FEATURE
test data to reduce ambiguous findings.
“If we see a [genetic] variant twice in
New York and the baby is, and remains,
asymptomatic,” she said, “it’s more likely
to be identified in asymptomatic infants
across the country.”
whole lot of ethical considerations.” She
explained, “When you test the genome,
you’re going to find mutations that may
not mean anything, and we won’t know
what’s significant and what’s not. And
how do you tell the family that; that you
found a variant and you don’t know what
that means, maybe nothing?”
Wadsworth is also working to enhance
long-term follow-up, so, Caggana said,
data “can feed back to [the laboratory] to
help us modify the testing algorithm so
we don’t catch the babies who will never
develop disease.”
Equivocal and false-positive findings
come at a cost.
Neena Champaigne, MD, FACMG, FAAP,
director of the metabolic treatment
program at South Carolina’s Greenwood
Genetic Center, diagnoses and follows
patients with metabolic NBS disorders
from birth onward. False-positives and
findings of unknown clinical significance,
she said “cause us a lot of concern.”
Among the consequences are:
• “Running the risk of inundating
providers,” who may then develop a
lack of urgency “because they now
have so many infants with abnormal
results and they don’t know how to sift
through them and triage them.”
• Placing unnecessary psycho-social
burdens on families. Champaigne said,
“I personally have seen families who
have medicalized their children even
after it’s proven that they don’t have
a NBS condition; they have a hyper-
awareness for that child, more doctor
visits, which can have ramifications
for years.”
• Compromising medical specialists
who are already “stretched thin,” and
must then follow individuals who may
never develop symptoms. Champaigne,
for example, is one of only two
biochemical geneticists serving the
entire state of South Carolina, plus
the nearby border regions of Georgia
and North Carolina. Some states, she
said, “don’t even have a biochemical
geneticist.” Although her training is in
pediatrics, of necessity, Champaigne
has followed some patients well into
adulthood.
“External pressures to meet
challenging timelines”
NBS programs are working diligently to
address these challenges; to improve the
accuracy and precision of existing tests
PublicHealthLabs
@APHL
I personally have seen families
who have medicalized their children
even after it’s proven that they don’t
have a NBS condition; they have
a hyper-awareness for that child,
more doctor visits, which can have
ramifications for years.”
Neena Champaigne, MD, FACMG, FAAP
and to bring on new disorders, even as
they continue the high-stakes work of
screening tens of thousands of infants a
year—in some states a six- or seven-day-
a-week job.
Hopkins oversaw one of the first Pompe
disease screening programs in the world,
demonstrating proof-of-concept for
Pompe NBS. To do so, his team adapted
and validated a brand-new methodology
called digital microfluidics fluorometry. A
statewide hiring freeze at the time meant
that no additional help was available in
a laboratory already screening 93,000
NBS specimens/year for over 60 other
disorders.
An early success, said Hopkins, was
detecting a child with infantile Pompe
on the second day of pilot screening.
And data from the first six months of
population-wide screening revealed about
twice as many Pompe cases as predicted
in the scientific literature. These outcomes
bolstered the case for adding Pompe to
the RUSP in 2013.
Caggana is working with colleagues to
create a forum for sharing molecular
APHL.org
Wadsworth scientists are in the midst
of refining the laboratory’s screening
algorithm for cystic fibrosis (CF) to reduce
the number of false-positive results—an
example that showcases the complexity
of modern-day NBS. In the first phase of
analysis, specimens are winnowed via a
biochemical test to measure levels of the
CF marker, immunoreactive trypsinogen
(IRT). Those with IRT levels among the top
5% of specimens screened in the past ten
days then advance to molecular testing.
New York is transitioning from a two-tier
genetic screening protocol—a 39-mutation
CF panel, followed by CFTR gene
sequencing for specimens meeting certain
criteria—to an enhanced process: “We’ll
take a bioinformatic look to interrogate
all the [CFTR gene] variants we’ve seen in
babies in New York,” said Caggana. “If a
baby has one variant, we’ll look at the rest
of the gene.” Infants with two CF variants
are reported as screen-positive and those
with one as “single variant detected.”
Although this multi-step process
increases test turn-around-time, it also
increases specificity. “We’re able to reduce
the number of families impacted and the
downstream number of babies who have
to undergo [a diagnostic] sweat test,” said
Caggana. “That makes the longer time
palatable.”
Further complicating the work of NBS
scientists, said Hopkins, are “external
pressures to meet challenging timelines
and quality in a very sensitive and
oftentimes emotional area of laboratory
testing.”
Earlier this year, Sanofi US—which
manufactures enzyme replacement
therapies for a group of NBS conditions
known as lysosomal storage disorders
(LSDs)—lobbied the Iowa legislature and
Spring 2019 LAB MATTERS
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