Noninvasive Detection of Fetal Trisomy 21 by Sequencing of DNA in Maternal Blood: A Study in a Clinical Setting

Ehrich, Mathias; Deciu, Cosmin; Zwiefelhofer, Tricia; Tynan, John A.; Cagasan, Lesley; Tim, Roger; Lu, Vivian; McCullough, Ron; McCarthy, Erin; Nygren, Anders O.H.; Dean, Jarrod; Tang, Lin; Hutchison, Don; Lu, Tim; Wang, Huiquan; Angkachatchai, Vach; Oeth, Paul; Cantor, Charles R.; Bombard, Allan T.; Boom, Dirk van den

doi:10.1097/ogx.0b013e31822c182b

Cited by 65 publications

(101 citation statements)

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“…

Sensitivity and specificity of a test are estimated from the overlapping distributions of affected and unaffected individuals using a specified cutoff.

…”

supporting

confidence: 74%

Genome-Wide Fetal Aneuploidy Detection by Maternal Plasma DNA Sequencing

Benn

Cuckle

Pergament

2012

Obstetrics & Gynecology

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Bianchi et al 1 have confirmed recent prospective studies [2][3][4] showing that massively parallel sequencing of cell-free DNA in maternal plasma is predictive of common nonmosaic autosomal trisomies in high-risk pregnancies. However, their estimates of sensitivity and specificity could lead to false conclusions.Sensitivity and specificity of a test are estimated from the overlapping distributions of affected and unaffected individuals using a specified cutoff. For massively parallel sequencing, sensitivity is the proportion of trisomy pregnancies with z-score above the cutoff, and specificity is the proportion of euploid pregnancies with lower scores.In Bianchi et al, 1 using a zϭ2.5 cutoff, the sensitivity and estimated specificity are: Down syndrome 100% (90/90) and 98.5% (404/410); Edwards syndrome 97.4% (37/38) and 99.4% (460/463); Patau syndrome 81.2% (13/ 16) and 100% (485/485). Using zϭ4.0, the rates are: Down syndrome 98.9% (89/90) and 410/410 (100%); Edwards syndrome 92.1% (35/38) and 100% (463/463); Patau syndrome 68.8% (11/ 16) and 100% (485/485).However, instead of using either set of rates, the authors overstated performance, because tests with z-scoresϭ2.5-4.0 were designated "unclassified" and excluded. No reason was given for this exclusion, which, unfortunately may give the impression that a positive result (zϾ4.0) is fully diagnostic. In fact, a study of this size cannot exclude the possibility of false-positive results being relatively frequent, particularly when many types of aneuploidy are evaluated.A result in the 2.5-4.0 range is associated with about a fivefold increased risk of aneuploidy: 3.5% (5/144) of trisomies had results in this range compared with 0.7% (9/1358) without the trisomy being evaluated. Women with results in such a range would need to receive information about their individual risk given their massively parallel sequencing result, as is done for conventional aneuploidy screening.At this early stage of development, confirmatory invasive testing is needed for women with a positive massively parallel sequencing test. 5 Risks are also very high for those in the 2.5-4.0 range, and they, too, might be offered invasive testing. When sufficient data become available, it will be possible to estimate individual post-massively parallel sequencing risks for all women and a more optimal cutoff for offering invasive testing then could be defined.

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“…

Sensitivity and specificity of a test are estimated from the overlapping distributions of affected and unaffected individuals using a specified cutoff.

…”

supporting

confidence: 74%

Genome-Wide Fetal Aneuploidy Detection by Maternal Plasma DNA Sequencing

Benn

Cuckle

Pergament

2012

Obstetrics & Gynecology

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“…Por el contrario, ya son muchos los grupos de trabajo que han presentado excelentes resultados mediante el análisis de ADN fetal libre en sangre materna con técnicas de secuenciación masiva paralela (MPSS) o análisis dirigido de las regiones de interés (DANSR TM ) [6][7][8][9][10] . Tras la secuenciación del material genético se emplea el algoritmo FORTE que cuantifica el riesgo de trisomía en el contexto de la FF, tomando en cuenta el riesgo a priori basado en la edad materna y gestacional, obteniendo un riesgo para cada trisomía que suele situarse en los rangos más extremos, tanto en pacientes de bajo riesgo (< 0,001%) como en aquellos casos de alto riesgo (> 99%), disminuyendo el número de resultados intermedios.…”

