Health

When they warn of rare disorders, these prenatal tests are usually wrong

But a few weeks later, as she was
driving her son home from school, her doctor’s office called. A prenatal blood
test indicated her foetus might be missing part of a chromosome, which could
lead to serious ailments and mental illness.

Sitting on the couch that evening with
her husband, she cried as she explained they might be facing a decision on
terminating the pregnancy. He sat quietly with the news. “How is this happening
to me?” Geller, 32, recalled thinking.

The next day, doctors used a long,
painful needle to retrieve a small piece of her placenta. It was tested and
showed the initial result was wrong. She now has a 6-month-old, Emmanuel, who
shows no signs of the condition he screened positive for.

Geller had been misled by a wondrous
promise that Silicon Valley has made to expectant mothers: that a few vials of
their blood, drawn in the first trimester, can allow companies to detect
serious developmental problems in the DNA of the foetus with remarkable
accuracy.

In just over a decade, the tests have
gone from laboratory experiments to an industry that serves more than one-third
of the pregnant women in America, luring major companies such as Labcorp and
Quest Diagnostics into the business, alongside many startups.

The tests initially looked for Down
syndrome and worked very well. But as manufacturers tried to outsell one
another, they began offering additional screenings for increasingly rare
conditions.

The grave predictions made by those newer
tests are usually wrong, an examination by The New York Times has found.

That includes the screening that came
back positive for Geller, which looks for Prader-Willi syndrome, a condition
that offers little chance of living independently as an adult. Studies have
found its positive results are incorrect more than 90% of the time.

Nonetheless, on product brochures and
test-result sheets, companies describe the tests to pregnant women and their
doctors as near certain. They advertise their findings as “reliable” and
“highly accurate,” offering “total confidence” and “peace of mind” for patients
who want to know as much as possible.

Some of the companies offer tests
without publishing any data on how well they perform, or point to numbers for
their best screenings while leaving out weaker ones. Others base their claims
on studies in which only one or two pregnancies actually had the condition in
question.

These aren’t the first Silicon Valley
firms to try to build a business around blood tests. Years before the first
prenatal testing company opened, another startup, Theranos, made claims that it
could run more than 1,000 tests on a tiny blood sample, before it collapsed
amid allegations of fraud.

In contrast with Theranos, the science
behind these companies’ ability to test blood for common disorders is not in
question. Experts say it has revolutionised Down syndrome screening,
significantly reducing the need for riskier tests.

However, the same technology — known as
noninvasive prenatal testing, or NIPT — performs much worse when it looks for
less-common conditions. Most are caused by small missing pieces of chromosomes
called microdeletions. Others stem from missing or extra copies of entire
chromosomes. They can have a wide range of symptoms, including intellectual
disability, heart defects, a shortened life span or a high infant-mortality
rate.

Not every patient is screened for every
condition; doctors decide what to order, and most companies sell microdeletion
testing as an optional add-on to the Down screening. Most test makers don’t say
how often their microdeletion tests are being performed.

But it is clear some of the tests are in
widespread use. One large test maker, Natera, said that in 2020 it performed
more than 400,000 screenings for one microdeletion — the equivalent of testing
roughly 10% of pregnant women in America.

To evaluate the newer tests, The Times
interviewed researchers and then combined data from multiple studies to produce
the best estimates available of how well the five most-common microdeletion
tests perform.

The analysis showed that positive
results on those tests are incorrect about 85% of the time.

Experts say there is no single threshold
for how often a test needs to get positive results right to be worth offering.
They note that when the tests do accurately identify an abnormality, it can
give expectant parents time to learn about and prepare for challenges to come.
Some said one common microdeletion screening, for DiGeorge syndrome, a disorder
associated with heart defects and intellectual disability, has the most
potential to do good.

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But there are hundreds of microdeletion
syndromes, and the most expansive tests look for between five and seven,
meaning women shouldn’t take a negative result as proof their baby doesn’t have
a genetic disorder. For patients who are especially worried, obstetricians who
study these screenings currently recommend other types of testing, which come
with a small risk of miscarriage but are more reliable.

Some said the blood screenings that look
for the rarest conditions are good for little more than bolstering testing
companies’ bottom lines.

“It’s a little like running mammograms
on kids,” said Mary Norton, an obstetrician and geneticist at the University of
California, San Francisco. “The chance of breast cancer is so low, so why are
you doing it? I

think it’s purely a marketing thing.”

There are few restrictions on what test
makers can offer. The Food and Drug Administration often requires evaluations
of how frequently other consequential medical tests are right and whether
shortfalls are clearly explained to patients and doctors. But the FDA does not
regulate this type of test.

Alberto Gutierrez, former director of
the FDA office that oversees many medical tests, reviewed marketing materials
from three testing companies and described them as “problematic.”

“I think the information they provide is
misleading,” he said.

