“Ethical Controversies in Genetic Testing” by Bonnie Arzuaga for OPENPediatrics

Ethical Controversies in Genetic Testing,
by Dr. Bonnie Arzuaga. Hello, my name is Dr. Bonnie Arzuaga. And
today, I’ll be talking about the ethics of genetic testing in infants and children. Introduction. Some learning objectives for today– there
are five– one, to describe four basic ethical controversies surrounding genetic testing
of pediatric patients; two, to define the best-interest standard and to demonstrate
how it can be applied to genetic testing of pediatric patients; three, to compare and
contrast predictive testing for carrier states, with predictive testing for actual phenotypic
disease; four, to list three characteristics that make a disease a good candidate for newborn
screening; and five, to identify ways that expansion of the newborn-screening program
may lead to ethical controversy. A little bit of background information about
genetic testing– in the year 2000, the Human Genome Project was completed. And this has
made it increasingly possible to test for specific genetic conditions at all stages
of the patient’s life. And actually, since then, genetic testing for patients has become
increasingly popular in the hospital, and also, in outpatient settings. However, the implementation of genetic testing
is ethically complex. And this is especially true with testing of pediatric patients. And
this is mainly because, A, they’re legally incompetent, meaning that they cannot legally
make their own medical decisions. But they have to have a surrogate decision maker, which
is usually their parents, but can sometimes be a guardian. The implementation of newborn screening programs
throughout the United States has made it possible for clinicians to conduct population level
genetic screening. However, there is a lack of knowledge about the correlation of many
genotypes and disease expression for many conditions that we now test for. Therefore,
many unaffected patients will be flagged, leading to anxiety, confusion, and sometimes
even over-treatment. So some questions for consideration when we
talk about genetic testing– the first one is, what if any, are the ethical concerns
regarding the newborn screening program, and also, of genetic testing in general? Should
disorders with a variety of presentations, some of which may not have successful treatments,
be included in newborn screening programs in order to detect those few cases with the
most severe and potentially treatable forms? Should parents be able to request genetic
testing, which may indicate that their child is a carrier for a condition, or to have a
condition that is of adult onset in nature? So in order to highlight some of these questions
and some of the problems that we face, let’s talk about a hypothetical case. So this is
a case of Baby Amelia. So baby Amelia is born full-term, following no prenatal complications.
She does well in the newborn nursery, and she’s discharged home with her parents. However, her newborn screen returns one week
later with positive findings for Krabbe disease. Her pediatrician cannot interpret these results
for her parents and therefore refers them to a pediatric neurologist. So a little bit about Krabbe for those who
aren’t familiar with the disease– it’s an autosomal-recessive lysosomal disorder. It
has an incidence of about one in 100,000 births in the United States. And it affects the white
matter of the central and peripheral nervous systems. Most patients present within the first six
months of life with what is known as infantile disease, which manifests as extreme irritability,
spasticity, and developmental delay. From there, there is severe motor and mental deterioration,
often leading to death by the age of two. However, 10% to 15% of patients with Krabbe
have a later onset, commonly differentiated as either late infantile, juvenile, and adult
onset forms. The later-onset forms have less disease severity and a slower progression.
These patients can be clinically normal until weakness, vision loss, and intellectual regression
become evident. And those with adult onset may have spastic paraparesis as the only symptom
and may live relatively normal lives prior to being diagnosed. One of the oldest patients
ever diagnosed with the adult onset form of this disease was an 84-year-old woman. Disease severity is variable, even within
families. So going back to baby Amelia– her parents bring her to the neurologist. And
the neurologist explains to her family that the infant’s DNA test indicated that she is
most likely a carrier for the disease but that further testing is required. However, the follow-up testing on baby Amelia
only provides ambiguous results. So why is this? Well, newborn screening and genetic
testing for this condition in particular cannot differentiate between the infantile, juvenile,
and adult onset forms. Additionally, it cannot tell whether a patient will be severely or
mildly affected. So the symptoms of early infantile onset of Krabbe typically include
irritability, feeding difficulties, episodes of fever without any sign of infection, a
stiff posture, and slowed mental and physical development. So now, imagine that you’re baby Amelia’s
parents. As we know, infants can sometimes be irritable, sometimes not eat well, have
unexplained fevers, or even delayed developmental milestones for benign or unknown reasons.
However, now that Amelia has had this testing done, her parents will likely be hypervigilant
and anxious about any aspect of her health and well-being that is not perfect. So even
if Amelia does not have the infantile form this disease, she will likely undergo more
invasive and expensive testing if her parents have any concerns that otherwise would not
normally raise any red flags. Controversies. So what are some of the basic
ethical controversies surrounding genetic testing? And we’re going to talk about four
in detail. The first one is that genetic information gathered from testing may have limited predictive
power. And that’s because possessing a gene does not always equate to having a specific
phenotypic condition. One example of this is possessing the B-R-C-A-1
or BRCA1 oncogene. Possessing this gene does not guarantee that a particular patient will
develop the clinical diseases of cancer. However, despite this, new technologies in preimplantation
genetic diagnosis have recently gained popularity. Through IVF techniques, parents can choose
to implant and gestate embryos which do not possess the BRCA1 gene or other identifiable,
quote, “undesirable” genes. Going back to our case, so Amelia happens
to have an 18-month-old brother who’s named Benjamin. He was born in a state that does
not provide Krabbe testing on their newborn screening panel. Benjamin currently displays
no symptoms of the disorder. However, now his parents want to know if they should have
him tested for this disease also. So the case of Benjamin brings us to our second
controversy, which is that information gathered is familial, meaning that results of one patient’s
tests are applicable to that person’s parents, their siblings, and also, their offspring.