Section: Discussionunclassified

Cribado prenatal no invasivo de aneuploidías mediante análisis de ADN fetal en sangre materna

Pérez-Pedregosa

Ros

Hernandez

et al. 2015

Progresos de Obstetricia y Ginecología

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Cell free DNA; Diagnóstico prenatal no invasivo; Cribado combinado; Trisomía 21; Aneuploidías; Diagnóstico prenatal Resumen El objetivo de este trabajo es analizar la sensibilidad y la especificidad en gestaciones únicas del análisis de cell free DNA (cfDNA) en sangre materna para el diagnóstico de las principales trisomías fetales (t21,t18 y t13), así como comparar los resultados con los obtenidos mediante el cribado combinado bioquímico ecográfico (CC); 582 gestaciones de más de 10 semanas fueron estudiadas. Todos los resultados con alto riesgo fueron confirmados mediante determinación prenatal del cariotipo o tras el nacimiento. Se realizó seguimiento posnatal en todos los casos, excepto en 5 gestaciones en las que no pudo ser confirmado el cariotipo por pérdida fetal tardía o aborto y renuncia de los padres a su estudio. El análisis de cfDNA fue posible tras la primera determinación en 97.1% de las muestras. En 3 (0,5%) no se obtuvo resultado tras 2 o incluso 3 extracciones; 14 fetos presentaron alto riesgo de t21 en sangre materna que fue confirmado en todos los casos; 3 fetos con alto riesgo de t18 en el estudio no invasivo fueron también confirmados tras el estudio del cariotipo fetal. No hubo falsos positivos ni negativos en la muestra analizada. La sensibilidad del CC fue del 87,5% para una tasa del 6,7% de falsos positivos. El análisis de cfDNA en sangre materna permite con alta sensibilidad y especificidad establecer el riesgo de las principales trisomías fetales. Los resultados obtenidos son probablemente superiores a los del CC. El número de procedimientos invasivos en la población de estudio se redujo de forma muy significativa. ß 2014 SEGO. Publicado por Elsevier España, S.L.U. Todos los derechos reservados.

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“…In 1997, Lo et al [10] demonstrated that 3-6% of cell-free DNA identified in maternal serum is of fetal origin. In 2011, several groups reported on the implementation of technology to isolate fetal or placental cell-free DNA for screening women at high risk for aneuploidy, demonstrating an approximate 98% detection rate for fetal Down syndrome with a 0.05% false-positive rate [11,12]. In December, 2012, the American College of Obstetricians and Gynecologists issued a committee opinion supporting the use of noninvasive prenatal testing (NIPT) in high-risk women, defined as women over age 35 years, those with sonographic findings consistent with aneuploidy, or those with a prior affected child [13 && ].…”

Section: Development Of Cell-free Dna For Aneuploidy Screeningmentioning

confidence: 99%

The impact of noninvasive fetal evaluation

Rose

Eller

2014

Current Opinion in Obstetrics &Amp; Gynecology

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Prenatal diagnosis procedures will continue to be necessary for direct fetal assessment but on a much more limited scale. It is possible that all trainees will not be able to become competent in amniocentesis and other even less common procedures. Furthermore, experienced physicians may lose competence, given the lack of available procedures for skill retention. Innovative methods of skill acquisition and maintenance may be required in the near future. Although long-term assessments of efficacy are currently lacking, the introduction of comprehensive, simulation-based curriculia has the potential to both educate trainees and help maintain physician competence.

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Noninvasive Detection of Fetal Trisomy 21 by Sequencing of DNA in Maternal Blood: A Study in a Clinical Setting

Cited by 65 publications

References 0 publications

Genome-Wide Fetal Aneuploidy Detection by Maternal Plasma DNA Sequencing

Genome-Wide Fetal Aneuploidy Detection by Maternal Plasma DNA Sequencing

Cribado prenatal no invasivo de aneuploidías mediante análisis de ADN fetal en sangre materna

The impact of noninvasive fetal evaluation

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