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Welch Wanderings

Revising the Risk of Dirty Air

For several years, a team of School researchers have been presenting the results of a massive analysis of air pollution’s daily effect on mortality in the nation’s 90 largest cities over an eight-year time span. After five years of work, they had strong evidence linking particulate pollutants to increased deaths and hospitalization from cardiac and pulmonary conditions.

Principal investigator Jonathan Samet, professor and chair of Epidemiology; Scott Zeger, professor and chair of Biostatistics; Francesca Dominici, assistant professor of Biostatistics; and Aidan McDermott, an assistant scientist in Biostatistics, were nearing their final goal, presentation of the results to an influential Environmental Protection Agency (EPA) committee, when they hit a small but alarming hitch.

Dominici, PhD, and McDermott, PhD, were working on what they thought would be their last paper on the National Morbidity, Mortality, and Air Pollution Study (NMMAPS) when they ran the analysis with an important analytical factor altered. The results should have changed dramatically but, to their amazement, nothing happened. Further dramatic alterations of this factor also produced no change in the results.

Bright ideas: Jonathan Samet (left), Scott Zeger, and Francesca Dominici

Time was excruciatingly short. The team had planned to present the results in July to the Clean Air Scientific Advisory Committee (CASAC), the group responsible for evaluating the EPA’s assessment of air pollution’s effects on health. That assessment (for particulate matter and other pollutants) is mandated every five years and shapes the EPA’s national air pollution control policy for years to come.

In hopes of understanding what was causing the strange lack of effect, Dominici and McDermott took a close look at S-Plus, the popular statistical analysis software they had used in NMMAPS. In what Zeger, PhD, calls “an amazing bit of detective work,” Dominici and McDermott discovered that default values in the S-Plus implementation of a widely used statistical method (called Generalized Additive Models) hadn’t been updated since the early 1990s. The values, known as the convergence criteria, affected the degree of processing given to statistical analyses. Its unchanged setting meant that a large fraction of currently available computing power—all the tremendous advances in computing speed and capacity since the early 1990s—wasn’t being brought to bear on the NNMAPS analyses when such power was merited.

Dominici and McDermott spent several sleepless weeks identifying stricter convergence parameters and then redoing the analyses (nearly 30,000 by Zeger’s estimate). They found that there was still a definite connection between increased particulate pollution and higher risk of death or illness.

“The revised results lowered that risk, but we still had strong, consistent evidence of association between air pollution and increased morbidity and mortality across the whole country,” says Zeger. “Our first results weren’t qualitatively wrong, they just weren’t optimal.”

The software issue and the new results were reported to the EPA, other concerned groups, and the scientific community by the Health Effects Institute (HEI), the nonprofit foundation that funded the project, according to Samet. HEI’s “scientific, peer-reviewed communication” on the matter explained the problem and described new results and plans for further analyses, Samet says.

When the story hit the media, however, many news reports misinterpreted the revisions as not only invalidating the results of NMMAPS, but as invalidating all previous studies of air pollution’s effects on health (since some prior assessments had used S-Plus as well).

Statistical detective: Aidan McDermott

Detractors focused particular attention on the percentage change in risk. Some claimed that the previous results were reduced by nearly 50 percent. Zeger says this relative change is true from a strictly numerical perspective—the average increase in risk declined from .41 percent to .27 percent per every 10 micrograms increase of particulate matter per cubic meter of air. That’s a .14 percent difference, or half of the final result, from the critic’s perspective. (Taken from another perspective, .27 is 65 percent of .41, meaning a 35 percent decline in estimated increased risk.)

However, emphasizing the change in relative risk can be misleading. Zeger and the other NMMAPS authors find it much more useful to focus on the absolute change in risk—how many people will die? Taking the city of Baltimore as their example, they calculated that their final result means that lowering average particulate pollution levels by 10 micrograms per cubic meter could prevent 20 deaths per year from acute exposure. Original risk estimates would have put this improvement at 30 deaths per year.

