A New Prenatal Blood Test for Down Syndrome (RNA)

The RNA (RNA-Based Noninvasive Aneuploidy) Study

The study will examine the sensitivity and specificity of a circulating cell-free nucleic acid test (DNA/RNA) to identify Down syndrome between about 10 weeks and 21 weeks 6 days gestation. In addition, the new test may be used to identify trisomy 13 and 18 as part of a more complete laboratory developed test. We hypothesize that the new circulating cell-free fetal NA-based test will accurately and precisely measure specific fetal markers in maternal circulation and that measurement will lead to the ability to noninvasively identify with high sensitivity and specificity, fetal chromosome abnormalities, such as Down syndrome.

Study Overview

• Status: Completed
• Conditions: Down Syndrome; Trisomy 21

Detailed Description

The RNA study is an observational trial whose primary aim is to document the performance (sensitivity and specificity) of one or more laboratory developed test (LDT) using circulating cell-free fetal nucleic acids from maternal plasma to identify Down syndrome. Multiple test modalities are being pursued, including massively parallel sequencing and those utilizing differential methylation. The population being studied is women already having a diagnostic test (e.g., amniocentesis, CVS) between 10 weeks and 21 weeks 6 days gestation, and whose pregnancy is at high risk for having Down syndrome. The women provide informed consent. The karyotype will provide the gold standard against which the LDT test is judged. Samples and karyotypes will be collected from up to 25 prenatal diagnostic centers around the world and tested in several laboratories in the United States. The secondary aim is to develop a nucleic acid sample bank to allow documentation of subsequent improvements or new methodologies to identify fetal aneuploidy using circulating cell-free fetal nucleic acids.

• Study Type: Observational
• Enrollment (Actual): 4664

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1431
    • Center for Medical Education and Clinical Investiagtion
  • Buenos Aires, Argentina, C1181ACH
    • Sociedad Italiana de Beneficencia en Buenos Aires - Hospital Italiano
• Australia
  • New South Wales
    • St. Leonards, New South Wales, Australia, 2065
      • University of Sydney
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • University of Calgary
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Children's and Women's Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • IWK Health Centre
  • Ontario
    • Toronto, Ontario, Canada, M2K 1E1
      • North York General Hospital
• Czech Republic
  • Ceske Budejovice, Czech Republic, 370 01
    • Centrum lekarske genetiky s.r.o.
  • Zlinsky kraj
    • Zlin, Zlinsky kraj, Czech Republic, 76001
      • Imalab
• Hungary
  • Budapest, Hungary
    • Semmelweis University
  • Pecs, Hungary, 17
    • Pécs University
• Ireland
  • Dublin, Ireland
    • Rotunda hospital
• Israel
  • Haifa, Israel, 31096
    • Rambam Medical Center
• Italy
  • Genova, Italy, 16147
    • U.O. Ostetricia e Ginecologia Laboratorio Sperimentale di Tecniche
• Spain
  • Catalonia
    • Barcelona, Catalonia, Spain, 08020
      • Hospital Clinic Barcelona - Maternitat Campus
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University, FSM
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Women and Infants Hospital
    • Providence, Rhode Island, United States, 02905
      • New Beginnings Perinatal Consultants
  • Texas
    • Houston, Texas, United States, 77021-2024
      • Baylor College of Medicine
  • Utah
    • Murray, Utah, United States, 84107-5701
      • Intermountain Health Care
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • UVA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Pregnant women between about 10 weeks and 21 weeks 6 days gestation who are undergoing a diagnostic procedure (i.e., chorionic villus sampling or amniocentesis) for karyotype analysis.

Description

Inclusion Criteria:

• Pregnant women between about 10 weeks and 21 weeks 6 days gestation who are undergoing a diagnostic procedure (i.e., chorionic villus sampling or amniocentesis) for karyotype analysis who have, on average, a high prevalence of Down syndrome (about 1:30 to 1:50).

• Three main sources are pregnancies screen positive for:

  1. the combined test at 10 to 13 weeks (NT, PAPP-A and hCG)
  2. the second trimester quadruple test at 15 to 18 weeks gestation
  3. integrated screening (PAPP-A and the quadruple test, with or without NT).
• Variations of the integrated test such as sequential testing will also be acceptable.
• Other, less common high risk groups would be women having diagnostic testing because of maternal age of 38 years or older at delivery, pregnancies with an abnormal ultrasound highly suggestive of a chromosome abnormality (e.g., major heart defect, clenched fist), and women with an inherited form of Down syndrome (Robertsonian translocation).