Patients who receive a positive result
are supposed to pursue follow-up testing, which often requires a drawing of amniotic
fluid or a sample of placental tissue. Those tests can cost thousands of
dollars, come with a small risk of miscarriage and can’t be performed until
later in pregnancy — in some states, past the point where abortions are legal.

The companies have known for years that
the follow-up testing doesn’t always happen. A 2014 study found that 6% of
patients who screened positive obtained an abortion without getting another
test to confirm the result. That same year, The Boston Globe quoted a doctor
describing three terminations after unconfirmed positive results.

Three geneticists recounted more recent
examples in interviews with The Times. One described a case in which the
follow-up testing revealed the foetus was healthy. But by the time the results
came, the patient had already ended her pregnancy.

After being presented with some of The
Times’ reporting, a half-dozen of the largest prenatal testing companies
declined interview requests. They issued written statements that said patients
should always review results with a doctor and cautioned that the tests are
meant not to diagnose a condition but rather to identify high-risk patients in
need of additional testing.

In interviews, 14 patients who got false
positives said the experience was agonising. They recalled frantically
researching conditions they had never heard of, followed by sleepless nights
and days hiding their bulging bellies from friends. Eight said they never
received any information about the possibility of a false positive, and five recalled
that their doctor treated the test results as definitive.

When Meredith Bannon’s pregnancy tested
positive for DiGeorge syndrome, a nurse called and told her she and her husband
would soon face “tough decisions” related to their child’s “quality of life,”
which Bannon took to mean a choice about whether to end the pregnancy.

The call came as Bannon was driving to
her parents’ house, with her son in the back seat wearing a “big brother”
T-shirt. “I was coming home to tell them that I was pregnant, but instead I had
to tell them the news I got this horrible result back,” Bannon recalled.

Further testing revealed that the result
was wrong. Her baby is due in April.

Some women began tentatively planning
abortions after receiving positive screenings.

“I couldn’t help but have termination on
my mind,” said Allison Mihalich, 33, whose screening incorrectly indicated her
baby might have Turner syndrome, which can cause infertility and heart defects.
(Studies show that the test’s positive results are wrong 74% of the time.) She
lived in Indiana at the time and recalled scrambling to arrange follow-up
testing before the state’s 22-week abortion ban.

A big market for rare conditions

Between 2011 and 2013, a small Silicon
Valley-based biotech company, Sequenom, tripled in size. The key to its
success: MaterniT21, a new prenatal screening test that did remarkably well at
detecting Down syndrome.

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Older screening tests took months and
required multiple blood tests. This new one generated fewer false positives with
a single blood draw.

The test could also determine the sex of
a foetus. It quickly became a hit. “You had people walking in saying, ‘I want
this sex test,’” recalled Dr Anjali Kaimal, a maternal-foetal medicine
specialist at Massachusetts General Hospital.

Competitors began launching their own
tests. Today, analyst estimates of the market’s size range from $600 million
into the billions, and the number of women taking these tests is expected to
double by 2025.

As companies began looking for ways to
differentiate their products, many decided to start screening for more and
rarer disorders. All the screenings could run on the same blood draw, and
doctors already order many tests during short prenatal care visits, meaning
some probably thought little of tacking on a few more.

For the testing company, however, adding
microdeletions can double what an insurer pays — from an average of $695 for
the basic tests to $1,349 for the expanded panel, according to health data
company Concert Genetics. (Patients whose insurance didn’t fully cover the
tests describe being billed wildly different figures, ranging from a few
hundred to thousands of dollars.)

But these conditions were so rare that
there were few instances for the tests to find.

Take Natera, which ran 400,000 tests in
2020 for DiGeorge syndrome.

Natera declined an interview request
after The Times presented its reporting. In statements, it said that the early
detection of DiGeorge syndrome can “profoundly improve” patient outcomes and
stressed how infrequently it identifies some of the other conditions. (It said
the screening that that gave a false positive for Prader-Willi syndrome in
Geller’s pregnancy, for example, had returned positive results only 113 times
since 2015.) It pointed to its recent study of 20,000 pregnant women that found
the condition to occur in 1 in 1,600 births — twice as common as other
estimates.

The company offers free genetic counselling
to patients who screen positive. Natera also publishes data on how often its
positive results are right and includes that information on patient results
sheets.

Other companies release little
information about how many tests they sell, and far less research on how well
their screenings work.

Myriad Genetics’ prenatal test, Prequel,
offers five microdeletion screenings, even though its study on the test
includes just two confirmed cases of microdeletions.

In a statement, Myriad estimated that
only 1 in 9,000 of its patients screen positive for a microdeletion. It said
its data showed a “very small fraction” of those are wrong, but declined to
provide specific figures.

Some companies test for conditions so
rare that there are few known examples for comparison.

Both Labcorp, which purchased Sequenom,
and Myriad Genetics offer screenings for one disorder that is so rare its
prevalence is unknown, and another, called Jacobsen syndrome, that affects 1 in
100,000 births.

