Short-circuiting the need for expensive clinical
trials, researchers uncovered an association between
androgen blockers and cognitive decline by examining
patient medical records.
A review of the electronic medical records of
thousands of prostate cancer patients at two major
medical institutions revealed a nearly two-fold
increase in the rate of Alzheimer’s disease
diagnosis among those treated with androgen
deprivation therapy.
The study, by researchers at the Stanford University
School of Medicine and the University of
Pennsylvania Perelman School of Medicine,
demonstrates emerging techniques for extracting
biomedical data from ordinary patient medical
records.
The paper was published online Dec. 7 in the Journal
of Clinical Oncology. Nigam Shah, MBBS, PhD,
associate professor of biomedical informatics
research at Stanford, is the senior author. The lead
author, Kevin Nead, MD, is a resident at the
University of Pennsylvania who got his medical
degree at Stanford.
Because testosterone can promote the growth of
prostate tumors, clinicians have used androgen
deprivation therapy to lower testosterone and other
androgens in prostate cancer patients since the
1940s. In the United States, about a half-million
men currently receive ADT as a treatment for
prostate cancer.
The researchers scanned the records of about 5.5
million patients from two hospitals: Stanford Health
Care, in Palo Alto, and, through a prior
institutional research agreement, 3.7 million
patients from Mount Sinai Hospital, in New York
City. Among this cohort, they identified about 9,000
prostate patients at each institution, 16,888 of
whom had non-metastatic prostate cancer. A total of
2,397 had been treated with androgen deprivation
therapy.
Patients in the study who had been treated with ADT
had about a 1.88 times increased rate of being
diagnosed with Alzheimer’s disease in a median
follow-up period of 2.7 years compared with prostate
cancer patients who did not receive ADT, the study
found. The subset of men treated with ADT for longer
than 12 months had a 2.12 higher risk — more than
double that of prostate cancer patients not treated
with ADT.
Shah said the idea for the study started with Nead,
who noticed some references in the medical
literature to men who had ADT treatment for prostate
cancer subsequently experiencing cognitive declines.
“There was some chatter in the literature,” said
Shah. But no one had formally tried to find out if
ADT therapy leads to cognitive defects.
“This is the kind of question that typically you
would need a large clinical trial to answer,” said
Shah. But a formal clinical trial would be
enormously expensive. “So instead, we’re making
secondary use of existing clinical data collected as
part of routine medical care” — clinical data that’s
practically free.
Although ADT may increase the risk of defects in
cognition and hand-eye coordination for reasons
other than Alzheimer’s disease, the team decided to
focus specifically on Alzheimer’s because the
condition is easier to identify in medical records,
said Shah. “Broader dementias and vascular dementia
are kind of hard to quantify and define, so we had
to narrow the scope of the analysis to make it
feasible with the methods that we have available,”
he said.
After making statistical adjustments to control for
biases, the team performed two kinds of tests to
assess the reliability of the findings. In
“falsification tests,” they looked for false
associations in the data. Specifically, they looked
for five associations with medical conditions such
as tuberculosis and allergies unlikely to be
connected to testosterone levels. Those tests all
came back negative.
They also looked for associations likely to be
positive, such as age and cardiovascular disease —
both conditions known to be associated with a risk
of Alzheimer’s disease. Those positive associations
were confirmed in the data.
Patients who are receiving ADT and are concerned
about the potential risks should discuss them with
their physicians. “The association found in this
study should be evaluated in the context of the
overall treatment choices available to any specific
patient,” Shah said. “This study demonstrates the
value of using existing EMR data to quantify the
trade-offs that various treatments offer.”
Although other institutions are beginning to use
patient records to ask and answer research
questions, Stanford is unusually well-situated to do
this work, said Shah. Patient records at Stanford
are managed by the Stanford Center for Clinical
Informatics. “If I was to go to another institution
and ask for this same data, I’d probably be waiting
a year, a year and a half; there would be so much
hassle involved in being able to access the clinical
documents that have detailed patient health
information in them, whereas here we have the
necessary infrastructure in place so that once you
get Institutional Review Board approval, getting to
the data doesn’t take you a year and a half or two
years,” he said. Depending on the complexity of the
data, it could take as little as two weeks at
Stanford. Worst case, it could take six months, he
said. “But it’s not in geological time-scale.”
The work was bolstered by electronic medical records
shared by Mount Sinai Hospital, which doubled the
number of relevant patient records — highlighting
the importance of such cross-institutional
collaborations. Harnessing the data in electronic
medical records is part of Stanford Medicine’s
efforts in precision health — health care whose goal
is to anticipate and prevent disease in the healthy
and precisely diagnose and treat disease in the ill.
Other Stanford-affiliated co-authors of the paper
are medical student Gregory Gaskin; life science
research assistant Cariad Chester; and associate
professor of surgery and of medicine Nicholas Leeper,
MD. The researchers collaborated with Joel Dudley,
PhD, assistant professor of genetics and genomic
sciences at the Icahn School of Medicine at Mount
Sinai.
This research was supported by the National
Institutes of Health (grant U54HG004028 for the
National Center for Biomedical Ontology), the
National Library of Medicine (grant R01LM011369) and
the National Institute of General Medical Sciences
(grant R01GM101430).
Stanford’s departments of Medicine, of Computer
Science and of Radiation Oncology also supported the
work.
Per saperne di più
Journal of Clinical Oncology
Androgen Deprivation Therapy and Future Alzheimer’s
Disease Risk
Kevin T. Nead, Greg Gaskin, Cariad Chester, Samuel
Swisher-McClure, Nicholas J. Leeper and Nigam H.
Shah
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