Wednesday, 9 July 2014

Non-invasive pre-natal testing for chromosomal abnormalities: bioinformatics and the UK NHS process

NIPT signal associated with a fetal micro
deletion on chromosome 22 causing
 DiGeorge syndrome.
Kitty Lo, a postdoctoral researcher in my group at UCL, just published a new bioinformatics application note and an associated R package called RAPIDR (available on CRAN) to streamline the bioinformatics of non-invasive pre-natal testing (NIPT). It is an opportunity to advertise the package and say a bit more on NIPT and what is happening in the UK with regard to this relatively new technology.
What is non-invasive pre-natal testing (NIPT) and how does it work?
Much has been written on the impact of DNA sequencing technologies on people’s lives, and some fields like genetic diagnosis for rare disorders clearly have been radically changed. But (thankfully) this type of application only concerns a small fraction of the general population. There is one application, however, that has the potential to affect thousands of people: the ability to diagnose chromosomal abnormalities, such as Down syndrome, from the blood of the pregnant mother.
While the technical aspects are clearly non trivial, the concept is relatively simple. It turns out that there are bits of DNA floating in the plasma of the mother. Some of these DNA fragments originate from the fetus (typically 10%, but this number varies quite a lot).  If the fetus has an extra chromosome 21, there will be more reads mapping to chromosome 21 than for a normal fetus. Statistics can detect this, and generate a firm diagnosis for the parents.
The key advantage of this non-invasive test of course is to avoid the invasive test, which carries a small but significant risk of miscarriage. It should be possible to test more women, hence increase the ability to detect Down syndrome while avoiding the risk associated with existing methodologies. There are also fierce legal and ongoing battles around the intellectual property associated with these tests but I am not best placed to comment on this.
NIPT in the UK: the RAPID project
Much of the development of NIPT for aneuploidy has been driven by US private companies. As a consequence, a large proportion of tests currently performed in the UK simply ship samples to the US for an analysis. Furthermore, it is currently only available through the private sector in the UK. Implementing this into routine clinical practice in a public sector health service will require more evaluation to see where in the care pathway it might fit, how we educate women and health professionals, the health economic aspects etc. The RAPID programme, which is funded by the NIHR PGfAR, is now evaluating some of these aspects and will report to the National Screening Committee in the next year.
As part of this project, my group (and in particular postdoctoral researcher Kitty Lo) collaborates with the chief investigator of the RAPID programme Prof Lyn Chitty in the development of the bioinformatics and statistical aspects of the RAPID project.
What women participate to the RAPID evaluation?
The RAPID project is working with selected maternity units located in the South of England and, more recently, Dundee. As traditionally done in the NHS, all pregnant women who opt for Down syndrome screening receive a risk based on the routine 12-week scan. Current NHS guidelines offer the option of an invasive test to women for which the estimated risk is greater than 1/150 (about 3% of pregnancies). In the context of the NIPT evaluation study NIPT is being offered to women undergoing Down syndrome screening who receive a risk of 1/1,000 or greater, we estimate that this will be around 12% of pregnancies. A blood test is then obtained, sent to the Regional Genetics Laboratory where cell free DNA is extracted and sequenced. Research midwives give the result of the NIPT to the mother. If NIPT suggests a chromosomal abnormality, an invasive test is recommended as there are a number of reasons why there may be discordance between the result obtained from maternal blood and the karyotype of the fetus.  
Does it work?
Remarkably well. It is already well understood that the science behind NIPT is robust and reliable but, as discussed above, the NHS needs data that goes beyond laboratory performance before making decisions if and how to implement this on a large scale. The study seems to be going well and is welcomed by women. An exhaustive description of the outcome of the study will be published in a few months.
Bioinformatics and the next steps
The bioinformatics are relatively simple but nevertheless need to be performed correctly. We think that an open source R package that researchers can use and modify is a useful step toward making the technique reliable and widespread.
A key challenge is the noise of sequencing assays, with parameters such as GC content of the DNA sequence creating noise and potential false positive. The RAPIDR package has been designed to correct for this using several previously published strategies. It is also designed to generate quality control measurements to identify unreliable samples, also a source of false positive. The package is freely available on CRAN, we are keen to see it used, and please get in touch if you are interested in trying it out. Ongoing work tackles the much more challenging issues of smaller abnormalities (partial chromosome deletions or duplications). These are harder to detect but are nevertheless important for the parents to make informed choices.

There is seems little doubt, based on worldwide experience, that NIPT is the future for pre-natal diagnosis. Implementation into routine maternity care will no doubt take time but hopefully our ongoing work (in the lab as well as for the bioinformatics) will help expedite these changes.

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