Dr Diana Bianchi runs a National
Institutes of Health laboratory studying prenatal blood screenings. She said of
Jacobsen syndrome: “I’ve never seen a case of that in my 20-plus years of
practicing genetics.”

‘Total confidence in every result’

Those shortfalls are rarely referenced
when companies explain the tests to doctors and patients.

A Labcorp MaterniT21 lab report tells
patients the test “detected” a problem, even though most studies show positives
on that screening are usually wrong. Myriad Genetics advertised “total
confidence in every result” on its prenatal testing website but said nothing
about how often false positives can occur.

After The Times inquired about these
tests, Myriad took down that language.

The Times reviewed 17 patient and doctor
brochures from eight of the testing companies, including Natera, Labcorp, Quest
and smaller competitors. Ten of the brochures never mention that a false
positive can happen. Only one mentioned how often each test gets positive
results wrong.

Genetic counsellors who have dealt with
false positives say some doctors may not understand how poorly the tests work.
And even when caregivers do correctly interpret the information, patients may
still be inclined to believe the confident-sounding results sheets.

When Cloey Canida, 25, got a positive
result from Roche’s Harmony test in September, the result sheet seemed clear:
It said her daughter had a “greater than 99/100” probability of being born with
Patau syndrome, a condition that babies often do not survive beyond a week.

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Her obstetrician tried to reassure her,
citing independent data showing that for a woman her age, 93% of positives turn
out to be wrong.

But Canida couldn’t stop thinking about
the result sheet. She recalls crying during an ultrasound, thinking it was one
of the few times she’d see her child moving.

After spending $1,200 on follow-up
tests, she learned that her pregnancy was healthy and that her daughter would
not be born with Patau syndrome. She is now in her third trimester.

“I wish that we would have been informed
of the false positive rate before I agreed to the test,” she said. “I was given
zero information about that.”

Roche, which recently sold the Harmony
test to another company, said in a statement that “all women should discuss
their results with their health care provider” before making any decisions based
on screening results.

Three experts reviewed marketing
materials and results sheets for The Times and identified obvious reasons a
patient would be confused.

“These numbers are meaningless,” said
Gutierrez, the former FDA official, after reviewing an advertisement for the
Quest Diagnostics QNatal Advanced Test.

The test is advertised as getting
positive microdeletion results right 75% of the time. But that figure comes
from a single study that included nine confirmed cases of microdeletions, for a
test that screens for seven such disorders. The company doesn’t specify how the
tests perform individually, and it declined to provide that data. (In a
statement, Quest said its test has “excellent performance.”)

The FDA considered regulating these
tests a decade ago but backed away. If the agency had oversight, Gutierrez
said, Quest would be required to publish a brochure, but “it would not look
like this.”

Nonetheless, companies are charging
ahead, viewing microdeletions as a major business opportunity — especially if
they can persuade more doctors to order them and more insurers to cover them.

Myriad Genetics has told investors that
it plans to start a “next-generation” microdeletion screening this year and
that it will lobby the professional society for obstetricians to begin
recommending the test to its members.

Natera has performed more than 2 million
screenings for Down syndrome since 2013. It went public in 2015, and the value
of its stock has grown to $8.8 billion.

With its expanded panel of screenings,
the company sees more growth ahead. “This is a really significant moment for
the microdeletions business,” CEO Steve Chapman said at an investor conference
last January.

The company’s 2020 revenues were $391
million, and it projected its 2021 revenues to exceed $615 million. But if more
insurers begin paying for microdeletion tests, Chapman said, the potential is
“enormous” — it could bring in up to another $300 million every year.

ABOUT THE ANALYSIS

To estimate the performance of
microdeletion screening tests, The Times interviewed genetic counselors and
experts on medical testing and prenatal care, then searched for peer-reviewed
studies of screenings by US-based labs that included follow-up diagnostic
testing. Six studies met these criteria: three from diagnostic testing labs,
and three studies funded by one of the test makers, Natera. An additional 2021
report by Natera was added as it included results from a recent clinical trial
of its microdeletion test. (An eighth study, published in 2015, was excluded
because experts identified multiple problems with its methodology.) Reporters
then combined the data from these studies and estimated the tests’ overall
positive predictive value to be 15%. Two researchers reviewed the resulting
analysis. In addition to clinical data, three of the four Natera studies
include projected performance numbers that are based on reanalysing the blood
samples they collected with a modified version of the original test. Some
experts cautioned that this technique (known as “post-hoc analysis”) can
inflate a test’s performance; others said it was a common practice that helped
improve results over time. At times, the company could not replicate those
projections in subsequent studies. To be conservative, The Times used Natera’s
higher projected numbers in its estimates; using the clinical data instead
would decrease the tests’ overall positive predictive value from 15% to 11%.

© 2022 The New York Times Company

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