Okay we're going to go ahead and get started.

And today we're going to talk about screening programs using genetics, and

focusing first on the very well established use of genetics in

newborn screening programs.

I'm going to talk a little bit bit about the history of how we came to

have newborn screening programs.

It really all pivoted on the discovery of phenylketonuria.

This was first described in the 1930s.

It stemmed from research looking for biochemical sources or

explanations for cognitive impairment, and

this research was done largely amongst institutionalized individuals.

Unlike today, institutionalization was the norm for

individuals with cognitive impairment.

And researchers in the 1930s found a small minority of individuals

with cognitive impairment who had too much phenylpyruvic acid in their urine,

that phenylpyruvic acid being a byproduct of the amino acid phenylalanine.

And had the insight that this represented a biochemical disorder,

an enzymatic disorder in fact.

A lack of the enzyme phenylalanine hydroxylase leading to

the accumulation of phenylalanine which turns out to be neurotoxic, and

hence the explanation for cognitive impairment.

The stage was set earlier by the work of Garrod,

one of the pioneers of genetics, who had had the insight in

the previous decades that there was such a thing as an inborn error of metabolism.

He described it in 1923 if any one step in the process failed the intermediate

product in being at the point of arrest will escape further change.

In other words, if you block an enzyme, the material that

was supposed to be metabolized by that en, enzyme gets hung up and

stuck, and that's what happened with a deficit of phenylalanine hydroxylase.

That enzyme normally metabolizes phenylalanine into

tyrosine and in individuals with this disorder there's too

much phenylalanine which is neurotoxic, and too little tyrosine.

So this was a very interesting demonstration of the proof of

Garrod's insight into biochemical genetics.

But equally important,

it gave researchers the idea that maybe diet would make a difference.

So over three decades, researchers investigated the possibility

with a lot of trial and error of using diets that were low in phenylalanine,

that couldn't be zero because phenylalanine is a required amino acid.

But low in phenylalanine, and

enriched in tyrosine because the body is having trouble making it.

And what they have found over time is that they could get to a diet that was safe,

that provided adequate nutrition, and

seem to improve somewhat kids who were symptomatic with PKU.

And because this is an autosomal recessive disorder they were able to

extend that research to looking at affected siblings who were tested,

their urine was tested at birth so they could determine who has PKU.

And from that developed anecdotal evidence that given the diet

right from birth could make a dramatic difference in the well-being of the child.

Concurrently as this work was being done, developing a strategy for

treating with diet, this this serious syndrome technical developments were,

were going forward and, and, in particular, a researcher Guthrie,

developed a very efficient and effective method for

detecting phenylalanine levels, from small blood samples,

tiny blood samples taken from pinpricks onto filter paper.

This has become called the Guthrie spot and this made it technically possible to

screen large numbers of people with very simple technology.

And the result of these two developments,

we've got a diet, we think it really makes a difference.

It can prevent mental retardation,

and the technical feasibility of doing it with the Guthrie spot,

we began to see intense advocacy for the idea of newborn screening.

Let's go find these kids right when they're born, get them on the diet,

and help them.

And that advocacy came from many different quarters.

Researchers were concerned,

Guthrie himself was among the researchers who advocated.

He had a relative with PKU with a personal, so had a personal involvement.

There were parents groups, and

in fact, the rise of disease advocacy occurred around this time,

with the National Association for Retarded Citizens being a major player.

And legislators were drawn again, remember this was an era in

which kids with mental retardation were warehoused in institutions, and

that was a major public concern.

The idea that you might pass a law that would help to

prevent such mental retardation was extremely attractive to legislators.

And this concerted advocacy had it's effect,

one by one states began to implement mandated, meaning required by law,

screening programs for newborns focused on finding newborns, with PKU.

Now in retrospect, it's quite interesting and

somewhat daunting to realize that the amount of evidence available to

support this approach at the time, was quite thin.

Susan Lindee, a historian, has estimated that

fewer than 20 cases of successful diet fueled the system.

Now admittedly, it was very dramatic evidence.

Arguably it would be unethical to do the kinds of randomized controlled

trials we would think about today but it was very sparse data.

