Transcript Document

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
The Faster Consortium
•
•
•
•
•
•
•
•
Mary D’Alton
overall 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
•
•
•
•
•
•
•
•
•
•
•
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
National Institute of Child Health and Human Development Grant RO1 HD 38652
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
The FASTER Consortium
Swedish Medical Center
Tufts University
William Beaumont Hospital
University of Utah
Intermountain HealthCare
University of Colorado
Brown University
Columbia University
Mount Sinai
Albert Einstein
New York University
UNC Chapel Hill
UTMB Galveston
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.
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
103 – 136 weeks
NT / PAPP-A / fβhCG / Age
Septated
cystic hygroma
First Second -
150 – 186 weeks
AFP / hCG / uE3 / Inh-A / Age
First Second +
First +
Second -
First +
Second +
Genetic Counseling
Amniocentesis offered
Follow-Up
(pregnancy / pediatric)
Karyotype
(amnio / SAB / cord blood)
Nuchal Translucency Sonography
• 102 sonographers
• Initial uniform
practical training
• Standard NT protocol
• > 50 images each to
confirm technique
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.
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)
Completeness of Ascertainment
Pregnancies enrolled
Outcome obtained (n)
Outcome obtained (%)
Downs expected*
Downs observed
38,189
37,002
97%
112
117
* Estimates based on maternal age distribution of enrolled patients, and 23% loss rate from 16 - 40 wks
Maternal Age Distribution*
21.6%
≥ 35
< 35
• Mean = 30.1 years
• SD = 5.8 years
• Range = 16 – 53 years
78.4%
* Maternal age in years at Estimated Date of Delivery
Maternal Race Distribution
Caucasian (67%)
Hispanic (22%)
Other (2%)
African-American (5%)
Asian (4%)
Down Syndrome Screening Performance
Directly Observed Results
1.
Combined First Trimester Screen
NT / PAPP-A / fβhCG / age
2.
Second Trimester Serum Screen
AFP / hCG / uE3 / Inhibin-A / age
Integrated 1st and 2nd Trimester Screen
3.
I.
II.
SERUM:
FULL:
PAPP-A / AFP / hCG / uE3 / Inh-A / age
NT / PAPP-A / AFP / hCG / uE3 / Inh-A / age
Observed Detection Rates and FPRs
Combined screen
DR
FPR
83%
5.6%
85%
8.5%
(1:300 term cut-off)
Quad screen
(1:300 term cut-off)
Based on pregnancies with complete 1st and 2nd trimester data (87 Downs; 33470 unaffected)
Combined Versus Quad Screening
Which is better?
Discordant pairs analysis:
p = 0.7
No significant difference.
Cystic Hygroma Outcome
134 Cases (1 : 285 Pregnancies)
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)
Observed Detection Rates and FPRs
Combined screen
DR
FPR
83%
5.6%
87%
5.6%
(1:300 term cut-off)
Combined screen
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)
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
PAPP-A
NT+PAPP-A
26
quad test = SERUM INTEGRATED
quad test = FULL INTEGRATED
Integrate results into a single risk
40
(weeks)
Observed Detection Rates for 5% FPR
100%
80%
60%
40%
31%
20%
0%
Age≥ 35
NT
Combined
1st Trimester
Triple
Quadruple
2nd Trimester
Serum
Full
Integrated 1st / 2nd Trim.
All screens include maternal age
Observed Detection Rates for 5% FPR
100%
83%
80%
67%
60%
40%
31%
20%
0%
Age≥ 35
NT
Combined
1st Trimester
Triple
Quadruple
2nd Trimester
Serum
Full
Integrated 1st / 2nd Trim.
All screens include maternal age
Observed Detection Rates for 5% FPR
100%
83%
80%
79%
72%
67%
60%
40%
31%
20%
0%
Age≥ 35
NT
Combined
1st Trimester
Triple
Quadruple
2nd Trimester
Serum
Full
Integrated 1st / 2nd Trim.
All screens include maternal age
Observed Detection Rates for 5% FPR
100%
83%
80%
79%
84%
88%
72%
67%
60%
40%
31%
20%
0%
Age≥ 35
NT
Combined
1st Trimester
Triple
Quadruple
2nd Trimester
Serum
Full
Integrated 1st / 2nd Trim.
All screens include maternal age
Observed FPR for 85% Detection Rate
20%
17.4%
15%
10%
7.6%
5%
0%
NT
Combined
1st Trimester
All screens include maternal age
Triple
Quadruple
2nd Trimester
Serum
Full
Integrated 1st / 2nd Trim.
Observed FPR for 85% Detection Rate
20%
17.4%
15%
11.5%
10%
7.6%
7.2%
5%
0%
NT
Combined
1st Trimester
All screens include maternal age
Triple
Quadruple
2nd Trimester
Serum
Full
Integrated 1st / 2nd Trim.
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
1st Trimester
All screens include maternal age
Triple
Quadruple
2nd Trimester
Serum
Full
Integrated 1st / 2nd Trim.
Down Syndrome Pregnancies
First 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
Down Syndrome Screening Performance
Using these data and applying them
to the U.S. population of pregnancies,
the following results were obtained:
FPR for 85% Detection Rate
40%
34%
30%
24%
20%
15.4%
10%
0%
11 weeks
NT alone
12 weeks
13 weeks
Quad
FPR for 85% Detection Rate
40%
34%
30%
24%
20%
15.4%
14%
10%
5.9%
1.4%
0%
11 weeks
NT alone
12 weeks
Combined
13 weeks
Quad
FPR for 85% Detection Rate
40%
34%
30%
24%
20%
15.4%
14%
10%
5.9%
4.7%
6.6%
1.4%1.7%
0%
11 weeks
NT alone
12 weeks
Combined
Serum Integrated
13 weeks
Quad
FPR for 85% Detection Rate
40%
34%
30%
24%
20%
15.4%
14%
10%
5.9%
1.4%1.7%0.2%
4.7%
6.6%
3%
0.8%
0%
11 weeks
NT alone
12 weeks
Combined
Serum Integrated
13 weeks
Full Integrated
Quad
FPR for 85% Detection Rate
40%
34%
30%
24%
20%
15.4%
14%
10%
5.9%
1.4%1.7%0.2%
4.7%
6.6%
3%
7.6%
0.8%
0%
11 weeks
NT alone
12 weeks
Combined
Serum Integrated
13 weeks
Full Integrated
Quad
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.
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