“This is very high stakes science. The evidence is looked at very carefully. It needs to hold up to scrutiny.” 
— Jonathan Samet

“But most importantly, NMMAPS only estimates the acute effects of exposure to pollution,” emphasizes Zeger. “If we take account of the effects of longer-term exposure in a city like Baltimore, the attributable deaths are an order of magnitude higher.

“Everybody’s trying to use this update, and this thing now seems to have a life of its own,” says Zeger. “Even after we posted a question and answer document about the revisions on the Internet, people still don’t seem to look to what’s true.” (See the document.)

Dominici presented the revised results in mid-July to the EPA’s CASAC, the panel in charge of reviewing and approving EPA’s summary and synthesis of the evidence on particulate matter, and a National Research Council committee.

“This is very high stakes science,” says Samet, MD, MS, who in addition to being principal investigator on NMMAPS, served as consultant to CASAC for particulate matter and chair of the National Research Council Committee on Research Priorities for Particulate Matter. “There are enormous financial implications for a huge sweep of industry, and that means the evidence is looked at very carefully. It needs to hold up to scrutiny.”

Samet says it will be several years before the final EPA documents and recommendation are completed.   — Michael Purdy

New Centers Address Critical Training Needs

One year after rallying its intellectual resources to help protect a nation stunned by terrorism, the School has launched three new centers dedicated to improving the skills and knowledge of the public health workforce.

As the School’s Center for Civilian Biodefense Strategies and the Hopkins Public Health Scientists Working to Address Terrorism (SWAT) continue working on policy, research, and national preparedness, the new centers will focus on a key weakness in the nation’s public health infrastructure: training for its workers.

The centers address “the fact that more than three-fourths of the people working in public health in the country are not trained in the core competencies of public health,” says Lynn Goldman , MD, MPH ’81, MS, a director of one of the new centers.

A well-educated, skilled public health workforce can better respond to threats, whether they be day-to-day public health challenges or bioterrorist attacks, says Dean Alfred Sommer, MD, MHS ’73.

The MidAtlantic Public Health Training Center, the Johns Hopkins Center for Public Health Preparedness, and the Center of Excellence in Community Environmental Health Practice may have different goals, but they will work closely together, sharing faculty, training materials, and the results of needs assessments, he says. “We’re able to deliver much more bang for the buck by coordinating this effort,” Sommer notes.

The centers have already sponsored an Aug. 6 risk communication seminar in Baltimore. A smallpox symposium, co-sponsored by the SWAT team, is scheduled for Sept. 25 and will school public health workers in the biology and epidemiology of the disease. A two-day course on training workers in the age of bioterrorism will follow on Oct. 26. Future training will deliver courses via the Web through the School’s Distance Education Division, allowing public health workers to pursue certificates in public health, and ultimately earn MPH degrees.

Above: Risk communication seminar participants confer; right, Professor Thomas Burke opened the conference with a review of post-9/11 communications.

The centers and their primary goals are:

Johns Hopkins Center for Public Health Preparedness
(Principal Investigator: Robert Lawrence, MD, associate dean and professor). One of 15 centers across the nation supported by the Centers for Disease Control and Prevention, JHCPHP is funded by its first yearlong $986,000 grant to help train public health workers in Maryland, Delaware, and Washington, D.C., to deal with public health emergencies, including bioterrorism.

Center of Excellence in Com-munity Environmental Health Practice
(Principal Investigator: Thomas Burke, PhD, MPH, professor, Health Policy and Management). Funded by a three-year $900,000 CDC cooperative agreement, CECEHP will educate practitioners in environmental issues such as water quality, indoor air quality, and hazardous waste sites, according to Beth Resnick, MPH ' 95, CECEHP associate director. The Center is also investigating the creation of Hopkins response teams that will rapidly assist government agencies during emergencies.

