The progress of developing and validating NIPTIFY began in 2013. The accuracy of the test has been based on 447 blood samples from expecting mothers.
|Trisomy||No of cases||Sensitivity||Specificity|
*One mosaic T18 case was not detected (~20% of aneuploidic cells).
The clinical validation study was performed in the Competence Centre on Health Technologies in collaboration with :
– Tartu University Hospital
– East-Tallinn Central Hospital
– KU Leuven Hospital
During the clinical validation study, the risk on trisomy was estimated in 447 samples from pregnant women:
– 172 samples from the general population, low risk for trisomy, Tartu University Hospital
– 259 samples with high risk for trisomy, Tartu University Hospital and East-Tallinn Central Hospital
– 16 external quality controls, KU Leuven Hospital
During the NIPTIFY test, the researchers did not know the foetal karyotype and validation method was a blind test. All pregnant women with high risk for trisomy went through an invasive foetal chromosome analysis (chorion villus biopsy method) in the Genetic Centre of Tartu University Hospital. The NIPTIFY results were compared to the results of invasive foetal chromosome analysis in the blind test method.
NIPTIFY test was validated based on the Estonian and Belgian samples. The results coincided 100%.
False Positive (FP) NIPTIFY test results:
One (1) T18 in low risk group , three (3) T13 in low risk group and two (2) T18 in high risk group.
False Positive (FP):
FP/T21 – 0%
FP/T13 – 0.67% (3/447)
FP/T18 – 0.67% (3/447)
FP/X0 – 0.45% (2/447)
In traditional screening, I trimester serum markers and ultrasound – FP 3-5%.
Sensitivity (True Positive/(True Positive + False Negative)):
T21 – 100%
T18 – 100%
T13 – 100%
45,XO – 100%
Foetal gender– 100%
Detection rate (DR) is in routine I trimester combined screening for T21 (serum markers β-hCG and PAPP-A with ultrasound): 88-89% (T21 general prevalence 1:700 pregnancies).
Specificity (True Negative/(True Negative + False Positive)):
T21 – 100%
T18 – 99.3%
T13 – 99.3%
X0 – 99.6%
Positive Predictive Value (PPV):
PPV = True Positive/(True Positive + False Positive)
PPV value for NIPTIFY test cannot be calculated at the moment because there have not been enough pregnancies with trisomy.
Negative Predictive Value (NPV):
NPV = True Negative/(True Negative + False Negative)
NPV is 100% for all trisomies.
All NIPT methods are not possible to perform unless there is enough foetal cfDNA in maternal plasma. For NIPTIFY, 4% of foetal cfDNA is needed; otherwise, a new sample is needed to repeat the test. During NIPTIFY clinical validation cfDNA in eight samples was less than <4% (1.8%, 8/447). In the validation phase, re-sampling was not performed.
Accreditation of NIPTIFY service
The Precision Medicine Laboratory will be accredited in accordance with ISO 15189.
In implementing the NIPTIFY service, we have taken into account the ISO procedures and the current service SOPs are compliant with ISO 15189 requirements.
Accreditation is in progress and due to be completed in autumn 2019. Since the method is new, we wish to use the service proving experience in ISO accreditation.
The science behind NIPTIFY technology
Bayindir et al. (2015) Noninvasive prenatal testing using a novel analysis pipeline to screen for all autosomal fetal aneuploidies improves pregnancy management. Eur J Hum Genet 23(10):1286-93. doi: 10.1038/ejhg.2014.282. Direct link to article.
Zhilina et al. (2018) Creating basis for introducing NIPT in the Estonian public health setting. bioRxiv. doi: https://doi.org/10.1101/431924. Direct link to article.