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Screening “the systematic application of a test procedure to identify individuals at sufficient risk to warrant diagnostic investigations” CVS 12wks Amniocentesis.

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Presentation on theme: "Screening “the systematic application of a test procedure to identify individuals at sufficient risk to warrant diagnostic investigations” CVS 12wks Amniocentesis."— Presentation transcript:

1 Screening “the systematic application of a test procedure to identify individuals at sufficient risk to warrant diagnostic investigations” CVS 12wks Amniocentesis 16wks Morphology Ultrasound 18wks Aim is to maximise detection of affected pregnancies and minimise false +ves

2 Biochemical Markers; 2nd Trimester1st Trimester AFP free  hCG uE3 Papp-A Inhibin A Other Markers; Nuchal Translucency Maternal age Gestational age Screening for trisomy 21

3 Marker Levels Change Significantly with Gestation Measured levels are converted to Multiples Of the Population Median or MoM values. Reference is therefore 1 MoM beta hCG at 10 wks GA Patient 120 IU/L = 2 multiples Median 60 IU/L MoMs are independent of gestational age and concentration Units LogMoM values are used in calculations as they exhibit a Gaussian distribution ( Mean +/- SD)

4 Maternal age Background Risk Years Risk %  Trisomy 21  Trisomy 18  Trisomy 13 xxx/xxy/xyy xxx/xxy/xyy 45x 45x Triploidy Triploidy Snijders et al 1995 Nicolaides et al., The week scan, London 1999

5 Snijders et al % Trisomy % Trisomy 13 12% Trisomy 18 <1% Triploidy <1% Triploidy 95% 47xxx/xxy/xyy 20% 45x % Gestational age Background Risk Nicolaides et al., The week scan, London 1999

6 Assessment of Risk Previous Chromosomal Abnormality } 45XO47XXY/XXXTriploidy Trisomy 21 Trisomy 18 Trisomy 13 } %

7 100,000 pregnancies Maternal age 60 30% Serum biochemistry at 16 wks % Nuchal translucency (NT) at 12 wks 75% 150 Fetal NT & ß-hCG & PAPP- A at 12 wks % Screening for trisomy 21 Effectiveness of different methods of screening Method of screening Number detected Detection rate Screen positive 5% N=5,000 Trisomy 21 N=200 Nicolaides KH. Fetal nuchal translucency. Am J Obstet Gynecol 2004

8 SAMSAS © Maternal Age Screening alone Second trimester biochemical screening First trimester combined screening Amniocenteses performed per case detected Fetal loss per case of Down syndrome detected 1 : 1 1 : 5 1 : 10

9 SAMSAS © 1 st trimester Risk Odds show better separation between Unaffected and Affected pregnancies when compared to 2 nd trimester Risk Odds.

10 SAMSAS ©

11 Unaffected Affected Detection Rate False -ve False +ve’s h1 h2 LR aff = h2/h1 Y= 0.425*ln_beta_MoM – 0.631*ln_Papp-a_MoM *ln_NT_MoM

12 SAMSAS © DS Risk =Mat. Age Risk × LR 20 yrs = 1 in 1600 ×2= 1 in yrs = 1 in 1100 × 2= 1 in yrs = 1 in 500 ×2= 1 in yrs = 1 in 156 × 2= 1 in yrs = 1 in 40 ×2= 1 in 20

13 SAMSAS © Noveux 1996, Graaf/Cuckle 2000, SAMSAS/Murdoch 2002

14 SAMSAS © FMF software uses data as published by Spencer, Br J Obstet Gynaecol March 2003, Vol. 110, pp Median MoMs free B-hCG = 2.15 and Papp-A = 1.93 weight corrected. Increasing Incidence of Twins (1990–2003) 1:70 to 1:55 * Assisted reproduction * Rate of twinning increases with age. >17% of pregnancies are now to women 35yrs or over, up from <9% in 1990.

15 Free ßhCG (SD) % Trisomy 21 Normal PAPP-A (SD) % Normal Trisomy 21 Biochemistry and Screening for trisomy 21 In trisomy 21 pregnancies at weeks, maternal serum free ß-hCG is increased and PAPP-A is decreased In trisomy 21 pregnancies at weeks, maternal serum free ß-hCG is increased and PAPP-A is decreased The alterations in maternal serum biochemistry are independent of fetal NT thickness The alterations in maternal serum biochemistry are independent of fetal NT thickness Screening by fetal NT and serum free ß-hCG and PAPP-A identifies 90% of cases for FPR of 5% Screening by fetal NT and serum free ß-hCG and PAPP-A identifies 90% of cases for FPR of 5% Maternal serum free ß-hCG & PAPP-A at wks Brizot et al 1994; 1995; Liao et al 2001; Noble et al 1995; Spencer et al 1999; 2000; 2001; 2002; 2003; 2004; 2005 ß-hCG: higher in Africans & IVF pregnancy, lower in smokers; PAPP-A: higher in Africans, lower in IVF & smokers

