APR 11, 2018 12:00 PM PDT

Emerging Trends: Cell Free (cf)DNA-Based Screening for Common Aneuploidies

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  • Professor, Department of Pathology and Laboratory Medicine, Women & Infants Hospital/Alpert Medical School at Brown University
      Glenn E. Palomaki, PhD is the Associate Director of the Division of Medical Screening and Special Testing at Women & Infants Hospital of Rhode Island and a Professor in the Department of Pathology and Laboratory Medicine at the Alpert Medical School of Brown University. His main research interests are the statistical and methodological evaluations of screening and diagnostic tests. He has conducted multiple external validation studies demonstrating the screening or diagnostic performance of tests for genetic disorders as well as chronic diseases. He has led structured evidence reviews funded by the Centers for Disease Control and Prevention and provided statistical analyses for several other agencies. Dr. Palomaki has served on the Quality Assurance Committee of the American College of Medical Genetics where he helped author multiple laboratory standards and guidelines. Currently, he is a member of the Molecular and Biochemical Genetics Resource Committee of the College of American Pathologists and is involved in developing external quality assessment for next generation sequencing of cell free DNA in maternal circulation to identify common fetal aneuploidies. Since 2006, Dr. Palomaki has authored or co-authored 107 peer-reviewed articles and made 38 national and 22 international invited presentations. During that same time period, he has been (is) PI or Co-PI on three large industry-sponsored but independent clinical trials of diagnostic testing for fetal aneuploidy using cell free DNA in maternal circulation.


    Screening for Down syndrome began with the question "How old will you be when you deliver?".  If the pregnant woman answered 35 years of age or older, she was offered amniocentesis and a karyotype (diagnostic testing). Since then, serum markers in the second trimester have been used to form the Quadruple test.  While in the first trimester the ultrasound  and serum markers are identified as the Combined test.  When results from both trimester are used, this is termed the integrated test.  The integrated test has about a 90% detection rate for a 2% false positive rate and was the highest performing test until 2011.  It is important to note that these are phenotypic-based tests.  The finding in 1997 that cfDNA from the feto-placenta unit was in the maternal circulation in a relatively high percentage, allowed for the eventual development of a screening test, once next generation sequencing was available.  It is now clear that cfDNA can detect about 99% of Down syndrome with a false positive rate of 1 or 2 per thousand.  Importantly, this is a genotypic-based test.  Since 2013, cfDNA screening has been routinely used as a secondary screening test in 'high risk' pregnancies.  High detection means that  most of these women will have a negative result and would likely avoid invasive testing.  The low false positive rate means the predictive value will be high.  Current cfDNA screening tests tend to focus on common autosomal aneuploidies, with some expanding coverage to the sex chromosomes.  Recently, laboratories have extending testing to other chromosomes as well as to a limited number of microdeletion syndromes.  However reduced costs and less complexity are needed to allow cfDNA screening to be offered as a first line prenatal test to the entire pregnancy population.  Some tests are now emerging that aim at reducing costs and complexity.  In addition, there are competing methodologies that can identify a broader array of disorders.

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