Siblings of the affected individual may not want to know their potential genetic destiny.
And they may inadvertently discover it through testing of their sister or brother. Siblings
who are unaffected may also suffer from forms of survivor guilt. And this has been shown
in at least a few studies. The third problem is that paternity may sometimes
come into question. If one parent is a carrier for a condition and the other parent is not,
then there may be a question about who is actually the father of the child. Going back to Amelia– so the neurologist
tells her parents that it’s possible that Amelia may develop Krabbe at some point in
the future. But he cannot say for certain. He can also not predict when it may happen,
if there is any way to prevent it, or if there will be a viable treatment option. So this brings us to our third controversy,
which is that the risks of genetic testing may not be easily or immediately appreciable,
as they tend to be psychological, financial, or social. Psychological risks occur not only
with the patient who has the disease, but can also affect the patient’s family, and
specifically, in pediatrics, the patient’s parents, who, because of the hereditary nature
of genetic disorders, can experience anxiety, guilt, and sometimes impaired self-esteem. There are also social and financial risks,
such as exclusion from sports or other activities. And we see this sometimes in children who
are carrier states for sickle-cell disease, for example, may be excluded from team sports
in high school. Patients may also have difficulty in obtaining
insurances, such as health insurance, life insurance, or disability insurance. And there
is also potential for employment discrimination, especially if it’s known that a patient possesses
a gene for a disease that will make them unable to work effectively within the next few years. The fourth controversy is that many genetic
conditions are difficult to treat or prevent. And this brings into question the clinical
value of testing for them at all. So on the one hand, if an adult patient requests
a genetic test, we know that in general, adult patients have the right to know their genotypic
information, even if that condition may not be treatable or preventable. However, the
right for a parent to know information pertaining to the conditions that are either untreatable
or unpreventable, or may not even have clinical onset until adolescence or adulthood, is debatable.
The older child or adolescent who may possess some decisional capacity may not wish to know
whether they are destined to have a particular untreatable disease. Or they may not wish
for their parents to know. Best Interest Standard. So this brings us now to the best interest
standard, which is a basic ethical standard that we usually talk about when we talk about
ethical dilemmas in general. So the definition of the best interest standard varies in the
traditional medical ethics text in the United States. But in general, it says that, “Parents
are given the right to make decisions for their children under a best interest standard.”
And this means that they’re not required to make the best decision possible, only one
that is, at the very least, neither abusive nor neglectful, by utilizing a basic standard
of reasonableness. Decisions, therefore, should reflect what is most reasonable to most people
and what most people would choose for themselves in similar circumstances. So here is a pretty simple example. Imagine
that it is January and it’s snowing outside. And you are on maternity leave with a new
infant. You really, really, really want a cup of coffee. And you have no coffee in your
house. So you put your infant in a snowsuit. And
you put him in his car seat. And you drive to get your morning coffee. This is technically not in the best interest
of the infant. But no one would arrest you for doing this type of thing. So if the best
interest standard is considered to be the primary guiding principle for pediatric decision-making,
then how can it be applied to predictive genetic testing in children? Predictive Genetic Testing. So what does the American Academy of Pediatrics
say about this? Well, first, they say that, “Genetic testing is best offered in the context
of genetic counseling and that all decisions about whether to offer testing should be driven
by the best interests of the child.” Two, they say that, “Health care providers should
inform families about potential familial implications prior to testing and encourage them to share
the information with their extended family, or refer them to genetic counseling.” So there are some problems that arise when
these first two recommendations are not followed. First, there’s a lack of knowledge from general
pediatricians about very rare diseases. And so sometimes, a pediatrician may not be able
to provide adequate counseling to a family about a particular disease state. There’s also a lack of access to specialists
in many areas of the country. And so even if a pediatrician is able to give the family
proper counseling, they may not be able to follow up with a specialist and gain adequate
treatment for their child. The third recommendation from the American
Academy of Pediatrics is that assent of the older child for testing, when appropriate,
is encouraged, although the final authority lies on his or her parents or guardians. Finally, the use of any direct-to-consumer
testing is strongly discouraged due to the lack of test oversight and appropriate counseling.
For those of you who aren’t familiar with direct-to-consumer testing, there’s essentially
a service that people can purchase in which they send a DNA sample to a company, usually
via a buccal swab. And the company will run their DNA, identify any mutations, and send
them back a report. However direct-to-consumer testing excludes
allowing families to talk about getting that testing or to encourage them to share their
results with the rest of their family. Consumers can also misinterpret results or demand further,
unnecessary testing from their physician after getting direct-to-consumer results without
appropriate counseling. But I want to talk about one more scenario.