MidAtlantic Public Health Training Center
(Director and Co-Principal Investigator: Lynn Goldman , professor, Environmental Health Sciences). The Health Resources and Services Administration (HRSA) launched MAPHTC with a five-year $1.9 million grant. MAPHTC has begun a comprehensive needs assessment of 15,000 public health workers in Maryland, Delaware, and Washing-ton, D.C., to determine training needs. MAPHTC will then share the information with centers at the School and work with regional university partners to design training.

Public health workers “have an obligation to protect the public’s health and also to protect individual dignity and civil rights.”
— Stephen Teret

In addition to the new centers, the School’s Center for Law and the Public’s Health has received a $240,000 boost to its CDC funding to teach public health workers across the country about the Model State Emergency Health Powers Act. The model legislation, drafted by a team at the Center, grants the states quarantine and other powers during extreme emergencies. Seventeen states and the District of Columbia have already adopted the law or portions of it. Public health workers in those areas need to understand their powers and responsibilities, says Stephen Teret , JD, MPH ’79, a director of the Center. Though seminars will need to be tailored to each state’s version of the law, Teret says the main lesson for public health workers remains the same: “They have an obligation to protect the public’s health and also to protect individual dignity and civil rights.”   
— Brian W. Simpson

Hauer Power

Since last fall’s terrorist attacks, the nation hasn’t had the luxury of taking a leisurely approach to public health preparedness.

Deadlines are now set in terms of weeks, not years, according to Jerry Hauer, MHS ’78, who in June was named acting assistant secretary for Public Health Emergency Preparedness at the U.S. Department of Health and Human Services (HHS). “We don’t have time to use calendars. We measure things with a watch,” says Hauer. “We have to be ready now. We cannot look at things five, ten years out. We have to look at things five, ten weeks out.”

The accelerated program for a national smallpox vaccine stockpile is an example of the government’s new time-tables, according to Hauer. An original goal to have 40 million doses of smallpox vaccine by 2005 was bumped up so that the nation will have 286 million doses—enough for all Americans—by the end of this year. “That’s the type of change you’re seeing in this department,” says Hauer.

In May, Hauer took over leadership of the new Office of Public Health Preparedness from another School alum,

former Dean D.A. Henderson, MD, MPH ’60. Henderson is now principal science advisor to Secretary Tommy G. Thompson.

National public health preparedness essentially needs to be established by yesterday—not a timetable normally associated with the government. “The challenges are difficult… but we’re working on it. We’re making some incredible progress in things,” says Hauer, who was director of New York City’s Office of Emergency Management in the late 1990s under Mayor Rudolph Giuliani. Plans established by Hauer brought in ambulances from four states to the city on Sept. 11. 

In his new position, Hauer draws on the experience of Henderson, who signed Hauer’s diploma, and other colleagues with School connections. They include Philip Russell, MD, a professor emeritus in the Department of International Health; William Lyerly, MPH ’83; Karen Becker, MPH ’95; and Rebecca Rabin, MHS ’02.

 “We’ve got the Hopkins mafia here,” Hauer jokes. In addition to the help from School alumni, Hauer says he can rely on the constant encouragement from Henderson: “D.A. keeps telling me, ‘Don’t screw up or I’ll revoke your degree.’ ” 
— Brian W. Simpson


"Human Capital” Tops Campaign Priorities

At the heart of every public health triumph is an individual. Scientific giants like E.V. McCollum, Abel Wolman, and Anna Baetjer have developed solutions to the world’s most pressing health problems.

It was no surprise, therefore, when the School announced its new $500 million fund-raising campaign that investment in the School’s “human capital” was the top priority. The campaign seeks to provide a major infusion to the Faculty Innovation Fund that encourages breakthrough research, and to endow new scholarship programs that will attract the world’s best students. The School’s effort, part of the University-wide $2 billion campaign dubbed “Johns Hopkins: Knowledge for the World,” was launched with a gala held on the Homewood campus on May 4.

