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Jacob Canick, PhD on behalf of the FASTER Consortium 12 th International Conference

First and Second Trimester Screening Markers: Results of the FASTER Trial. Jacob Canick, PhD on behalf of the FASTER Consortium 12 th International Conference on Prenatal Diagnosis and Therapy Budapest June 24-27, 2004. The Faster Consortium. Robert Ball Intermountain Utah

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Jacob Canick, PhD on behalf of the FASTER Consortium 12 th International Conference

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  1. First and Second Trimester Screening Markers:Results of the FASTER Trial Jacob Canick, PhD on behalf of the FASTER Consortium 12th International Conference on Prenatal Diagnosis and Therapy Budapest June 24-27, 2004

  2. The Faster Consortium • Robert Ball Intermountain Utah • David Nyberg Swedish Med Ctr • Christine Comstock Beaumont • Radek Bukowski UT-Galveston • Richard Berkowitz Mount Sinai • Susan Gross Albert Einstein • Lorraine Dugoff Univ Colorado • Sabrina Craigo Tufts NE Med Ctr • Ilan Timor NYU • Stephen Carr Women & Infants • Honor Wolfe UNC Chapel Hill • Mary D’Altonoverall PI • Fergal Malone co-PI • Nicholas Wald analysis • Alicja Rudnicka analysis • Allan Hackshaw analysis • Jacob Canick laboratory • Geralyn Messerlian lab • Diana Bianchi fetal cells and fetal outcome • Kimberly Dukes data mgmt National Institute of Child Health and Human Development Grant RO1 HD 38652

  3. FASTER Components • Coordinating and educational center • Columbia University, New York • Enrollment centers • 15 prenatal diagnostic centers in the U.S. • Assays, reporting, and NT management • Women & Infants Hospital, Brown Medical School • Data management • DMStat, Inc., Boston • Data analysis • Wolfson Institute for Preventive Medicine, London

  4. The FASTER Consortium Swedish Medical Center Tufts University Brown University William Beaumont Hospital Columbia University Mount Sinai Albert Einstein New York University University of Utah Intermountain HealthCare University of Colorado UNC Chapel Hill UTMB Galveston

  5. OBJECTIVES • To define performance of first trimester combined ultrasound and serum screening. • To compare performance of first trimester combined screening and second trimester quad marker screening in the same women. • To describe optimal combinations of tests for population-based Down syndrome screening.

  6. STUDY DESIGN • Prospective trial: intervention only after both 1st and 2nd trimester screening completed. • A direct comparison is the only way to compare 1st and 2nd trimester screening fairly. • Inclusion criteria: • Viable singleton pregnancy (≥ 16 yrs) • 103 – 136 weeks (CRL 36 – 79 mm) • Exclusion criteria: • Anencephaly • Septated cystic hygroma

  7. 103 – 136 weeks NT / PAPP-A / fβhCG / Age Septated cystic hygroma 150 – 186 weeks AFP / hCG / uE3 / Inh-A / Age First - Second - First - Second + First + Second - First + Second + Genetic Counseling Amniocentesis offered Follow-Up (pregnancy / pediatric) Karyotype (amnio / SAB / cord blood)

  8. Nuchal Translucency Sonography • 102 sonographers • Initial uniform practical training • Standard NT protocol • > 50 images each to confirm technique

  9. RESULTS • These results were reported at the Society for Maternal Fetal Medicine annual meeting, held in New Orleans in February 2004. • The results are from an interim analysis. • Final data analysis has now been completed, and the principal findings of the FASTER Trial are being prepared for publication. • The performance estimates will be slightly different in the final analysis.

  10. RESULTS 42,367 Evaluated 4,178 Ineligible* 38,189 Eligible 134 Cystic Hygroma 22 Anencephaly 38,033 First Trimester Screening 2,789 No quad sample 35,244 Second Trimester Screening (93%) *Ineligible due to: CRL outside range (2636); multiple (896); <16 years (357); refused (203); other (69)

  11. Completeness of Ascertainment Pregnancies enrolled 38,189 Outcome obtained (n) 37,002 Outcome obtained (%) 97% Downs expected* 112 Downs observed 117 * Estimates based on maternal age distribution of enrolled patients, and 23% loss rate from 16 - 40 wks

  12. Mean = 30.1 years SD = 5.8 years Range = 16 – 53 years Maternal Age Distribution* ≥ 35 < 35 * Maternal age in years at Estimated Date of Delivery

  13. Maternal Race Distribution Caucasian (67%) Hispanic (22%) African-American (5%) Other (2%) Asian (4%)

  14. Down Syndrome Screening PerformanceDirectly Observed Results • Combined First Trimester Screen NT / PAPP-A / fβhCG / age • Second Trimester Serum Screen AFP / hCG / uE3 / Inhibin-A / age • Integrated 1st and 2nd Trimester Screen • SERUM: PAPP-A / AFP / hCG / uE3 / Inh-A / age • FULL: NT / PAPP-A / AFP / hCG / uE3 / Inh-A / age

  15. Observed Detection Rates and FPRs DR FPR Combined screen 83% 5.6% (1:300 term cut-off) Quad screen 85% 8.5% (1:300 term cut-off) Based on pregnancies with complete 1st and 2nd trimester data (87 Downs; 33470 unaffected)

  16. Combined Versus Quad ScreeningWhich is better? Discordant pairs analysis: p = 0.7 No significant difference.

  17. 50% Aneuploidy (n=67): 37% Down (n=25) 28% Turner (n=19) 20% Trisomy 18 (n=13) 15% Other (n=10) 50% Euploid (n=67): 32% Cardiac anomaly (n=21) 12% Skeletal anomaly (n=8) 10% Fetal demise (n=7) 46% “Normal” (n=31) Cystic Hygroma Outcome134 Cases (1 : 285 Pregnancies)

