g$#"h(#-$"./!"#$%&'(&)*++,&!"#$%&'$&('$&)'$*$+$,-./0$ 12"3#$!"#$,-./0$ $,-./0$!"##$%&'()*+,-$./012)13$%4506(,7-$ More efficient

20 K4:7/7-(=';(#/89/ Fetal cfdna Extra fragments derived from fetal trisomy 21 Maternal cfdna Comparison Chromosome sequences Chromosome 21 sequences

21 I#0'U#)/ 40 % über 35 % CVS

22 I#0'U#)/ 40 % über 35 % CVS

23 I#0'U#)/ 40 % d CVS mit T

24 I#0'U#)/ 8 % CVS %NIPT

25 I#0'U#)/K4:7/ x Redraw! Patientin mit 130kg! 2 x Patientinnen die Eizellspende verschwiegen haben 5 x Hochrisikoergebnis für Trisomie 21! nach CT 1:6301, 1:840, 1:79, 1:226, 1:5 (alle bestätigt) 2 x Hochrisikoergebnis für Trisomie 18! nach CT Risiko 1:99 (bestätigt), CT Risiko 1:20 (Amnio Karyogramm unauffällig)

26 I#0'U#)/K4:7/ % Setting: Privates Zentrum für pränatale Diagnostik Nur Patienten die primär zum CT zugewiesen wurden Zeitraum _$#&&#Y/U1`(;(&(1"/+,3;()F/I#0';#)/

27 :$"XD'"=-10#/ 2,7% (79/2.976) 1,2% (36/2.976) -54% Setting: Privates Zentrum für pränatale Diagnostik Nur Patienten die primär zum CT zugewiesen wurden Zeitraum _$#&&#Y/U1`(;(&(1"/+,3;()F/I#0';#)/

28 :103'&'.(#"/"1,3/SG+/ 26,6% (21/79) 50% (18/36) Setting: Privates Zentrum für pränatale Diagnostik Nur Patienten die primär zum CT zugewiesen wurden Zeitraum _$#&&#Y/U1`(;(&(1"/+,3;()F/I#0';#)/

29 ANWENDUNG VON NIPT C#)(".0#=/ +,-##"("./ S';L("#)/7#=0/BS7J/1&=/%-(;<-#=/+,-##"("./G#-213-#"/ NT > 3.5mm, Risiko > 1:10, Fehlbildung -> Invasive PND +/- Microarray anbieten :-(;<-#=/ +,-##"("./ I'&.#L#=$,3/8/?',3#"/=%<0#-/++?/98A/! C#=%-#,3$"./K4:7/C#2$")/! M$-,32N3-$"./K7/$")/2-N3#=/O-.1"=,-##"("./! K7/P/Q6R;;/')#-/I#3&L(&)$"./SG+/AT*/U(,-'1--1V/1"L(#0#"/ +%<0#=/ +,-##"("./ S';L("#)/7#=0/BS7J/]#-%1==0/31L#"/ K4:7/2N-/:1D#"D""#"/;(0/I#3&L(&)$".T3'3#;/W(=(X'/2N-/!"#$%&')(#/2N-/ )(#/#("/+,351".#-=,31^=1LL-$,3/"(,30/("/I-1.#/X';;0/ _$#&&#Y/U1`(;(&(1"/+,3;()/ 2 9

30 :-(;<-#=/+,-##"("./ CVS C#=D;;$"./E!/B++jJ/ K4:7/C&$01L"13;#// S7/C&$01L"13;#/ Bk3SEF:1%%*!F/:jEIJ/ ++?/98AY/ M#01(&&(#-0#=/>+/+,-##"("./ C#=%-#,3$"./K4:7/l-.#L"(=/ $")/:lt4>ew/w(=(x'/ l"0=,3#()$"./nl#-/("]1=(]#/ :KM/ b!/k4:7y/i'3#=/w(=(x'// b!/i#3&l(&)$".b#"j/ b!/k7/pq6r/;;/ Quelle: Kypros Nicolaides, NIPT webcast auf

31 +,-##"("./;(0/,2MK!/ cfdna test result for risk for trisomies 21, 18 and 13 CVS at 12 weeks All cases NT > 3.5 mm or major defects High risk on combined test High risk Low risk No result Further management Anomaly scan at 20 weeks for all (additional scan at 16 weeks if: fetal NT > 3.5 mm, TR, abnormal DV a-wave) Growth scan at 32 weeks for all (additional scan at 28 weeks if: PAPP-A < 0.3MoM) Gil M, Nicolaides KH Ultrasound Obstet Gynecol 2013

