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Unbroken news: non-invasive prenatal testing

7 May 2013
Appeared in BioNews 703

I know what they say about yesterday's news and today's fish and chip paper but what I'm about to tell you is six months old and still a little way off as a headline.

But headline it will be, trailed by a pack of comment, feature and analysis like any top news item should be. It mightn't generate the sort of debate that mitochondrial transfer ('three-person IVF') has done but it's nearly impossible in this field to make technological advances without discomforting sceptics adept in 'slippery slope' rhetoric.

There's no genetic engineering involved this time around, but there is genetic testing of fetuses. Every pregnant woman may one day be offered the tests in question, and in most cases only her blood sample would be required. The rigmarole, uncertainty and dilemma currently surrounding prenatal testing for many disorders (including Down's syndrome) would be largely dispelled. It's a big deal, in anyone's book.

Yet RAPID, the UK programme exploring the technology, has pushed on for the most part under the media radar since its inception four years ago. As I found out when I went to a programme update meeting in November last year, the acronym (which stands for Reliable Accurate Prenatal non-Invasive Diagnosis) was prescient; everything seems to have run to deadline.

And just the fact that the project exists and we're within touching distance of widespread clinical adoption of non-invasive prenatal testing (NIPT) is testament to how fast things now move in science. It would have been unthinkable just 16 years ago.

NIPT relies on the 1997 discovery by Professor Dennis Lo and colleagues of genetic material from the fetus, called cell-free fetal DNA (cffDNA). The paradigm-shifting potential was immediately apparent. Before then the only ways to test fetuses for inherited genetic conditions or aneuploidies would necessarily have been invasive, and therefore carry a risk of miscarriage.

In the majority of cases that's how things work today. For Down's syndrome, for example, an ultrasound scan provides indicators for risk calculation but diagnosis can only be made after amniocentesis, which carries a one in 100 risk of miscarriage.

Expectant couples who would not wish to terminate a Down's fetus are unable to properly prepare for their arrival while those who would are forced into some fairly cruel calculus. As Professor Lyn Chitty, principal investigator for RAPID, said during a discussion of the economics of NIPT, any expense would be difficult to compare 'with the cost of losing a healthy fetus'.

RAPID, which has been funded by the National Institute for Health Research, is ambitious, bordering on all-encompassing, in its scope. Its various arms include not only research to expand testing capability, refine techniques and verify reliability but also into 'stakeholder perspectives' (or how potential users feel about the technology) and the preparedness of health staff to administer the tests.

Then there's the health economics to be considered and the more mundane but frustratingly complex considerations of how, as the NHS shifts its massive bulk into a new configuration once again, the tests would get commissioned.

And then, more prosaically, how would they be used? Would they be offered to everyone? Only after the 12-week ultrasound in high risk cases? Could NIPT eventually replace ultrasound for the majority of mothers? Would we want that?

I don't have the space to do justice to all this and a review by Professor Chitty and colleagues is available in a recent British Society of Genetic Medicine newsletter. Just a few highlights, though. First, to mention some of the more fundamental research that's been done by scientists in the RAPID teams.

One particular challenge of NIPT is that the technology is often called upon when very small quantities of cffDNA are present in the sample. How to be sure that cffDNA is present at all and so not give a false negative result? The RAPID scientists have verified a marker for cffDNA which should improve NIPT's reliability.

Second, I have little doubt that when NIPT is made widely available and the headlines hit, it's the improved detection of Down's syndrome, or at least the aneuploidies, that'll claim most column inches. Fair enough - most people will use NIPT for that reason. But a presentation by Fiona McKay of Great Ormond Street Hospital pointed out just how much work has gone into developing reliable protocols to use NIPT for testing for single gene disorders.

Over 10,000 samples, collected at 42 centres around the UK, have now been donated to the biobank for RAPID scientists to use. Researchers are currently developing and testing NIPT in a wide range of disorders from achondroplasia to beta-thalassemia to cystic fibrosis.

In fact, it was frustrating not to hear more on progress in cystic fibrosis. But the overall impression from the meeting was that NIPT is a reliable, robust technology for detection of Down's syndrome and the aneuploidies, that there's been less work on congenital disorders because of the lower prevalence, but NIPT is looking very promising there, too.

The major questions now seem to be those 'hows', especially with regard to Down's syndrome. I've been to conferences before that have concluded by the chair asking for any questions and only the air conditioning unit responds. This was not like that. After quick consensus on some fundamental matters (when during pregnancy to offer NIPT, for example) a lively debate on how exactly to implement NIPT followed. Expect to hear much more about that before NIPT is rolled out.

What, hopefully, you won't hear more about is the intellectual property saga currently being played out in US courtrooms; it would be bad news if legal wrangles impacted implementation of NIPT. I learnt at the RAPID update that all the major technology players are suing each other. I'm simplifying, but honestly, not that much.

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10 June 2013 - by James Brooks 
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4 February 2013 - by Sandy Starr 
In 2010, Professor Sir Robert Edwards was awarded a long overdue Nobel Prize in Physiology or Medicine, for his the part he played in pioneering both the theory and practice of IVF. This conference focused on the kind of cutting-edge research that takes Professor Edwards' legacy forward...
14 January 2013 - by Dr Daniel Grimes 
US biotech company Verinata Health has reported sequencing fetal DNA taken from pregnant women's blood to test for genetic abnormalities...
10 December 2012 - by Dr Lux Fatimathas 
More sensitive prenatal testing of fetal DNA could improve the detection of genetic diseases, studies find...
24 October 2011 - by Julianna Photopoulos 
A new prenatal test that can detect Down's syndrome by using a sample of the mother's blood was launched in twenty US cities last Monday....
29 September 2008 - by Ailsa Stevens 
A decade ago, it was found that the blood of pregnant women contains DNA from the fetus. The discovery of this 'free fetal DNA' (ffDNA) has led to the development of non-invasive prenatal diagnosis, where genetic characteristics of the fetus can be analysed a mere few weeks into pregnancy by...
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