16 Biochemistry and screening for trisomy 21 OSCAR: Fetal NT, maternal serum free ß-hCG & PAPP-A at wks Nicolaides et al 2005 Normal Risk >1 in 300 3,909/75,277 ( 5.2%) Trisomy 21301/325 (92.6%) Trisomy 18/13108/122 (88.5%) Other defects83/97 (85.6%) Singleton pregnancies n=75,821; Maternal age 31 (13-49) yrs

17 Digynic Diandric

18 Combined or Integrated Screening? Combined Integrated weeks: NT NT PAPP-A PAPP-A PAPP-A PAPP-A  hCG  hCG weeks: hCG AFP AFP UE3 UE3 Inhibin A Biochemistry and Screening for Trisomy 21

19 Triple test 77% 66% Quadruple test 83% 75% 77% Nuchal translucency 34% Integrated test 93% Double test 71% 61% DR FPR 5% FPR (%) DR (%) Double test Triple test Quadruple test Integrated test 90% NT & ß-hCG/PAPP-A 83% FPR for DR 85% Wald % 1.2% Wald % MaloneWald2004 Integrated Screening Biochemistry and Screening for Trisomy 21

20 Combined Integrated Multiphase anxiety Increased default rate Delayed screening result Delayed diagnosis Late termination High detection rate Single visit Earlier screening result Early reassurance (for most) Early Diagnosis / ToP Combined or Integrated Screening? Biochemistry and Screening for Trisomy 21

21 False Positive Rate (%) Detection Rate (%) Comb / Int NT / quad triple double Receiver Operator Curves for Down Screening Tests Wald et al. 2003; Nicolaides et al Biochemistry and screening for trisomy 21 UKNSC ~ benchmark by April 2007 ~ 3% FPR 75% DR

22 Monni:options of NT or triple test information on CVS and Amnio 496 of 500 opted for NT Lancet ‘98 Kornmann: 109 2nd trimester screen - 76% would prefer 1st trimester 49 declined 2nd trimester screening - 2 would consider earlier 79 had CVS - 32% would have had 1st trimester screening Prenat Diagn ‘97 Women’s attitudes towards screening Biochemistry and screening for trisomy 21

23 Mulvey et al. BJOG 2000 Hypothesis:when informed about the rate of miscarriage of Downs pregnancies, most women would prefer to delay screening. Results:the clear majority of women wanted the earliest possible test, even if this only identified pregnancies destined to miscarry Women’s attitudes towards screening Biochemistry and screening for trisomy 21

24 SAMSAS © Rates of fetal death in Down syndrome pregnancies.

25 Assume 10% will abort before 2nd TR (90% progress to 2TR). OBS prevalence of T21 in 1 st TR = 1:347 17,600 pregnancies x 1:347 = 50 cases 45 cases progress to 2 nd TR 61.9% Detected in 2 nd TR = 27 cases 77.8% Detected in 1 st TR= 35 cases or 8 more viable cases. SAMSAS ©

26 Spencer et al Log10 PAPP-A or Free ß-hCG (MoM) Gestation (wks) ß-hCG in Tr21 PAPP-A in Tr21 NORMAL At 10 wks PAPP-A is better At 14 wks ß-hCG is better Analytical error in biochemical screening Gestational Changes in BhCG and PAPP-A in T21

27 Spencer et al, Ann Clin Biochem 2002;39: Log10 PAPP-A or Free ß-hCG (MoM) Gestation (wks) t-hCG t-hCG ß-hCG PAPP-A Overall TotalFree ß GA (wks) Detection Rates at 5% FPR (using correct variable separation model) Screening by PAPP-A & hCG (free ß vs total) Spencer et al, Ann Clin Biochem ; NORMAL Analytical error in biochemical screening Screening performance with difference types hCG

28 Analytical error in biochemical screening Impact of analytical error in risk assessment Marker CV LR CV 12.5% 7% 21.5% 4% 34-5% 15% 46-7% 25% Age 24y CRL 55mm NT 2.2mm fB-hCG 2.50MoM PAPP-A 0.55MoM Spencer 2003 DS News KryptorDelfia Imm Risk: 1 in…. FMF risk calculation software has specific medians and distributions for Kryptor and Delfia. These systems meet the analytical imprecision criteria.

29 Risk Calculation MoM values Maternal Age Gestational Age Recurrence Risk Singleton vs Twins Maternal Weight Ethnic Origin Smoking IVF Analytical Imprecision NT vs Biochemistry vs Combined vs Integrated OUTCOME


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