32 and six cases in which the interval between sampling and delivery of the sample to the laboratory was 6 days), second, fetal fraction below the minimal requirement of 4% (n D 23) and third, assay failure (n D 17). In 40 of the 48 cases with no result, a further blood sample was obtained and a risk score was provided in 27 (67.5%), including all seven cases in which on first sampling there normal karyotype. In this case, which was 20 weeks gestation at the time of writing, detailed ultrasound examination did not show any of the usual sonographic features of trisomy 18. Trisomy 21 was also diagnosed in a case for which cfdna testing did not provide a result and CVS was carried out because the risk from the combined test was 1:2. +,-##"("./;(0/,2MK!/ (a) (b) 1:1 1:10 Estimated risk for trisomy 1:10 Estimated risk for trisomy 1:1 1:100 1:1000 1:100 1:1000 1: : : : Crown rump length (mm) Crown rump length (mm) Gil M, Nicolaides KH Ultrasound Obstet Gynecol 2013 Figure 5 Estimated risk for trisomy in the pregnancies with trisomy 21 ( ), trisomy 18 ( ) or trisomy 13 ( ) and assumed euploid fetuses ( ), by combined test (a) and maternal blood cell-free DNA test provided at time of 12-week scan (b) (n D 984).

33 +,-##"("./;(0/,2MK!/ Presentation at 10 weeks (n = 1111) Inappropriate (n = 170; 15.3%): CRL < 32 mm (n = 64; 5.8%) CRL > 45 mm (n = 50; 4.5%) Miscarriage (n = 46; 4.1%) Twins (n = 10; 0.9%) (n = 64) Appropriate* (n = 941; 84.7%) cfdna testing (n = 1005) No result (n = 48; 4.8%) Repeat blood draw (n = 40) Result (n = 957; 95.2%): No trisomy (n = 940) Trisomy 21 (n = 11) Trisomy 18 (n = 5) Trisomy 13 (n = 1) No result (n = 13; 32.5%) Result (n = 27; 67.5%): No trisomy (n = 27) Gil M, Nicolaides KH Ultrasound Obstet Gynecol 2013

34 :-(;<-/]=/L#)(".0/ Detektionsratee Trisomie 21 Trisomie 13/18 Rate an invasiver iver PND Falsch-Positiv sitiv Rate Annahmen: Schwangerschaften T21 Prävalenz 1:340 (294/ ) T13+T18 Prävalenz 1:617 (162/ ) Contingent screening: NIPT ab Risiko >1:2500 NIPT Versagen in 5% CT wenn NIPT Versagen Invasive PND bei NIPT positiv oder CT Risiko >100 DR T %, DR T18/T13 96,5% Kumulierte FPR 0,5% Nicolaides KH Fetal Diagn Ther. 2013

35 100,000 pregnancies Unaffected n=99,544 Trisomy 21 n=294 Trisomies 18/13 n=162 Maternal blood cfdna testing Result 95% n=94,567 No result 5% n=4,977 No result 5% n=15 Result 95% n=279 No result 5% n=8 Result 95% n= % Combined test risk >1:100 Combined test risk >1: % Combined test risk >1: % 2.2% 87.0% 91.8% Positive n=473 Positive n=109 Positive n=13 Positive n=278 Positive n=7 Positive n=149 False positive rate 582 / 99,544 (0.58%) Detection rate trisomy / 294 (99.0%) Detection rate trisomies 18/ / 162 (96.3%) Nicolaides KH Fetal Diagn Ther Chorionic villus sampling 1,029 / 100,000 (1.03%)

36 100,000 pregnancies Unaffected n=99,544 Trisomy 21 n=294 Trisomies 18/13 n=162 Positive 23.9%, n=23,791 Combined test risk >1:2500 Positive 98%, n=288 Positive 99%, n=160 Maternal blood cfdna testing Result 95% n=22,601 No result 5% n=1,190 Result 95% n=274 No result 5% n=14 Result 95% n=152 No result 5% n=8 0.5% 99.5% 96.5% Positive n=113 Combined risk >1:100 n=110 Positive n=273 Combined risk >1:100 n=12 Positive n=147 Combined risk >1:100 n=7 False positive rate 223/ 99,544 (0.25%) Detection rate 285 / 294 (96.9%) Detection rate 154 / 162 (95.1%) Nicolaides KH Fetal Diagn Ther Chorionic villus sampling 662 / 100,000 (0.66%)

37 j1$2#")#/+0$)(#/ki+/>m/ b! 73#/i1--(=/C(-03-(.30/S#"0-#/2'-/I#01&/U#)(,("#/ b! 4;%&#;#"D#-$"./)#-/,#&&*2-##/MK!/ >"0#-=$,3$"./ b! b!

