FAQs - Section 5: Results and Confirmatory Testing

The turn around time for the Harmony Prenatal Test is approximately 5-8 business days from collection.

On rare occasions, further analysis of the sample may be required before a result can be issued; in some of these instances, a repeat blood collection will be recommended.

Yes.

All medical tests are deemed to be sensitive personal information, and there are strict requirements placed on healthcare providers in Australia regarding how such information is managed.

A Harmony Prenatal Test may fail i.e., not give any result, for biological or technical reasons.

A biological failure is most often due to insufficient fetal DNA in the mother’s blood sample for analysis. This is not a failure of the laboratory’s procedures; it simply reflects the biology of the fetus and mother at the time the sample was collected. One reason for biological failure is maternal weight. Increasing maternal body weight is associated with reduced concentration of fetal DNA.

One of the reasons that Sonic Genetics recommends the Harmony™ Prenatal Test is that it can detect biological failures. Non-invasive prenatal testing methods which do not measure the amount of fetal DNA will not identify biological failures, and may inaccurately report that the sample is “normal”.

A technical failure can be due to the DNA in the mother’s sample being degraded and not suitable for analysis. This degradation may occur because the sample was collected into the wrong type of tube, there being insufficient blood, prolonged transport, or (rarely) a process error in the laboratory.

The risk of technical failure can be reduced by ensuring that an adequate sample of blood is collected into the special Harmony™ tube, and that it is shipped to the local Sonic laboratory promptly.

Overall, 3% of samples collected for the Harmony™ Prenatal Test may not yield a result. These samples may be recollected and re-analysed at no additional charge. Approximately half of the recollected samples yield results, however the remaining recollected samples will again not yield a result.

We do not recommend a third collection for the Harmony test. It is unlike that this will result in a successful report.

We do not recommend that a different form of non-invasive prenatal testing be used. Most other providers do not include an accurate measurement of fetal fraction, and a “normal result” from such a test may simply reflect the chromosome status of the patient rather than her baby.

If analysis of the recollected sample still does not yield a result, there is some evidence that there may be an increased risk of fetal chromosome abnormality in this group of patients (N Engl J Med 2015, 372:1589-97). The risk of fetal aneuploidy is approximately 10 times higher in this group than in the general maternal population. In this study, the small number of foetuses in which there was insufficient fetal DNA to analyse and who turned out to have trisomy 21, 18, or 13 had all had “high risk” results on first trimester screening. The increased risk of aneuploidy associated with a failed test may be due to an abnormal placenta releasing less DNA into the maternal circulation. The combination of a “high risk” on first trimester screening and failure of a recollected sample to yield a result may constitute sufficient reason to offer invasive genetic testing by amniocentesis or CVS. We recommend that the results be reviewed with an experienced clinician.

Yes. The accuracy of the Harmony test is not affected by maternal weight. However, maternal obesity does increase the chance of there being insufficient fetal DNA to analyse. This is a well-documented biological feature in pregnancy: as maternal weight increases, there is less fetal DNA to analyse. In contrast to other forms of NIPT, Harmony tests each sample to determine if there is sufficient fetal DNA to analyse. Harmony will only provide a result if there is sufficient fetal DNA to test. Many other NIPT providers simply assume that there is sufficient fetal DNA and potentially provide false-negative reports.

The amount of fetal DNA gradually declines with increasing maternal weight.

  • For a mother who weighs 80 kg, the probability of there being sufficient fetal DNA is 97%.
  • For a mother who weighs 100 kg, the probability of there being sufficient fetal DNA is 90%.
  • For a mother who weighs 120 kg, the probability of there being sufficient fetal DNA is 80%.
  • For a mother who weighs 140 kg, the probability of there being sufficient fetal DNA is 70%.

If Harmony cannot issue a report because there is insufficient fetal DNA, we recommend recollecting the sample; this will be analysed at no charge. If Harmony cannot issue a report because there is insufficient fetal DNA in the recollected sample, we will refund the cost of the test.

The Harmony test examines DNA fragments from the fetus and placenta that are circulating in the mother’s blood. These DNA fragments, known as cell-free DNA, last only an hour or so, and are replaced continuously from the placenta throughout the pregnancy.

Once the baby has been delivered, the last remaining fragments of the baby’s DNA disappear from the mother’s circulation within a couple of hours. As a result, there are no remaining DNA fragments from the baby that might interfere with the Harmony test in the woman’s next pregnancy.

The positive predictive value (PPV) of a test is the probability that an abnormal test result is correct. This is a particularly important measure in non-invasive prenatal testing because the chromosomal status of the placenta (the main source of “fetal DNA” in maternal blood) and the baby can differ. This means that there is always a small but definite chance that an abnormal result will be found despite the fetus being normal. For this reason, many authorities recommend that doctors and patients discuss the PPV of Harmony as part of discussions before and, if appropriate, after the test is done.

The PPV of a test varies according to the population in which it is used. The PPV of Harmony for different trisomies and different patient groups has been published in a large study (N. Engl. J. Med. 372, 1589–97 [2015]), and the results are summarized in the FAQ What is the accuracy and PPV of Harmony?. The various PPV values presented there are derived from this large study, and could be used to inform discussions between doctor and patient. But it is important to recognize that the patient population in this study does not necessarily reflect the particular situation of an individual patient.

Some clinicians may want to estimate the PPV of the Harmony test for a particular trisomy in a particular patient. There are various calculators available on the internet to provide such estimates. We do not recommend that such calculations be made for an individual patient using the Harmony test result. Our reasons for this caution are as follows:

  • The calculations underlying the Harmony test result incorporate the maternal age risk of a chromosome abnormality. If the test result and any measure that is related to maternal age were used to calculate the PPV, the information relating to maternal age would in effect be used twice.
  • The component of the calculations that is independent of maternal age is dependent on the fetal fraction. If the test result and any measure that is related to fetal fraction were used to calculate the PPV, the information relating to fetal fraction would in effect be used twice.

Our recommendation that PPV not be calculated for an individual patient is consistent with advice provided by the manufacturer of the Harmony test, Ariosa Diagnostics.

No.

NIPT provides information to inform the decisions that the patient and her doctor make. These decisions are not dictated by the NIPT result. Sonic Genetics provides information (such as this website) to assist the patient and doctor to make an informed decision.

NIPT is a very good test, but it is not a definitive diagnostic test. There is a small chance that a normal NIPT result is incorrect. This is usually due for biological rather than technical reasons.

NIPT detects approximately 80% of chromosome abnormalities in the fetus, but does not test for every possible abnormality. If the NIPT result is normal, but other investigations suggest that there is likely to be a genetic abnormality, it may still be appropriate to proceed to invasive testing rather than rely on the NIPT result. For this reason, NIPT is not recommended if there is a high risk of a fetal chromosome abnormality e.g. associated with fetal malformations detected by ultrasound.

The risk of a ‘false negative’ result is higher with NIPT methods which, unlike the Harmony™ Prenatal Test, do not accurately measure the amount of fetal DNA.