And there were many unanswered questions.

I'm now citing here from a document published in 1975 so

in very, real time acknowledging all of the things that we didn't know at

the time that newborn screening, was begun.

The proportion of infants with increased phenylalanine were truly at risk.

It was only over time that we began to understand that there are kids who

have infants who have elevations of phenylalanine that are physiologic.

And only with repeat levels being able to confirm the sustained elevation at a,

at a, defined level could we be sure to identify kids who were truly at risk.

There wasn't even evidence because there hadn't been long enough observation to

know for sure that phenylalanine restriction would

prevent the cognitive impairment that came only over time.

What was the appropriate maintenance level, again not known.

What was the right duration of phenylalanine restriction?

There was hope initially that if you could just get infants through the first two or

three years of brain development, you might be able to go on a regular diet.

And it was only over time that it became apparent that that was not the case.

And there were, as one might expect,

some unanticipated outcomes from the newborn screening po, process.

Clearly there were false positives, the, historians have

looked very carefully at the question of whether kids were actually harmed,

because of the uncertainties about who should be on the diet.

And it does not appear that there's any evidence that the newborn

screening program itself harmed kids.

That was probably because clinicians understood the uncertainties.

Clinicians who were taking care of these kids understood the uncertainties, were

monitoring closely and were able to pick up kids who didn't really need the diet.

It was an unanticipated outcome that moms with

PKU would put their kids at risk if they weren't on a careful diet.

So, again, the, this was a, a transformative opportunity.

So, girls who had PKU, before the diet, generally did not reproduce,

they were in institutions.

With the diet, they were able to grow normally,

have normal intellectual capacity, have normal lives, marry, have kids.

And it was only as some of these young women began having kids that it

became clear that without very, very strict dietary control from

the time of conception, so ideally preconception, the fetus would be exposed

to high phenylalanine levels in utero and that would be neurotoxic to the fetus.

so, that was, a lesson that had to be learned by, that happening.

And then finally, of, a,

a, as one could say, a fundamental principle of screening programs.

If you screen to find individuals,

in order to give them benefits that will improve their outcome.

Your screening will fail if they don't get the benefits and

some families found it difficult to afford the specialized diet.

Over time many states have instituted subsidized programs in order to

guarantee that low income families will have access to the diet and

without that the screening is really pointless.

So, over time despite the unanticipated outcomes I think it would be fair

to say that the PKU screening program is considered a significant success.

Kids with PKU today have life opportunities that they clearly did not

have 50 years ago.

And careful genetic research and then careful efforts to figure out how to

treat and how to implement both screening and treatment have made the difference.

That's a very strong argument for

what the legislators originally did on rather thin evidence.

So mandated programs, as we've said,

were started based on rather scant data but it was a success.

Let's look at some of the other implications of the mandated program.

There was no formal process to seek parental permission.

These programs were mandated, newborns were screened.

Today the responsibility tends to lie at the hospital where the child is born.

Hospitals are responsible for

making sure, under law that the newborn screening process occurs.

The concept of informed consent developed somewhat after

the development of newborn screening programs the concept,

as we understand it today, both in clinical care and in research.

But even today,

mandated newborn screening programs go forward without formal parental consent.

States have variable policies about opt out.

Most states will let parents opt out.

however, if you don't know that the screening is happening,

you have no opportunity to opt out.

And a number of studies have documented that parents are generally unaware of this

process, it is one of the many processes that happens to their newborn after birth.

And often only know it's happened after they get

a result from the newborn screening program, and that tells us also,

that whatever approach the states have taken to educate parents,

either before or at the time of newborn screening, are rather ineffective.

Parents are often unaware of these programs.

in, in the state of Washington where I live parents are given

a little tri-fold brochure at the time that the nurse comes by,

if the mom happens to be there the nurse will say I'm here to do the PKU test, and

takes the baby and sticks the heel.

But the education is, is rather sparse, the brochure is well written,

but parents of newborns have lots of other things to be thinking about at the time.

Well, with that early success, the program began to grow.