  18. Observed Detection Rates and FPRs DR FPR Combined screen 83% 5.6% (1:300 term cut-off) Combined screen 87% 5.6% With hygromas (1:300 term cut-off) Quad screen 85% 8.5% (1:300 term cut-off) Based on pregnancies with complete 1st and 2nd trimester data (87 Downs; 33470 unaffected)

  19. Other Combinations of Markers:The Integrated Test • Developed by Nick Wald in 1999. • The integration of the best tests performed at different times in pregnancy into a single test. • A single risk is estimated after the two parts of the test have been completed. 0 13 26 40 PAPP-A quad test = SERUM INTEGRATED NT+PAPP-A quad test= FULL INTEGRATED (weeks) Integrate results into a single risk

  20. Observed Detection Rates for 5% FPR 100% 80% 60% 40% 31% 20% 0% ≥ Age 35 NT Combined Triple Quadruple Serum Full 1st Trimester 2nd Trimester Integrated 1st / 2nd Trim. All screens include maternal age

  21. Observed Detection Rates for 5% FPR 100% 83% 80% 67% 60% 40% 31% 20% 0% ≥ Age 35 NT Combined Triple Quadruple Serum Full 1st Trimester 2nd Trimester Integrated 1st / 2nd Trim. All screens include maternal age

  22. Observed Detection Rates for 5% FPR 100% 83% 79% 80% 72% 67% 60% 40% 31% 20% 0% ≥ Age 35 NT Combined Triple Quadruple Serum Full 1st Trimester 2nd Trimester Integrated 1st / 2nd Trim. All screens include maternal age

  23. Observed Detection Rates for 5% FPR 100% 88% 84% 83% 79% 80% 72% 67% 60% 40% 31% 20% 0% ≥ Age 35 NT Combined Triple Quadruple Serum Full 1st Trimester 2nd Trimester Integrated 1st / 2nd Trim. All screens include maternal age

  24. Observed FPR for 85% Detection Rate 20% 17.4% 15% 10% 7.6% 5% 0% NT Combined Triple Quadruple Serum Full 1st Trimester 2nd Trimester Integrated 1st / 2nd Trim. All screens include maternal age

  25. Observed FPR for 85% Detection Rate 20% 17.4% 15% 11.5% 10% 7.6% 7.2% 5% 0% NT Combined Triple Quadruple Serum Full 1st Trimester 2nd Trimester Integrated 1st / 2nd Trim. All screens include maternal age

  26. Observed FPR for 85% Detection Rate 20% 17.4% 15% 11.5% 10% 7.6% 7.2% 5.5% 5% 2.4% 0% NT Combined Triple Quadruple Serum Full 1st Trimester 2nd Trimester Integrated 1st / 2nd Trim. All screens include maternal age

  27. Down Syndrome PregnanciesFirst Trimester Median MoMs Completed week 11 12 13 NT 2.20 1.75 1.39 PAPP-A 0.30 0.49 0.78 fβhCG 1.66 2.03 2.49 Calculated from linear regression of individual Downs cases

  28. Down Syndrome Screening Performance Using these data and applying them to the U.S. population of pregnancies, the following results were obtained:

  29. FPR for 85% Detection Rate 40% 34% 30% 24% 20% 15.4% 10% 0% 11 weeks 12 weeks 13 weeks Quad NT alone

  30. FPR for 85% Detection Rate 40% 34% 30% 24% 20% 15.4% 14% 10% 5.9% 1.4% 0% 11 weeks 12 weeks 13 weeks Quad NT alone Combined

  31. FPR for 85% Detection Rate 40% 34% 30% 24% 20% 15.4% 14% 10% 6.6% 5.9% 4.7% 1.7% 1.4% 0% 11 weeks 12 weeks 13 weeks Quad NT alone Combined Serum Integrated

  32. FPR for 85% Detection Rate 40% 34% 30% 24% 20% 15.4% 14% 10% 6.6% 5.9% 4.7% 3% 1.7% 1.4% 0.8% 0.2% 0% 11 weeks 12 weeks 13 weeks Quad NT alone Combined Serum Integrated Full Integrated

  33. FPR for 85% Detection Rate 40% 34% 30% 24% 20% 15.4% 14% 10% 7.6% 6.6% 5.9% 4.7% 3% 1.7% 1.4% 0.8% 0.2% 0% 11 weeks 12 weeks 13 weeks Quad NT alone Combined Serum Integrated Full Integrated

  34. CONCLUSIONS • 1st trimester combined and 2nd trimester quad screening are similarly effective . • The Integrated test performs better than either the 1st or 2nd trimester screening methods. • 1st trimester markers vary by gestational age. Algorithms should account for these gestational age effects.

  35. ACKNOWLEDGMENTS • Columbia: K. Welch, R. Denchy, K. Berentsen • Univ Utah: F. Porter, L. Cannon, K. Nelson, C. Loucks, A. Yoshimura • Swedish: D. Luthy, S. Coe • Beaumont: D. Schmidt, J. Esler • UTMB: G. Saade, G. Hankins, J. Lee • Mount Sinai: K. Eddleman, Y. Kharbutli • Montefiore: I. Merkatz, S. Carter • U Colorado: J. Hobbins, L. Schultz • Tufts U: B. Isquith, B. Berlin • NYU: M. Paidas, J. Borsuk • Brown U: C. Duquette • UNC: R. Baughman • DM-STAT: D. Emig, T. Tripp, J. Vidaver, L. Sullivan, N. Tibbetts, P. Folan • NICHD: J. Hanson, D. Alexander, F. de la Cruz • ….. and all 102 sonographers who participated

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