Name: Bartha Knoppers
Title: Director, Centre of Genomics and Policy, McGill University
Experience: Canada Research Chair in Law and Medicine; Distinguished visiting scientist at the Netherlands Genomics Initiative from 2009-2012;
Professor, University of Montreal, 1985-2009; Chair of the International Ethics committee of the Human Genome Organization, 1996-2004; Co-founder of the International Institute of Research in Ethics and Biomedicine; Founder, Population Project in Genomics, 2003
Whole-genome sequencing to screen newborns may be the next clinical frontier for next-generation sequencing technology, but the practice raises a slew of ethical, legal, and social issues that should first be addressed, according to authors of a recent commentary in Science Translational Medicine.
Next-generation sequencing to diagnose rare and unknown disorders in children is already starting to be implemented more broadly in clinical practice, as the cost of sequencing continues to decline and research begins to show that the method has clinical utility and is reimbursable. And in at least one case, whole-genome sequencing is even being used to diagnose newborns admitted to the neonatal intensive care unit.
The technology has yet to be used as a broad population screen for newborns, although over the last several years, a number of studies have begun to look at the feasibility of such a practice. The National Institutes of Health last year awarded up to $25 million in funding to four groups over five years as part of the Genomic Sequencing and Newborn Screening Disorders program. The goals of the projects are to assess whether exome or whole-genome sequencing of newborns provides useful medical information beyond current newborn screening programs and to study the technical aspects, as well as the legal, ethical, and social issues of doing whole-genome sequencing in newborns.
At last year's American Society of Human Genetics meeting, a number of geneticists tackled the issue in a panel discussion and, more recently, a survey of Canadian adults found that significantly fewer people would be willing to participate in genome sequencing-based newborn screening than standard NBS programs.
Bartha Knoppers, director of the Centre of Genomics and Policy at McGill University in Montreal and lead author of the Science Translational Medicine article, recently spoke with Clinical Sequencing News about the issues around whole-genome sequencing as a newborn screen. Following is an edited transcript of the interview.
How did you become interested in this topic?
I personally have been involved in newborn screening since 1985. I'm very much interested in not only how emerging technologies affect research or medical care, but also [public health]. Newborn screening is part of public health programs in around 60 countries around the world. So, it has a different rationality, a different raison d'être, and the advent of whole-genome sequencing, should it one day be integrated into public health programs, would I think have a ripple effect across other public health initiatives as well.
Why did you decide to look at this issue of whole-genome sequencing as a newborn screening test?
Whole population screening is in contrast to other situations where, if you don't feel well, or your child doesn't feel well or your baby's born and you have suspicion that maybe the baby is not 100 percent correct, you go in and you get a diagnosis. But screening goes across an asymptomatic population looking for potentially at-risk individuals. Once those potentially at-risk individuals are identified, then they go through the regular diagnostic pathway for treatment and prevention.
But, there are rules to screening. One, it has to be a presumably asymptomatic population. Two, there has to be a certain incidence or prevalence of whatever you're looking for to justify the resource allocation and state-mandated approach to finding individuals. And three, it has to have a certain level of sensitivity and specificity, to justify the role of the state both in resource allocation and in treatment or prevention that it then offers. If you go looking, then obviously, the state has to have something to offer individuals. So that makes it quite unique. And what makes it more unique in the newborn context is that you're not dealing with mature adults, like for breast cancer screening, for example.
What's interesting here is that this is still a hypothetical that we're raising. Whole-genome sequencing has just hit the road running with all kinds of permutations of ramifications for adults.
We already have this technology slowly battering at the walls of the traditional divide between research and clinic. We're already using whole-genome sequencing when a newborn presents with a condition of unknown etiology. They will, as a diagnostic tool, do a whole exome or a whole genome, just because they don't know what the child has and it avoids going to 15 specialists in 15 different places in two years.
So, it's slowly moving into the diagnostic arena for rare conditions. It has not yet and hopefully will not yet move into the newborn arena. But there are proponents who would argue that having such a tool at birth would allow you to, as knowledge progresses and as tests become more specific and sensitive, to keep an eye on it for the child's interest.
Why do you think whole-genome sequencing should not yet be used for newborn screening?
There has been lots of literature on newborn screening since 1968 when the World Health Organization first set forth the universal international standard for newborn screening. In many countries, newborn screening, because it's a public program mandated either by law or it's just simply done as standard pediatric care, is also a way of making sure that every child is seen once. Some countries only screen for one condition because they don't have resources to do the prevention or treatment of the other ones.