Currently, researchers at the School are often unable to pursue truly innovative directions because they must bring in 75 to 80 percent of their own salaries through outside grants and other support, notes Dean Alfred Sommer, MD, MHS ’73. Most faculty funding comes from federal agencies such as the National Institutes of Health and the Centers for Disease Control. “These funds support activities that are more or less proven to be headed in an accepted direction,” Sommer explains. “What they don’t support are right-hand turns in the road—the paradigm shifts—because nobody else has tried it.” However, it is these high-risk, high-reward directions that can ultimately make the difference in public health.

Campaign launch: Dean Alfred Sommer (left) with Edward Ludwig, Health Advisory Board chairman.

Thus the School seeks to add $50 million to its Faculty Innovation Fund, which was established in 1991 to offer faculty stable support early in their careers so that they can pursue their own research on the very edge of scientific discovery. Take, for example, the work of Karl Broman, assistant professor of Biostatistics. With support from the Fund, Broman, PhD, has developed innovative methods for studying how diseases and other traits are passed from one generation to the next.

Student support is the other major focus of the campaign. Though the School has numerous endowed student support funds that provide partial scholarships, with a student body of just over 2,000, the School falls woefully short of the ultimate goal of helping to support every student.

Ameena Batada is one of the lucky ones. A DrPH candidate, she seeks out every opportunity to apply her academic course work to the health needs of vulnerable children in East Baltimore. This year Batada was awarded the John and Alice Chenoweth-Pate Fellowship Award, enabling her to continue her field work and take classes.

“We are at an enormous disadvantage in recruiting the best students, who become discouraged because we cannot provide financial assistance,” says Sommer. The student body at the School is unique—many students are from other countries, are older, and have young families to support, so they are hard-pressed to take time off to pursue a public health degree. “We often miss out on people who should be the future of public health,” explains Sommer.

In October 2001, the School’s leadership created a new policy that allocated 10 percent of all new endowment gifts to the School to fund graduate education. One of the most innovative goals for this campaign is a $50 million to $75 million scholarship program modeled after the Rhodes Scholars program. The aim: to recruit the best students from around the world who can ultimately be trained to become part of an informed cadre of distinguished public health leaders. After graduation, they will return to their own countries, equipped with the tools of public health, to tackle health issues around the world.

In a further effort to aid students, plans are in place to radically revise the DrPH program to make it more accessible (via the Web and through brief, periodic residence at the School) to full-time professionals who cannot leave their jobs to seek the degree.

Another major campaign goal is raising $15 million for the School’s ongoing work in bioterrorism and public health preparedness. The School’s efforts have already provided expertise, insight, and discoveries that are helping to protect the nation’s health.  — Susan Muaddi Darraj

T. gondii: The Movie

Glowing an unnatural emerald green, the oval-shaped parasite glides along the surface of its prey. After locating a prime space, the parasite binds itself to the cell and then pushes into its membrane. Once inside, it begins to replicate rapidly, feeding off its host and doubling every six hours.

Within two days, the single Toxoplasma gondii (T. gondii) parasite yields as many as 128 “daughter cells” that destroy their host cell and burst forth to invade others. It’s a textbook parasite invasion like any other, except this drama unfolds in front of a digital camera that snaps pictures every half-second, essentially creating a movie of T. gondii’s conquest. Using knowledge of the parasite gained by such methods, Vern Carruthers, PhD, assistant professor of Molecular Microbiology and Immunology, and his team have scored a recent breakthrough that may lead to drug treatments that will reduce this microscopic family’s ability to spread and infect humans.

Parasite insight: Vern Carruthers and his team knocked out a gene essential to T. gondii ’s ability to invade cells, raising hopes for new drug treatments against the parasite.

Scientists estimate that nearly one-quarter of the world’s adult population is infected with the Toxoplasma parasite (spread most commonly through the consumption of infected, undercooked meat). The mild form of toxoplasmosis, the disease caused by T. gondii, may result in flu-like muscle aches, but people with healthy immune systems usually show no symptoms. Its severe form can cause eye or brain damage.