What if parents request that their infant or child be tested in order to identify a
carrier status, just like baby Amelia’s parents did in the case of her brother Benjamin. So,
here we have to ask ourselves four questions. How does this differ from testing for actual
phenotypic disease? Well, on the one hand, a carrier status really has no clinical significance.
If anything, it may have significance for when a patient decides to have children of
their own. Two, if a carrier state imparts some phenotypic effect but not the full phenotype,
is that different? So here, we can consider, for example, fragile
X syndrome in women. So fragile X syndrome is essentially a syndrome in which there are
a triplet repeat on the X chromosome. The more repeats that you have, the more neurologically
impaired you are, and the more severe your phenotype. Women who are carriers of fragile
X may be variably affected, depending on how many repeats they have on their one X chromosome. The third question is, what if the carrier
state imparts a protective effect? For example, if you’re a sickle cell carrier, in which
case you have some protection against malaria. Therefore, if you’re planning a trip to Africa
or going to move to Africa, you would be less at risk for actually getting malaria. So it
may be useful to know that information. And the fourth question is, what if parents
are requesting to test for a carrier status in the sibling of a child either identified
as a carrier themselves or affected by the disease? So what are our professional institutions
saying about the potential answers to these questions? Well, the American Academy of Pediatrics,
the American College of Medical Genetics, and the Institute of Medicine all recommend
against determining a child’s carrier status. The AAP and the ACNG also go so far as advising
against school-based testing or screening programs in the schools, which presently,
is not widely done, at least in this country. So school-based testing aside, then what is
the significance for other screening programs, in particular, the expansion of the newborn
screening program? Newborn Screening Program. While the Institute of Medicine has suggested
that three criteria must be filled in order for any population-based screening program
to be effective. The first is that there must be a clear indication
of benefit to the newborn. Two, there must be a system in place to confirm a diagnosis
once a newborn is flagged. And three, there must be treatment and follow-up available
to any effected newborn. So then, with this in mind, how do we decide
what diseases should be included in a newborn screening program? And as you may be well
aware, the newborn screening program started in the mid 20th century with PKU, which is
a disease that if infants or children ingest phenylalanine, it can actually cause neurodevelopmental
delay. However, if they avoid any food products with phenylalanine in them, they can be neurologically
spared. So since the 1970s, newborn screening has
expanded to include over 50 diseases. Newborn screening is available in every state. There
is a core list of diseases that are federally mandated, but besides that core list, states
are basically able to decide which diseases and which conditions they’re going to include
on their screening panels. So in order to be a candidate for newborn
screening, a condition should be an important health problem defined either by the prevalence
of the condition in the state or about the consequences of the disease on the individual.
There should be a recognized treatment for patients as well as a benefit to early detection.
And there should be a suitable test for the condition which is easily performed on a large
scale and has no false negatives and very few false positives. So with this, what we see in newborn screening
programs is that tests that are done within these panels have a very high sensitivity.
However, they have a low specificity. And so sometimes, you can get many false positives,
and this is accentuated in babies who are born prematurely, for example. And so babies
will be flagged for having rare conditions, often metabolic conditions, that when further
testing is done, it is determined that they actually do not have these conditions at all. So with this in mind, we should think about
mandatory newborn screening. There are very few states in the United States where newborns
are mandated to have screening. However, in the vast majority of states, newborns
are screened without necessarily asking their parents about it first. Parents have a right
to opt-out of testing if they don’t want it. However, most parents actually don’t even
realize that their babies will be screened when they’re in the hospital prior to discharge.
And therefore parents have to be savvy and know that this is going to happen in order
to opt-out of it before it happens. So with that, what, if any, are the ethical
concerns regarding newborn screening program and genetic testing in general? Should disorders
with a variety of presentations, some of which may not have successful treatments, be included
in the newborn screening program in order to detect those few cases with the most severe
and potentially treatable forms? Should parents be able to request genetic testing, which
might indicate their child be a carrier for a condition or to have a condition that is
adult onset in nature? Summary. So I know I’ve brought up a lot of
questions today, not very many answers. And that’s really because we don’t, at this junction,
have very many answers. Genetic testing, as I said in the beginning, is widely done. Newborn screening programs are available in
every state. The vast majority of newborns get screened. And the consequences of that
screening can sometimes be severe, even if a patient doesn’t necessarily have the condition
that has been flagged as positive. So we must carefully consider the complexity
of these issues prior to testing being offered to any family or any patient. Any testing
that is done should be preceded by detailed counseling, informed consent, and careful
attention to confidentiality. The addition of new conditions to newborn screens should
be carefully scrutinized prior to widespread incorporation of testing. And the ethical
principle of beneficence, which means doing good for the affected patients, should be
balanced by the principle of nonmaleficence, avoiding harm to non-affected patients, before
considering actually doing any genetic testing on a patient. Thank you very much for watching. I hope you
learned something today. And more importantly, I hope that this presentation brought up more
questions for you to consider as you go about your clinical care of newborn infants. Please help us improve the content by providing
us with some feedback.

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