Newborn screening: the UK National Screening Committee answers your questions

The recent Progress Educational Trust event 'Newborn Screening: What Should Be Screened for and How?' (a film of which can be watched on BioNews) opened with a presentation by Professor Anne Mackie, Director of Programmes for the UK National Screening Committee (UK NSC).

Professor Mackie and her colleagues at the UK NSC agreed to provide written responses to questions submitted by people who participated in the event. Some of these questions are included below, together with responses from the UK NSC.

Anonymous attendee: Is newborn screening necessary for children who have been conceived using donor sperm from a donor who has already undergone screening for genetic conditions?

UK NSC: For some inherited disorders, known as 'recessive', it is necessary for both parents to be carriers. But, for 'dominant' disorders, it is usually only one parent who is affected. In some dominantly inherited cases, the genetic change happens newly in the baby 'de novo'. In this case, neither parent is a carrier or is affected. Where there is a genetic mechanism behind the disorders we screen for, the overwhelming number are recessive.

Shamima Rahman: What is the definition of a treatable condition?

UK NSC: A condition where something can be done, as a result of early detection, to improve the health and wellbeing of the child being screened.

Madison McIntyre: How do we define a meaningful diagnosis? Would someone being diagnosed with a disease that currently has no/limited treatment make the diagnosis less meaningful?

UK NSC: The term used most commonly is 'actionable'. This means that by making the diagnosis in a baby with no symptoms, something can be done to improve the health of the child. That need not be medication. It could be diet or physiotherapy for example. Where there is no current evidence to support an effective treatment, research is the way to learn what might be possible.

Victoria Miller: How do you approach ethical consent for participation in Genomics England's Newborn Genomes Programme pilot?

UK NSC: In a newborn pilot or evaluation, we would ensure that the person being screened, or their carer or parents are aware that this is not yet part of routine care, because there are uncertainties about the value of the programme or how best to carry it out. As with 'routine' programmes, they would be given information about the programme and would be reminded that they could opt out of the particular screening programme, if they were unhappy with it. This would in no way affect the other care being offered.

Layla Jader: How long can we keep whole genome sequencing (WGS) results after birth? What about old Guthrie cards [containing blood spot samples] which have been stored at various UK regions over many years?

UK NSC: The results for the genes tested will form part of someone's medical record and will be kept as long as the medical record is kept. How long the results of the WGS will be kept is something that will be decided in conjunction with the general public. Currently, the 'Guthrie' cards are kept for at least five years.

Anonymous attendee: Considering that the UK NSC put so much weight on not screening due to causing more harm than good, will the UK NSC be carrying out work to see what the thoughts are about newborn screening in the general public? Why are they not more concerned about doing good and saving children?

The UK NSC is totally committed to doing good. But the committee must, according to its terms of reference and governance, look at harms too. As the UK NSC is almost unique in this it seems that this is a major pre-occupation. It isn't.

Internationally and amongst clinical groups and those affected by these diseases the focus is those with the disease so often harms are not seen or overlooked. Thus the UK NSC seems often to be the only voice raised to make the downsides of screening more obvious.

Whatever policy choices are made there is always a balance between doing good and the harm, whether that be medicines, vaccines, screening, sports, driving, etc. The general public do understand this, as has been shown in the dialogue about WGS and next generation sequencing.

The issue is how one measures both the harms and benefits and then compares them. People differ in how they view this – some do not want to risk harm arising from a screening programme, others do not want to risk harm by missing something. There is no simple solution, but the UK NSC along with the National Institute for Health and Care Excellence and the Joint Committee on Vaccination and Immunisation are constantly trying to improve how we reach this balance.

Anonymous attendee: What are the dangers of screening out babies with 'diseases', 'illnesses' and using it as a form of eugenics? (Anonymous attendee)

UK NSC: WGS is only being looked at in relation to newborn screening, so there is no question of it being used as a form of eugenics. On the contrary, if successful, it will enable care to be given to more babies with serious conditions and improve the quality of their lives.

Victoria Hedley: I guess the 'general' patient perspective would be that it is better to risk false positives or false negatives than to lose that chance for early diagnosis and all that a diagnosis brings? Does the UK NSC membership feel it is better to include the condition in newborn screening even if the system around it isn't perfect?