In the early 1970s and 80s, there was very, very slow growth.

Significantly the addition of hypothyroidism, congenital hypothyroidism,

low thyroid, etiology not entirely clear.

This is not a classic genetic condition, but

it has consequences very similar to PKU.

That is to say a child, who has low thyroid in infancy will have

a cognitive impairment, will often have growth impairment as well, and

this can be readily treated with thyroid replacement, so

it had the same kind of urgency as finding kids with PKU.

A number of other rare metabolic disorders for

which testing was available were found and added to panels in various states.

In the 1980s a very interesting development happened through the newborn

screening program, and that was that there was clinical trial data

that indicated that there was a very significant benefit to infants with sickle

cell disease if they were identified early and given antibiotic treatment.

These kids are vulnerable to sepsis, to a widespread body infection.

It can be prevented with prophylactic antibiotics, but

you've got to find kids early before they're necessarily symptomatic from their

disease to institute the benefit.

And the trial indicated this benefit and

led to a push to add sickle cell disease to newborn screening panels.

Now it wasn't as urgent PKU or hypothyroidism, so

generally speaking you want a child with sickle cell disease to be on

the antibiotic by about four to six months of life.

It doesn't have to be within weeks the way it is with PKU.

Nevertheless it was a benefit very similar, lets find these kids, lets make

sure that we have treatment for them and and improve their long term outcomes.

But it also raised a very interesting question about whether race

based screening was the right way to go.

Because sickle cell disease is predominately found in

African populations, to some extent in Mediterranean populations.

And so for the populations of some states, my own in Washington, for

example, the Dakotas, various other states in the union,

the proportion of population at risk is relatively small.

There were interesting discussions at the time,

about whether it was more cost effective to do race based screening.

Whether that was stigmatizing whether that was inequitable and ultimately the,

the history is actually a little bit hard to discern, not well recorded.

But as best we can tell, some states did initially institute targeted screening,

but over time the norm became universal screening.

And one of the major reasons for that is that a racial label on a birth

certificate can be somewhat arbitrary and not necessarily a good indicator to what

child, whether the, or not the child is at risk for sickle cell disease.

However this issue of when is it useful or,

appropriate to think about screening based on a demographic like

racial identification remains a very, interesting and important conversation.

In the decade between 2000 and 2010, another major

development in newborn screening occurred, and it was technologically driven.

The development of a technology called tandem mass spectrometry which allowed for

a very broad comprehensive assessment of metabolites in the body and

therefore a very quick way to scan newborn blood and

figure out if any metabolite was out of the normal range.

What that meant was that with a single test, one could identify conditions that

we already knew were good candidates for newborn screening like phenylketonuria.

But also lots of other metabolic abnormalities that either we

weren't entirely sure what their clinical significance was or

we knew it was associated with a disorder, but

not a disorder we had an effective treatment for.

And this has lead to a lot of debate about disease severity and

its implications for putting conditions on newborn screening panels,

availability of treatment as a criterion and just how we should

manage the decision making process of what to screen for and what not to screen for.

Now within this context what we're clearly seeing is an evolving focus

that Scott Grosse and others who I'm quoting here,

have talked about as a, an evolution of the newborn screening program,

not only in size, but also in focus.

So, it was started initially to address what

they called public health emergencies.

The child with PKU, the small infant with PKU or

low thyroid who needs to be found now if we're going to give them the benefit we

want to give them that we can give them.

To conditions like sickle cell disease, where there isn't that same kind of

urgency, cystic fibrosis falls in this category too.

It's probably fine to find kids with cystic fibrosis sometime in

the first year of life to institute treatment.

With sickle cell disease probably in the first six months of life.

And we can improve outcomes if we find them that soon.

But given that we already have a newborn screening program in place, why not

add these conditions to the newborn screening to make sure that we find them,

to make sure that we've got equity in our strategies to find these kids.

So that was very much part of the thinking as people began to

debate just what conditions should be added with the panel expanding.

There has clearly been ongoing parental advocacy of newborn

screening and I'm quoting from one website of

a very prominent advocacy organization called savebabies.org.

hopefully, you've had the chance to visit this website.