What would happen if you were to throw all that out? How many countries would still have newborn screening if the new norm was whole-genome, even when the cost goes down? Even in industrialized countries, the interpretation of the findings and the scientific validity and clinical utility are not yet demonstrated.
What would happen were you to throw [newborn screening] open to whole-genome sequencing, most of which is largely not understandable, especially when looking at an asymptomatic population? Right now, [whole-genome sequencing] doesn't meet any of the traditional newborn screening requirements.
There was an article in [the Journal of the American Medical Association] saying that there are very few variants that can be called that are sufficiently scientifically validated and clinically useful at this time. So you're using a technology that doesn't really meet any of the traditional newborn screening criteria. That's the reason for our article, to start the discussion from a policy maker's point of view, from a pediatrician's point of view, from a parental point of view.
There are so many parties and so many issues, we just decided it was time to elucidate what they were and begin a discussion, hopefully at all those levels.
There are three societies — [the Pediatric Platform of the P3G, the Ethics Committee of the Human Genome Organization, and the Professional and Public Policy Committee of the ESHG] — who have been looking at this for a year and will be presenting some cautions and recommendations probably later this spring. This is a short, start-thinking, start-talking document. A more developed article will be coming along with recommendations in four to five months.
In the Science Translational Medicine article, you bring up the issue of false positives in using whole-genome sequencing as a newborn screening tool. Can you elaborate on the extent of the problem?
In screening, you're running a swath of tests through a population or subpopulation, let's say for example, mammographies for women over 50. When you have a screening program, you have a higher rate of false positives than you would have on one diagnostic test situation. In whole-genome sequencing, simply because the science isn't quite ready, false positives will be extremely high.
And you make the point that this could impact a person's ability to obtain insurance?
Yes. Let's presume that in countries with universal health care programs, they have health insurance as part of a state-run program. Nevertheless, most countries do not cover life or disability insurance. So the presence of misunderstood, uninterpreted, undecipherable, or erroneously interpreted data in a medical record, because [the whole-genome sequencing data] would go in the newborn medical record, could lead to untoward consequences as far as insurability is concerned.
Do you think that whole-genome sequencing of newborns will be implemented soon?
As diagnostic tool, yes. As a screening tool, no. If you're in these public health programs, [newborn screening] is paid for and covered by the state. If you are an individual and you want to do direct to consumer and pay for it, or if you are a physician and faced with a patient that nobody knows what the person has, then this technology is already available.
But, we're talking at a programmatic level, and about vulnerable newborns. The information that will be given, will it really be as precise, treatable, and preventable as the current metabolic conditions for which newborn screenings are known to be helpful?
Moving forward, how will professional organizations and stakeholders address these issues?
[Based on] the combined efforts of these ethics committees [the Pediatric Platform of the P3G, the Ethics Committee of the Human Genome Organization, and the Professional and Public Policy Committee of the ESHG ], and based on a much more thorough and longer paper … recommendations [will be] coming forward that will help at least provide some guidance for countries that are already thinking — as the cost goes down so rapidly and presuming that it gains greater scientific and clinical utility — whether they should implement whole-genome sequencing in newborn screening.
I can't presume what the recommendations will be, but they probably will say that some sort of targeted approach is necessary.
You mean a next-gen sequencing-based panel of known conditions?
A panel, yes. And that of course could change over time, but the recommendations are still under discussion. We wanted the shorter paper to set the stage for other professional societies, policy makers, and pediatric societies, public health programs, to begin discussing these issues and get it out. We don't want to destroy traditional screening programs because there seems to be a lack of policy direction as to what to do with whole-genome sequencing in this particular field.
One thing, I don't think we can have a mandatory approach. A public health program would have to decide what conditions to put in [the panel] because it would be applied to a whole population at birth. A country can choose which conditions to include because it's all a matter of resources and treatability and prevention and that can differ.
But the criteria for choosing the conditions, that is what makes screening programs standard of care for newborns. Under what criteria would a public health care program decide what to include in the panel?
Is there anything else you'd like to add?
I'm hopeful that the legitimacy and the utility of current, classical newborn screening are not affected, because it has been very effective and in the child's best interest. We'd like to keep it that way.
This is a larger issue of when an emerging technology is ready not only for the diagnostic and clinical arena, but the public health newborn screening arena, which is totally different.