UK NSC: It is rare for people unaffected by the conditions, especially rare ones, to consider them at all, so in reality when the UK NSC asks for people's opinions about the prospects of false positives there is no reply from those who are most likely to receive them.

This is why the newborn dialogue was so important and informative. In this exercise people who have no experience of rare genetic diseases were asked what they thought and given support and information to help them think the issues through. In fact, there was a nuanced set of responses reflecting the problems and anxieties that uncertain results might bring.

So, the balance is not necessarily as the questioner implies. Hopefully the WGS evaluation will be an opportunity to talk to and explore the feelings of parents who find themselves in this situation, so as to better understand it.

Karen Harrison: As far as I am aware there is no recent data about harm vs good, we at Alex – the Leukodystrophy Charity are now looking at doing commissioning our own research. We have had screening for adrenoleukodystrophy (ALD) refused twice now with lack of evidence and questions around the test being cited despite it being tested for in some states in the USA and in the Netherlands. The efficacy of treatment has also been queried despite it being used for decades in the UK.

UK NSC: The UK is often criticised because of the lower number of conditions included in the newborn screening panel. However, this comparison, by itself, is too narrow. The UK NSC's rigorous approach towards evaluating the benefits and harms of screening often contrasts with evaluations of newborn blood spot tests done by policy makers in other countries. Not all countries appear to apply the same robust approach of conducting evidence reviews and health economic assessments before making a recommendation on newborn blood spot screening, as is standard in the UK.

In the UK, newborn screening is also an intensively quality assured process which includes a full end-to-end pathway. This pathway is managed from the invitation to take part in screening, which is extended to every parent, testing, further testing as required, referral, diagnosis and treatment. It is uncertain whether other countries have such a robust service. This ultimately leads to safer programmes and better outcomes for children and their families in the UK.

The UK NSC last reviewed screening for ALD earlier this year (2021). There were still limitations in both volume and type of evidence relating to the incidence of ALD in the UK, to how ALD might present over time and to the accuracy of screening tests. The studies that were found on treatment tended to focus on describing how the condition progresses and is managed. There was very limited information on the outcome of treatment and whether it is more effective in individuals without symptoms, compared to those already presenting with symptoms. Also, uncertainties remain about the impact of receiving an early diagnosis of ALD. This is particularly relevant for those who do not go on to develop the most severe form of ALD (childhood cerebral ALD) and for those babies identified with conditions other than ALD, for which there are no treatments.

Virginie Bros-Facer: The experience from the Baby Bear Project in the USA and the work from Lucy Raymond in Cambridge in the UK showing the benefits of using rapid WGS to diagnose critically ill infants – does that not make you hope that we can safely use WGS for newborn screening in the near future?

UK NSC: Using WGS to make a diagnosis in a sick baby is very different from screening all apparently well babies. This is true for any comparison between making a diagnosis and screening. If a baby is sick, for example having fits, and a gene that may cause fits is found, this is likely to be the cause of the baby's illness. On the other hand, if a baby is well and by WGS is found to have a gene that causes epilepsy in 50 percent of cases, there will be considerable uncertainty as to what the future holds for that child. They may never develop fits, but the parents will have had a lot of anxiety. We cannot assume that if screening for a condition in sick babies is of value, it will be of value in well babies. However, the experience from sick babies will be helpful and a part of the evidence used.

Zosia Miedzybrodzka: I fear that the emphasis on WGS will deflect from efforts to develop the basics of newborn screening in the short and medium term.

UK NSC: We don't think this will be the case. There is work underway on several rare/bloodspot conditions using biochemical markers as of writing.

Mira Furgoch: It is understood that our knowledge and understanding of genetic variation is biased, based on the lack of ethnic diversity in current genomic databases. How will you take this into consideration when doing targeted sequencing panels or WGS analysis as part of newborn screening?

UK NSC: The NHS and UK NSC are very concerned that any screening programmes will be, as far as possible, of benefit to all the population in question. Ensuring this will form an important part of the planning and evaluation of the research project.