FAQs - Section 8: Results and Confirmatory Testing
The turnaround 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 and analysis (at no additional charge) may be required.
The positive predictive value (PPV) of a test is the probability that an abnormal 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 fetus 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, any abnormal NIPT test should be regarded as a screening test which requires confirmation by definitive cytogenetic studies. This issue should be discussed with the patient as part of pre-test counselling.
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 ), and the results are summarised in the FAQ 'What is the predictive value of Harmony?'. The various PPV values presented could be used to inform discussions between doctor and patient, but it is important to note 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 already incorporate the probability of a chromosome disorder based on maternal age and gestation. If the test result and any measure that is related to maternal age or gestation were used to calculate the PPV, this information 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.
There is an inverse relationship between maternal body weight and the concentration of fetal DNA (fetal fraction) in maternal plasma.
- For a pregnant woman weighing 60 kg, there is a 99% chance that there will be sufficient fetal DNA for NIPT at 10 weeks’ gestation.
- For a pregnant woman weighing 100 kg, the chance that there will be sufficient fetal DNA for NIPT drops to 90%.
- For a pregnant woman weighing 150 kg, the chance that there will be sufficient fetal DNA for NIPT drops further to 50%.
This relationship between maternal weight and fetal fraction does not compromise the accuracy of Harmony. Irrespective of a woman’s weight, Harmony will provide a highly accurate screening test if there is sufficient fetal DNA. If there is insufficient fetal DNA, Harmony identifies this fact and does not provide a risk assessment.
If Harmony cannot issue a report because there is insufficient fetal DNA, we recommend re-collecting the sample, as the quantity of fetal DNA may have increased over this period; this will be analysed at no charge. If Harmony cannot issue a report because there is insufficient fetal DNA in a re-collected sample, we do not recommend further re-collections and will refund the cost of the test to the payer on request.
Please note that maternal weight should not necessarily be assumed to be the only cause of insufficient fetal DNA for analysis. Some autosomal trisomies (specifically trisomies 18 and 13) are associated with impaired placental function and reduced fetal fraction. The risk of fetal aneuploidy is approximately 10 times higher in this group than in the general maternal population. The combination of a ‘high risk’ on first trimester screening and failure of a re-collected sample to yield a result may constitute sufficient reason to offer invasive genetic testing. We recommend that the results be reviewed with an experienced clinician.
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 issue 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 re-collected and re-analysed at no additional charge. Approximately two-thirds of the re-collected samples yield results, i.e. Harmony provides a result for 99% of patients tested. For patients who paid for Harmony themselves and who do not have a result after two collections, we offer a full refund upon application.
The manufacturer of the test does not recommend a third collection for the Harmony test. It is unlikely that this will result in a successful report, and it may delay consideration of other investigations. Similarly, 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 mother rather than her baby.
If analysis of the second collection 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 fetuses 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.
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.
For more information, please see here.
Sonic Genetics recommends that doctors refer patients for genetic counselling before or after NIPT according to the patient’s needs and doctor’s ability to provide information and support.
If the Harmony Prenatal Test result indicates a high probability for any chromosome disorder, Sonic Genetics offers genetic counselling at no additional cost to the patient (the report will include instructions on how the patient can be referred for this service).
This offer is limited to Australian-based patients who have prepaid Sonic Genetics for the Harmony test. Genetic counselling is provided by independent accredited genetic counsellors. Please note that this counselling service is primarily designed to address the information needs of the patient, and does not include further management of genetic testing or the pregnancy.
Referrals for free genetic counselling for NIPT screening must be received within one month of the latest Sonic Genetics report being issued. To access genetic counselling outside this period, or for genetic counselling for other purposes, patients can be directly referred to a genetic counselling provider. A list of potential providers can be found here.
The genetic pathologists at Sonic Genetics are readily available for discussions with requesting doctors. Our genetic pathologists cannot provide clinical consultations for patients.
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 help the patient and doctor make an informed decision. Sonic Genetics offers confirmatory diagnostic pathology tests for Medicare-eligible patients for rebate value only. Doctors may also wish to refer a patient for genetic counselling to discuss the NIPT result.
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 for the targeted chromosomes. This is usually due to biological rather than technical reasons. In addition, while NIPT targets the most common chromosomal abnormalities, it 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.
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.