DIgiT21: Diagnosis Accuracy of Noninvasive Screening by PCR Digital for Down Syndrom

Sponsor

University Hospital, Grenoble (Other)

Overall Status

Completed

CT.gov ID

NCT02872948

Collaborator

(none)

1,260

Enrollment

Location

Actual Duration (Months)

54.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main objective of this study is to estimate the intrinsic diagnostic qualities of the digital dPCR in the screening of T21 from a multicentrique sample of patients with pregnancies at high risk of T21 (risk > 1/250).

The profit expected from this technique is to propose to the encircled women a screening more successful than that of the screening combined(organized) of the 1st quarter, simple of realization and in a moderate cost. We thus propose here an original alternative(alternate) method to the exclusive, expensive and binding techniques of top-debit(-flow). The recent technical improvements and his(her,its) advantages medical - economic allow to envisage a reliable, strong and long-lasting use of the dPCR in clinical routine in the DPNI of T21 in most of the laboratories. This pilot project could serve for the later development of a study of clinical validation multicentrique of large scale(big turntable ladder).

Condition or Disease	Intervention/Treatment	Phase
Trisomy 21	Genetic: Diagnostic

Detailed Description

Context

Currently, non-invasive screening test for trisomy 21 (Down syndrome) is proposed to every pregnant woman. This first trimester combined test consists of ultrasound nuchal translucency measurement, associated with different maternal serum biochemical assay and maternal age.

Since the discovery of the presence of cell-free fetal DNA in maternal plasma, the noninvasive prenatal testing (NIPT), using mainly a massive parallel sequencing (MPS) approach, has been introduced. The chromosomal origin of each sequenced plasma DNA molecule and the over- or under-representation of any chromosome can be identified by MPS in maternal plasma. The specificity and sensibility of such high-throughput techniques are excellent, close to 100 %. However, MPS remains time-consuming, very expensive (> 1000 euros per patient) and can't be used in clinical routine in most genetics laboratories worldwide.

Digital PCR represents an interesting alternative to the MPS due to its targeted approach, cost (>10x less than MPS), speed and relative simplicity allowing a clinical routine practice. However, its clinical an analytical relevance remains insufficiently demonstrated in literature data . Therefore, our main objective is to evaluate the diagnosis accuracy of noninvasive screening by PCR digital for Down syndrome.

Expected results This study will assess the sensitivity, specificity and likelihood ratio with a satisfactory accuracy. The no call rate will be also evaluated and considered as a positive test.

The optimal number of replicates (leading to a false positive rate <5%) will be determined using a ROC curve. Our hypothesis is that the sensitivity of the screening test will be upper to 95% with a false positive rate <5%.

If results are conclusive, this pilot project will be a strong argument in favor of the development of a further large scale study. It may challenge current screening strategy and allow to propose an inexpensive, fast, and accessible NIPT of trisomy 21 to a large number of laboratories in our territory.

Experimental design We will evaluate this approach on a pregnant women cohort with high risk for T21 (>1/250), prospectively recruited from three regional hospitals with a cytogenetics laboratory. We propose to preform single-blind retrospective analyses of cell free DNA of 100 pregnancies (including 70 euploid and 30 T21fetuses). Results obtained with the dPCR approach will be compared with the fetal karyotype beforehand performed. Digital PCR analyses will be performed at the Grenoble University Hospital, our team having a significant experience in digital PCR technology. Digital PCR reactions will be done on a QuantStudio™ 3D (LifeTechnologies) with the commercial high density chips etched with 20,000 consistently-sized nanoscale reaction wells. To improve the analytical sensitivity, 10 replicates will be performed for each patient.

Study Design

Study Type:

Observational

Actual Enrollment :

1260 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Diagnosis Accuracy of Noninvasive Screening by PCR Digital for Down Syndrom

Actual Study Start Date :

Aug 1, 2015

Actual Primary Completion Date :

Feb 1, 2017

Actual Study Completion Date :

Jul 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
70 euploïdes foeti samples Patients with foetus euploïde ("no sick")	Genetic: Diagnostic
30 trisomies 21 samples Patients with foetus reached(affected) by trisomy 21 ("sick")	Genetic: Diagnostic

Arm

Intervention/Treatment

70 euploïdes foeti samples

Patients with foetus euploïde ("no sick")

Genetic: Diagnostic

30 trisomies 21 samples

Patients with foetus reached(affected) by trisomy 21 ("sick")

Genetic: Diagnostic

Outcome Measures

Primary Outcome Measures

Intrinsic diagnostic qualities of the digital dPCR in the screening of T21 from a sample multicentrique of patients with pregnancies at high risk of T21 (risk > 1/250) [24 months]
The main criterion is the estimation of the intrinsic qualities of the dPCR in the screening of T21. The sensibility of the screening will be favored and the reserved value will be the one giving a rate of acceptable positive forgery fixed to 5 %.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

major Patients
unique(only) Pregnancies
Screening combined(organized) by the 1st quarter of the trisomy 21 with risk > 1/250
Patients wishing to realize a foetal taking with diagnostic aim
Sent in maternity(maternity hospital) for this taking between 12 and 17 weeks of amenorrhea