And I want to note that in this parental advocacy statement what we're seeing

is a very strong adherence to the original screening principles of newborn screening.

Nothing is more devastating than learning a few months or

years down the road that your child has a terrible disease that could have

been treated, had newborn screening taken place.

So, this advocacy organization argues strongly by, by this kind of statement,

that newborn screening, really, is for the purpose of finding kids we can help.

Adhering to a very what I would called strict newborn screening principle or

screening principle and suggesting that we shouldn't add conditions for

which we don't have treatments.

The social context of current advocacy is also worth notice, noting,

as contrasted with the advocacy that lead to the institution

of newborn screening in the 60s, there's strong industry support.

Often advocacy organizations receive industry support.

Both disease advocates and industry sit on policy advisory groups,

and as there is this push for classic screening principles for

a commitment to to making sure that we save babies that we can save,

there is also a tendency to minimize the importance of cost, kind of deflect cost.

It's worth any price to save a child as Diane Paul a historian who's

looked at this issue notes, though while,

while a concern with the focus on saving babies, on finding babies and

making sure they get the treatment they need is understandable, it

potentially ignores very significant trade offs as we add more and more conditions.

And this is important because part of the discourse around newborn screening is,

is a discourse that says maybe we want to push on the goals for newborn screening.

We've got this wonderful program, we now have technology that enables us to

find many kids who don't quite fit the newborn screening criteria.

Kids like PKU who do, but kids with other undefined or poorly defined metabolic

disorders, or kids with metabolic disorders that we don't know yet

how to treat, and there might be benefits from finding those kids too.

Part of the discourse about newborn screening then is,

should we think about changing the goals.

So here the former head of the National Institute of Child Health and

Human Development points out that the other benefits that could come from

finding a kid who doesn't have a treatable disease include avoiding

a diagnostic odyssey, we know what's going on with the kid.

Informing reproductive decisions of the parents, if this is a genetic condition.

Assuring what he calls adjunctive if not curative therapy, meaning support.

And very importantly, allowing the creation of registries, finding kids so

we can pull them into research.

And he ties this in the quote that you see to the idea that by pulling them

into research, that's how we're going to figure out how to treat them.

So we don't know how to treat them now, but we want to use newborn screening to

pull them into research so we can figure out how to treat them.

If we don't find these kids with rare diseases, we may not be able to do so, and

this is a very interesting idea about changing the focus of newborn screening.

in, in, in terms of the concept that we started with, which is this is

a mandated screening program and there's no parental permission for doing it.

So, as a counterpoint, the president, the President's council on Bioethics,

Bioethics Commission, of George W Bush published

a statement in 2008 really going against the views I just showed you.

They argued that mandated screening, the screening we do

without parental permission, should be limited to conditions that do meet crat,

classic screening crit, criteria like PKU.

That it would be okay for states to offer screening for other conditions, but

it should be voluntary.

In other words, a two-tier system, we'll do some automatically,

others you have to give us permission to do and ideally under a research paradigm.

In making these suggestions they have a very strong assertion of

the idea that we should reject the technologic imperative.

Just because we can find kids, doesn't mean we should.

And I will just end by saying that there is one other controversy in newborn

screening, that has to do with the fact that the collection of

newborn screening samples represents a wonderful opportunity for

research, not just finding rare kit, rare kids with rare diseases.

But also because this is a unique sample set that

represents a truly representative sampling of the population.

It's ideal for studying the prevalence of genetic traits.

It will have increased value if the samples can be linked to other data

registries like cancer registries, or death records, and some states have

stored samples and allowed them to be used for research without parental knowledge.

Parents, again, didn't give permission in the first place that

the samples be collected, and if the samples then are just a, taken off for

research parents may never know and that did happen in several states.

And it led to public campaigns as we saw last week against research use of

newborn screening samples.

A loss really to research from value, of valuable samples because

in the views of many parents the way in which the samples were used

was done in an untrustworthy, secretive manner.

Screening: Newborn Screening Programs

Ethical and Social Challenges of Genomic and Precision Medicine

Meet the Instructors