Carruthers and his team have been able to disrupt a protein that binds Toxoplasma to its host cell. “We knocked out a gene that encodes that protein, impairing the parasite’s ability to invade,” he explains. “We also restored the gene, which repaired its ability to invade —so now we’re sure this gene is responsible for disrupting the invasion.” Carruthers and his team are currently preparing a research paper on their discovery.

To simplify the observation of T. gondii’s invasion, Carruthers, along with PhD students Susannah Brydges and Jill Harper, uses a process called fusion polymerase chain reaction (fusion PCR) to attach a green fluorescent protein (GFP) to the gene that encodes one of the parasite’s proteins. The fused protein emits the eerie green glow that enables Carruthers to track the parasite by using an inverted light microscope (in which the lens sits below the specimen dish or flask).

The most significant development in Carruthers’ research so far relates to the role of the parasite’s secretory proteins. Carruthers’ team has been able to illustrate that Toxoplasma secretes these proteins at different stages of the invasion of the host cell. The first cohort of proteins helps the parasite bind itself to the cell; the second pushes into the cell and forms a compartment for the parasite to occupy; and the third modifies that compartment to begin taking in the cell’s resources. Carruthers and former graduate student Karen Rabenau disabled M2AP, one of the most important secretory proteins the parasite releases. “M2AP is partnered with another parasite protein called MIC2, which binds to the host cell,” Carruthers explains. He and his team found that disruption of M2AP impairs the parasite’s ability to secrete MIC2, thus proving a connection between them and invasion—and revealing a possible way to disrupt the parasite’s ability to spread.

Since cell invasion is an essential process for both Toxoplasma and its cousin Plasmodium (the malaria parasite), Carruthers notes that his research may also help malaria scientists in their quest for new drug treatments.   — SMD

Sorting Out the Science of Sludge

“It’s 10 o’clock. Do you know where your poop is?” jokes Thomas Burke, PhD, MPH, professor of Health Policy and Management and co-director of the Risk Sciences and Public Policy Institute. 

Burke recently chaired a National Research Council panel on the potential health risks of a primary usage of sewage sludge: as a fertilizer for farmland, parks, landfills, old strip-mining sites, and home lawns and gardens. The United States banned ocean dumping of sewage sludge in 1992. The rate of recycling of sludge as fertilizer has increased since then; it’s estimated  that 60 percent of the 5.6 million dry tons of sewage sludge disposed of annually is applied as fertilizer.

“This is not on the radar for many policymakers, particularly given the attention on potential terrorist attacks, but as more farmland is lost to development, and more people live closer to areas where these materials are applied, more people are becoming exposed to this practice,” Burke says. The panel found a number of anecdotal reports of illnesses attributed to exposure, ranging from mild conditions to severe chronic health problems.

The panel’s final report, presented to the EPA on July 2, recommends a thorough reassessment of the health risks of sludge as fertilizer, and expanded resources for oversight.

Trucks dump sludge for use as fertilizer in Riverside County, California.

“We don’t appear to have a public health crisis yet,” Burke comments, “but good public health is about prevention.”

 Techniques for assessing health risks have improved significantly since a 1988 study that many current  EPA rules are based on, and Burke and the other members of the panel believe it’s important to see those improved techniques applied to potential concerns about sludge. Potential risks include pathogens, like viruses, bacteria, and parasites; inorganic contaminants like metals; and pharmaceutical contamination.

“The large majority of these applications of sludge don’t appear to be causing problems, but this report is a call for sorting out the science,” says Burke.  “We want to take the next step and make sure we prevent adverse exposures and effects.”  — MP

Lessons from Circletown

An invader has quietly slipped into Circletown and Squaretown.

As the 400 residents of each small town travel to and from work, school, social events, and the hospital, one of them has unwittingly become infected with the deadly scourge of smallpox. Soon, the once all-but-eliminated virus will be spreading through both towns, leading to hospitalizations and deaths.

Fortunately, all the residents of Circletown and Squaretown are virtual. The simulation is part of a new effort by School researchers to use complex computational models to discern patterns in the chaotic dance of infection through a populace.

