THE ICEBERG EFFECT
Using statistical techniques that he pioneered in
the AIDS epidemic, Ron Brookmeyer has illuminated the depths of
the fall anthrax attacks.
By Michael Purdy
Art by Michael Gibbs
Brookmeyer sounds the depths of epidemiological icebergs for
When a new disease outbreak emerges, one of the biggest concerns
for public health officials and the public is the question of whether
the patients diagnosed with the disease represent the majority of
those already infected. Are those patients it? Or are they just
the tip of a huge iceberg of infection that already reaches deep
down below the level of clinical detection, waiting to emerge at
some point to endanger the lives of many?
The key to the iceberg effect is the disease's incubation period,
the time between infection and the first symptoms of illness. Incubation
periods can vary widely by disease. For example, the median incubation
period for HIV is about 10 years, while anthrax has a median incubation
period of 11 days.
Brookmeyer, PhD, professor, Biostatistics, belongs to a pioneering
group of scientists who first developed statistical models that
allow researchers to apply the incubation period and other factors
to a population in order to sketch the true shape and size of an
"Here's a simplified example: The median incubation period
is the length of time by which half of the people infected will
develop symptoms. If we established that a disease had an 11-day
median incubation period, and we knew that there had already been
10 cases at the 11-day point after the exposure, we would then know
that we needed to look for approximately 10 more cases," Brookmeyer
He and his colleagues first applied the techniques during the emergence
of the AIDS epidemic in the 1980s. By combining the data available
on HIV's incubation period with reports of AIDS cases and other
factors monitored by physicians, they were able to produce a clearer
picture of the true spread of AIDS.
As concern grew over the possibility of a bioterror attack, Brookmeyer
joined efforts at the School to help prepare for such an event.
His first effort in this area actually took place more than a year
before Sept.11, when D.
A. Henderson, then-director of the School's Center for Civilian
Biodefense Strategies, asked him to take a look at the data available
on an outbreak of anthrax in 1979.
That outbreak took place in Sverdlovsk in the former Soviet Union
and killed 70 people. At first linked to contaminated meat, the
outbreak was later traced to an accidental release of anthrax spores
from a nearby Soviet biowarfare laboratory.
Anthrax spores are essentially inert, but after entering the body
they germinate into their disease-causing form after a period of
time that can vary by days or weeks. The result of Brookmeyer's
study was a mathematical curve that shows over time what percentage
of a group of people exposed to a sufficiently large dose of anthrax
will develop the inhalation form of the disease.
Initially, Brookmeyer says, the work was lukewarmly received. "I
gave a couple of talks about the results, and I saw a lot of people
getting glazed looks that said, 'What is anthrax again?'" he
After the anthrax attacks last fall, though, many more people started
paying attention. Brookmeyer and Natalie Blades, a graduate student
at the School, resolved to use the findings on Sverdlovsk to gain
new insight into the U.S. anthrax outbreaks. Their goal was to determine
how many cases of inhalation anthrax were prevented by the use of
prophylactic antibiotics among the thousands of people most at risk
They analyzed eight cases of inhalation anthrax in three clusters:
in Florida at a supermarket tabloid, among New Jersey postal workers,
and among District of Columbia postal workers. Three additional
cases of inhalation anthrax could not be studied because investigators
were never able to determine the sources of exposure that led to
For the eight cases, they had information on exposure times (with
the exception of the Florida cluster, where an exposure date had
to be estimated because a letter was never found), the time when
each case of anthrax began, and the time when prophylactic antibiotics
Based on this data and the anthrax incubation period, they estimated
antibiotics had prevented nine cases of potentially fatal inhalation
anthrax. Their results were published in the March 8 issue of Science.
Brookmeyer thinks statistical modeling techniques can help scientists
prepare for and respond to bioterror attacks in several ways, including
assessing potential responses in advance in simulations of attacks,
predicting the size of an outbreak based on early data, and weighing
the potential hazards of prophylactic treatment against the risks
He says it might even be possible to use statistical modeling to
help officials zero in on the tip of the iceberg: an as-yet undetermined
source of an emergent outbreak.
"If we can help pinpoint the exposure date, then we can help
identify other people who may have been around the cases at the
same time and were therefore exposed and in need of treatment,"
he explains, adding, "Of course, helping find an exposure date
may also help find the perpetrator."
How well known are the incubation periods for other potential bioterror
agents like smallpox and plague? Thomas Inglesby, deputy director
of the Center for Civilian Biodefense Strategies, says incubation
periods for both pathogens have been previously established.
"For smallpox, the range of the expected incubation period
is about seven to 17 days, and for plague it's one to six days,"
Inglesby says. "It's not clear, though, how weaponization will
affect those figures. Adding some form of carrier to a smallpox
powder, as was done in the anthrax attacks of 2001, or finding a
way to deliver a particularly large dose to victims might alter
the incubation period."
Brookmeyer is running simulations to see how scientists can better
account for sources of uncertainty like dosage, ages of those exposed,
and the suppressed immune systems of HIV patients, transplant recipients,