The clinical performance of the IONA® NIPT Workflow is assessed as part of the development process prior to product launch. Post-launch, as required by the medical device regulation and for our quality system we monitor performance via a process called ‘post-market surveillance’. Post-market surveillance is a set of activities conducted by manufacturers to collect and evaluate experience gained from medical devices that have been placed on the market. It is done with the intention of ensuring we can identify any trends that suggest the need to take any action e.g. withdrawing a faulty batch from the market.
The data from both the initial validation work and post-market surveillance activities is provided below.
| IONA® Nx trisomy validation studyA | ||
|---|---|---|
| Sensitivity | Specificity | |
| Trisomy 21 |
>99.99% |
>99.99% |
| Trisomy 18 |
>99.99% |
>99.99% |
| Trisomy 13 |
>99.99% |
>99.99% |
A Validation performance has been demonstrated by evaluating 472 clinical samples from singleton and monochorionic/dichorionic twin pregnancies and comparing them to a reference result. Reference results include an amniocentesis or chorionic villus sample (CVS) sample or a birth outcome.
| IONA® Nx additional validation studyB | ||
|
|
Sensitivity |
Specificity |
|
XO |
>99.99% |
>99.99% |
|
XXY |
>99.99% |
99.5% |
|
XYY |
N/A |
>99.99% |
|
XXX |
>99.99% |
>99.99% |
|
Autosomal Aneuploidy |
>99.9% |
99.3% |
|
Monosomy |
N/A |
>99.9% |
BValidation performance has been demonstrated by evaluating 443 clinical samples from and comparing them to a reference result. Reference results include an amniocentesis or chorionic villus sample (CVS),or a birth outcome..
This has been demonstrated using the IONA® Nx cfDNA Library Preparation DX kit and the IONA® analysis software version 2.0.2. Data held on file by Yourgene Health Plc.
The above data for IONA® Nx trisomy validationA is from a sample set that includes singleton, monochorionic and dichorionic twin pregnancies. Please note that in dichorionic twins, the test sensitivity for Trisomy 21 has been observed in our Genomic Services laboratory to be reduced from >99% to about 95%. The IONA® Analysis Software uses a specific proprietary algorithm iteration for dichorionic twins, but it will not distinguish which twin is high risk.
Please note that the additional validation studyB results do not include data from dichorionic pregnancies. Therefore, sex chromosomal aneuploidy and autosomal aneuploidy analysis have not been validated for application in dichorionic twins at this time.
Fetal sex determination is not available for twins.
Table 1 – Global IONA® Test performance observed following post-market surveillance on 52,258 singleton, monochorionic & dichorionic twin pregnancies for Trisomy Screening
| Post-Market Surveillance Dataa | |||||||
|
Condition |
Observed Sensitivity |
Observed Specificity |
Observed Positive Predictive Value (PPV)b |
Observed Negative Predictive Value (NPV)b |
Observed False Positive Rate |
Observed False Negative Rate |
Prevalence for the population tested |
|
Trisomy 21 Down's syndrome (808 / 52,258) |
99.63% (805/808) 95% CI: 98.92-99.92% |
>99.99% (51,448/51,450) 95% CI: 99.99-100% |
99.75%
|
99.99%
|
0.0039%
|
0.0058%
|
1.55%
|
|
Trisomy 18 Edwards' syndrome (288/52,258) |
96.88% (279/288) 95% CI: 94.33-98.61% |
99.98% (51,962/51,970) 95% CI: 99.97-99.99% |
97.21% |
99.98%
|
0.0154%
|
0.0173%
|
0.55%
|
|
Trisomy 13 Patau's syndrome (127/52,258) |
>99.21% (126/127) 95% CI: 95.72-99.98% |
<99.99% (52,130/52,131) 95% CI: 99.99-100% |
99.21%
|
>99.99%
|
0.0019%
|
0.0019%
|
0.24%
|
a Observed performances are based on Post-Market Surveillance of the IONA® Nx workflow in over 52,258 singleton, monochorionic & dichorionic twin pregnancies, from a population of women who are predominantly at a higher risk of having a fetus with Down’s syndrome (see prevalence for the population tested).
Performances are dependant of laboratories fully reporting discordant results to Yourgene Health as they occur. From data held on file by Yourgene Health Plc. Correct as of 31st Oct 2022.
Table 2 – Global IONA® Test performance observed following Post-market surveillance on singleton and monochorionic twin pregnancies
| Post-Market Surveillance Dataa | |||||||
|
Condition |
Observed Sensitivity |
Observed Specificity |
Observed Positive Predictive Value (PPV) |
Observed Negative Predictive Value (NPV) |
Observed False Positive Rate |
Observed False Negative Rate |
Prevalence for the population tested |
|
SCA Sex Chromosome Aneuploidy (86 / 9,461) |
>97.65% (83/85) |
99.97% (9,373/9,376) |
96.51% |
99.98% |
0.0320% |
0.0213% |
0.90% |
|
AA Autosomal Aneuploidy (14 / 5,183) |
>99.99% (13/13) |
99.98% (5,169/5,170) |
92.86% |
>99.99% |
0.0193% |
<0.01% |
0.25% |
|
Microdeletions (3 / 315) |
>99.99% (3/3) |
>99.99% (312/312) |
>99.99% |
>99.99% |
<0.01% |
<0.01% |
<0.95% |
a Observed performances are based on Post-Market Surveillance of the IONA® Nx workflow in singleton and monochorionic twin pregnancies, from a population of women who are predominantly at a higher risk of having a fetus with Down’s syndrome (see prevalence for the population tested).
Performances are dependant of laboratories fully reporting discordant results to Yourgene Health as they occur. From data held on file by Yourgene Health Plc. Correct as of 31st Oct 2022.
Table 3 – Definitions used for the performance calculations
|
Sensitivity |
False Negative Rate |
Specificity |
False Positive Rate |
Positive Predictive Value |
Negative Predictive Value |
|
The proportion of truly affected pregnancies that screen positive |
The proportion of pregnancies that have the syndrome but have screened negative |
The proportion of truly unaffected pregnancies that screen negative |
The proportion of pregnancies that do not have the syndrome but have screened positive |
The likelihood that a screened positive pregnancy, is truly affected with a trisomy |
The likelihood that a screened negative pregnancy, really doesn't have a trisomy |
|
True Positive / (True Positive + FN) |
False Negative / True Positive |
True Negatives / (True Negative + FP) |
False Positive / True Negative |
True Positive / (True Positive + FP) |
True Negative / (True Negative + FN) |
| Sensitivity of the test was calculated by dividing the number of samples positive for each trisomy by the total number of samples determined as positive plus the false negative sample as determined by the reference method | Specificity was calculated by dividing the number of samples determined as unaffected for each trisomy by the total number of samples determined as unaffected plus the false positive samples as determined by the reference method |
|
Predictive Values are the actual values observed in the test population. The PPV or NPV of a screening test are dependent on the prevalence of the condition within the test population |
||
* Predictive values are more relevant than sensitivity and specificity for clinical decision and counselling of patients as they represent the actual performance in the test population.
The prevalence of trisomies 21, 18 and 13 increase with increasing maternal age so to calculate the PPV for a specific age group an online calculator can be used (e.g. https://www.perinatalquality.org/Vendors/NSGC/NIPT)