Spurred in part by last fall’s anthrax attacks, Donald Burke, MD, director of the School’s Center for Immunization Research, struck up a collaboration with Josh Epstein, a researcher at the Brookings Institute, to develop better ways to respond to bioterror attacks through agent-based computational modeling.

“Computational modeling is not focused so much on a statistical output where you get actual numbers, but is instead directed toward detailing patterns of flow,” Burke explains. “You can use it to build simulations where you create a large number of entities that can represent people, microbes, or almost anything else. You then put these entities on a 2-D framework, and allow them to move about in that framework so that they interact with each other.”

Model researcher: Donald Burke

According to Burke, the approach may be particularly useful because it allows researchers to simulate highly inhomogeneous populations whose variety in behavior, vulnerability to infection, and other factors are similar to those of real-world populations.

Derek Cummings and Ramesh Singa, two graduate students active in the Burke group’s modeling work, can run the Circletown and Squaretown model on a laptop they keep in a room down the hall from Burke’s office.

Cummings, an MHS student and a doctoral candidate in Geography and Environmental Engineering at Homewood, notes that for each one of the towns’ 800 residents, the researchers can adjust such factors as age, activity levels, social contacts, and susceptibility. Residents who become infected progress through the established stages of the disease, and that has an impact on their chances of passing the infection to others. 

“The reason this is useful is that many times the outcomes of these complex adaptive systems are not at all obvious,” says Burke.

Every time the program is run, chance factors have countless small impacts on the model’s results. But Cummings and Singa, an MHS student, have also been adjusting the overall model to match its results to patterns of infection spread observed in smallpox outbreaks in Europe in the 1970s. In addition, they’ve begun to try quelling the epidemic, providing a means of testing the effectiveness of various public health policies.

Burke notes that similar agent-based techniques are being used in military training, economics re-search, and management of traffic flow in urban areas.

“It’s potentially a highly complementary approach to statistical modeling, which should help supply us with the parameters we use to govern the behavior of individual agents,” Burke says. “No one can promise that this approach will be a substantial advance over existing techniques, but my intuition is that the time to test it is now, given the advances in computational power, epidemiology, and microbiology.”

Burke anticipates submission of a first paper from his group on the new approach’s results early this fall.   — MP

Henderson Awarded Nation’s Highest Civilian Honor

The guest list was the sort that only a president could draw up: comedian Bill Cosby, former first lady Nancy Reagan, home run king Hank Aaron, television’s “Mister Rogers”—Fred Rogers himself—and D.A. Henderson, former dean of the School and the man who led the successful World Health Organization effort to eradicate smallpox.

Henderson and the elite, eclectic group were honored July 9 as Presidential Medal of Freedom winners during a White House ceremony.

Medal Man: D.A. Henderson with President Bush (White House Photo by Paul Morse)

“D.A. Henderson is a great general in mankind’s war against disease,” said President George W. Bush, lauding Henderson’s efforts to subdue smallpox and his recent work against bioterrorism. “Our nation is fortunate to be able to draw on D.A. Henderson’s great store of wisdom and experience as we work to lift the dark threat of terrorism from the nation and our world.”

In selecting Henderson for the nation’s highest civilian honor, Bush was recognizing one of his own employees. Henderson, MD, MPH ’60, is principal science advisor to Health and Human Services Secretary Tommy G. Thompson. 

“To be selected to receive from the President the nation’s highest honor is an exceptional distinction quite beyond any other recognition I have received, or could ever hope to receive,” said Henderson, 74. “At the same time, I can’t help but reflect on what actually is being recognized. Certainly, it is not the work of one person but, rather, achievements in public health and the contributions of so many friends and colleagues who have worked so tirelessly and with a degree of dedication that has been an inspiration to me.”

The July awards ceremony was Henderson’s second trip to the East Room of the White House to be honored. Henderson, the School’s dean from 1977 to 1990, received the National Medal of Science in 1986 from President Ronald Reagan.   — BWS

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