Letters to the Editors
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Positive predictive value of cell free DNA analysis TO THE EDITORS: We read with interest the Clinical Opinion piece titled “Is it time to sound an alarm about false positive cell-free DNA testing for fetal aneuploidy?” by Mennuti et al.1 As they point out, practitioners “should not be surprised when they encounter false-positive results, perhaps without ever having experienced a true positive test result.” The positive predictive value (PPV) of all of the cellfree DNA (cfDNA) products, coupled with the low incidence of the conditions that were screened, makes it clear that any result received may be a false positive. We too have been struck by the fact that “scientific publications, marketing materials, and clinical laboratory reports emphasize the high sensitivity of the testing but do not state the positive predictive value.” Even with the remarkably high sensitivity and specificity of each of the commercial products, the PPV leaves room for many false-positive results. With that in mind, we calculated the PPV for a 35-year-old woman using the highest and lowest specificities and sensitivities that were listed on the web pages of the 4 companies that currently are marketing noninvasive prenatal testing in the United States. The PPV for Down syndrome for a 35-year-old woman with no other risk factors ranges from >28% (that company lists sensitivity as >99% and specificity at 99%) to >80% (sensitivity of >99.9% and specificity of >99.9%). The PPV for the rarer conditions (trisomy 13 and 18) drops off dramatically to approximately 10% for the 35-yearold with a sonographically normal-appearing fetus. As the authors also noted, as the panel of disorders is expanded to
include rare microdeletion syndromes, (even for the 22q11 deletion syndrome, which is the most common of these) in an otherwise normal appearing fetus, the PPV is in the 2-4% range. The PPV for the rarer conditions (eg, 1p36 deletion) is 99%. It seems apparent that cfDNA is and should remain a screening technology and that clinical decision-making should be done only after confirmation of the findings by more traditional cytogenetic means. Michael L. Begleiter, MS, CGC Division of Genetics Children’s Mercy Hospitals & Clinics Kansas City, MO [email protected] Brent E. Finley, MD, MBA Midwest Perinatal Associates Overland Park, KS The authors report no conflict of interest.
REFERENCE 1. Mennuti MT, Cherry AM, Morrissette JD, Dugoff L. Is it time to sound an alarm about false-positive cell-free DNA testing for fetal aneuploidy? Am J Obstet Gynecol 2013;209:415-9. ª 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2014.01.014
MONTH 2014 American Journal of Obstetrics & Gynecology
1
www.AJOG .org
Positive predictive value of cell free DNA analysis TO THE EDITORS: We read with interest the Clinical Opinion piece titled “Is it time to sound an alarm about false positive cell-free DNA testing for fetal aneuploidy?” by Mennuti et al.1 As they point out, practitioners “should not be surprised when they encounter false-positive results, perhaps without ever having experienced a true positive test result.” The positive predictive value (PPV) of all of the cellfree DNA (cfDNA) products, coupled with the low incidence of the conditions that were screened, makes it clear that any result received may be a false positive. We too have been struck by the fact that “scientific publications, marketing materials, and clinical laboratory reports emphasize the high sensitivity of the testing but do not state the positive predictive value.” Even with the remarkably high sensitivity and specificity of each of the commercial products, the PPV leaves room for many false-positive results. With that in mind, we calculated the PPV for a 35-year-old woman using the highest and lowest specificities and sensitivities that were listed on the web pages of the 4 companies that currently are marketing noninvasive prenatal testing in the United States. The PPV for Down syndrome for a 35-year-old woman with no other risk factors ranges from >28% (that company lists sensitivity as >99% and specificity at 99%) to >80% (sensitivity of >99.9% and specificity of >99.9%). The PPV for the rarer conditions (trisomy 13 and 18) drops off dramatically to approximately 10% for the 35-yearold with a sonographically normal-appearing fetus. As the authors also noted, as the panel of disorders is expanded to
include rare microdeletion syndromes, (even for the 22q11 deletion syndrome, which is the most common of these) in an otherwise normal appearing fetus, the PPV is in the 2-4% range. The PPV for the rarer conditions (eg, 1p36 deletion) is 99%. It seems apparent that cfDNA is and should remain a screening technology and that clinical decision-making should be done only after confirmation of the findings by more traditional cytogenetic means. Michael L. Begleiter, MS, CGC Division of Genetics Children’s Mercy Hospitals & Clinics Kansas City, MO [email protected] Brent E. Finley, MD, MBA Midwest Perinatal Associates Overland Park, KS The authors report no conflict of interest.
REFERENCE 1. Mennuti MT, Cherry AM, Morrissette JD, Dugoff L. Is it time to sound an alarm about false-positive cell-free DNA testing for fetal aneuploidy? Am J Obstet Gynecol 2013;209:415-9. ª 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2014.01.014
MONTH 2014 American Journal of Obstetrics & Gynecology
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