Exclusion Criteria:

• Nonpregnant women and women at relatively low risk for a Down syndrome baby.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Down syndrome; Women having CVS or amniocentesis who, as a group, have a high prevalence of Down syndrome.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The RNA study is an observational trial whose primary aim is to document the performance (sensitivity and specificity) of a laboratory developed test (LDT), using fetal nucleic acid in maternal plasma to identify Down syndrome in early pregnancy.	Within 1st and 2nd trimesters

Secondary Outcome Measures

Outcome Measure	Time Frame
The secondary aim is to develop a sample bank to allow documentation of subsequent improvements in the existing LDT or documenting performance of new methodologies.	Late1st and early 2nd trimesters

Collaborators and Investigators

• Sponsor: Women and Infants Hospital of Rhode Island
• Collaborators: Sequenom, Inc.
• Investigators: Principal Investigator: Barbara O'Brien, MD, Women and Infants Hospital

Publications and helpful links

General Publications

• Palomaki GE, Ashwood ER, Best RG, Lambert-Messerlian G, Knight GJ. Is maternal plasma DNA testing impacting serum-based screening for aneuploidy in the United States? Genet Med. 2015 Nov;17(11):897-900. doi: 10.1038/gim.2015.39. Epub 2015 Apr 2.
• Palomaki GE, Deciu C, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, van den Boom D, Bombard AT, Grody WW, Nelson SF, Canick JA. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med. 2012 Mar;14(3):296-305. doi: 10.1038/gim.2011.73. Epub 2012 Feb 2.
• Canick JA, Kloza EM, Lambert-Messerlian GM, Haddow JE, Ehrich M, van den Boom D, Bombard AT, Deciu C, Palomaki GE. DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations. Prenat Diagn. 2012 Aug;32(8):730-4. doi: 10.1002/pd.3892. Epub 2012 May 14.
• Palomaki GE, Kloza EM, Lambert-Messerlian GM, van den Boom D, Ehrich M, Deciu C, Bombard AT, Haddow JE. Circulating cell free DNA testing: are some test failures informative? Prenat Diagn. 2015 Mar;35(3):289-93. doi: 10.1002/pd.4541. Epub 2015 Jan 8.
• Lambert-Messerlian G, Kloza EM, Williams J 3rd, Loucky J, O'Brien B, Wilkins-Haug L, Mahoney MJ, De Biasio P, Borrell A, Ehrich M, van den Boom D, Bombard AT, Deciu C, Palomaki GE. Maternal plasma DNA testing for aneuploidy in pregnancies achieved by assisted reproductive technologies. Genet Med. 2014 May;16(5):419-22. doi: 10.1038/gim.2013.149. Epub 2013 Oct 3.
• Mazloom AR, Dzakula Z, Oeth P, Wang H, Jensen T, Tynan J, McCullough R, Saldivar JS, Ehrich M, van den Boom D, Bombard AT, Maeder M, McLennan G, Meschino W, Palomaki GE, Canick JA, Deciu C. Noninvasive prenatal detection of sex chromosomal aneuploidies by sequencing circulating cell-free DNA from maternal plasma. Prenat Diagn. 2013 Jun;33(6):591-7. doi: 10.1002/pd.4127.
• Canick JA, Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE. The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies. Prenat Diagn. 2013 Jul;33(7):667-74. doi: 10.1002/pd.4126. Epub 2013 May 31.
• Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, van den Boom D, Bombard AT, Deciu C, Grody WW, Nelson SF, Canick JA. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med. 2011 Nov;13(11):913-20. doi: 10.1097/GIM.0b013e3182368a0e.
• Kloza EM, Haddow PK, Halliday JV, O'Brien BM, Lambert-Messerlian GM, Palomaki GE. Evaluation of patient education materials: the example of circulating cell free DNA testing for aneuploidy. J Genet Couns. 2015 Apr;24(2):259-66. doi: 10.1007/s10897-014-9758-8. Epub 2014 Sep 10.

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: April 6, 2009
• First Submitted That Met QC Criteria: April 6, 2009
• First Posted (Estimate): April 7, 2009

Study Record Updates

• Last Update Posted (Estimate): June 3, 2015
• Last Update Submitted That Met QC Criteria: June 1, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: pregnant women; Down Syndrome; trisomy 21; prenatal testing
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Intellectual Disability; Abnormalities, Multiple; Chromosome Disorders; Chromosome Aberrations; Aneuploidy; Chromosome Duplication; Syndrome; Down Syndrome; Trisomy
• Other Study ID Numbers: 09-0004