38 ANWENDUNG VON NIPT C#)(".0#=/ +,-##"("./ S';L("#)/7#=0/BS7J/1&=/%-(;<-#=/+,-##"("./G#-213-#"/ NT > 3.5mm, Risiko > 1:10, Fehlbildung -> Invasive PND +/- Microarray anbieten :-(;<-#=/ +,-##"("./ I'&.#L#=$,3/8/?',3#"/=%<0#-/++?/98A/! C#=%-#,3$"./K4:7/C#2$")/! M$-,32N3-$"./K7/$")/2-N3#=/O-.1"=,-##"("./! K7/P/Q6R;;/')#-/I#3&L(&)$"./SG+/AT*/U(,-'1--1V/1"L(#0#"/ +%<0#=/ +,-##"("./ S';L("#)/7#=0/BS7J/]#-%1==0/31L#"/ K4:7/2N-/:1D#"D""#"/;(0/I#3&L(&)$".T3'3#;/W(=(X'/2N-/!"#$%&')(#/2N-/ )(#/#("/+,351".#-=,31^=1LL-$,3/"(,30/("/I-1.#/X';;0/ _$#&&#Y/U1`(;(&(1"/+,3;()/ 3 8

39 _$#&&#Y/5556,1-0''"=0',X6,';/ M#-/3#(&(.#/E-1&c/

40 ULTRASCHALL Detektionsrate von strukturellen Fehlbildungen SSW % (472/957)

41 :-'%3V&1`#/ b! :-<#X&1;%=(#/ f! b! I-N3.#L$-0/ f! f! /:-'%3V&1`#/:-'.#=0#-'"/

42 M(#/E-#"H#"/)#-/,#&&*2-##/MK!/>"0#-=$,3$".//

43 METAANALYSE :#-2'-;1",#/K4:7/ Detektionsrate Falsch Positiv Rate 0,08% 0,16% 0,19% 0,11% Quelle: adaptiert nach Kypros Nicolaides Vortrag Prenatal aneuploidy screening in the cfdna world: current perspectives bei Kongress Non-invasive prenatal testing: implementation in the EU/The HARMONY TM Prenatal Test,7. November 2013, Florenz, Italien

44 K4Si7/)(1."'=D=,3/ K4:7/:#-2'-;1",#/ :-<]1&#"H/7-(=';(#/89/ 8/`/7-(=';(#/89/ B%$.!C! B%$.!D! qqs/k'-;1&/ B%$.!C! B%$.!D! RECHENBEISPIEL 9/ qqn/ l("/%'=(d]#=/7#=0/w#=$&010/=d;;0/"$-/("/8tq/)#-/i<&&#/ Quelle: Ariosa

45 7#=0]#-=1.#"/ Kein Resultat: 4,6% Niedrige fetale Fraktion: 1,8% Test Versagen: 2,8%

46 :&1H#"01;'=1(X/ Embryoblast! Fetus Trophoblast! Plazenta (Chorion) Zellteilungsfehler nach ca. 4 Tagen können zu Plazenta-mosaiken und falsch positive Befunde führen (1%)

47 M(=X-#%1"0#/C#2$")#/ Plazentamosaik (CPM) Vanishing twin Maternale Chromosomenaberration Maternales Malignom Laborfehler Niederige fetale Fraktion/counts Quelle: adaptiert nach Peter Benn False positives, Vortrag beim 12. World Congress of Fetal Medicine 2013, Marbella, Spanien

48 G(#&#/$".#&u=0#/I-1.#"/ Wo ist der Einsatz von NIPT am sinnvollsten? Low risk oder high risk Kollektiv? Invasive Abklärung nach positiven Befund - CVS oder AC? Wie klärt man diskrepante Befunde am besten weiter ab? Wie gut sind die positven und negativen Vorhersagewerte (PPV/NPV)? Wie ist die Test Performance bei Zwillingen? Was beeinflusst die Fetale Fraktion außer dem maternalen Gewicht noch? Was bringt die Erweiterung um neue Indikationen (z.b. Mikrodeletionen, Geschlechtschromosomen) außer eine Erhöhung der Falsch-Positiv Rate? Braucht es verschiedene NIPT Tests für verschiedene Indikationen?

49 71X#/3';#6666/ b! K4:7/"'"/("]1=(]#/%-#"101&/0#=D"./ b! >"0#-=$,3$"./)#-/H#&&2-#(#"/2#01&#"/MK!/,2MK!/ b! 4+7/)#-/L#=0#/+,-##"(".*7#=0/1$2/7-(=';(#/89/ f! l"0)#,x$".=-10#/pqqr/ f! b! ml4kl/m4!eko+l/ b! lwewkz>ke/h$;/>&0-1=,31&&*+,-##"("./