Unbroken news: non-invasive prenatal testing

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.