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The Study of a Lifetime
Thanks to the prescience and persistence of a feisty medical school professor, a landmark health survey launched 55 years ago continues to bear fruit.

By Elaine F. Weiss
Illustration by Terry Miura

The envelope arrives in late winter, like clockwork, as it has for half a century. And when it comes, more than a thousand Hopkins-educated physicians will answer its call by mailing back their vital signs.

These doctors, in every state, on every continent, comprise the loyal cohort of the Johns Hopkins Precursors Study, the granddaddy of longitudinal health surveys. What began for them as gently coerced participation in a curious experiment during their student days has evolved into a lifelong scientific duty, but one they seem happy to fulfill.

Members of the School of Medicine classes of 1948 through 1964, they've volunteered to keep a running medical chart of their entire lives, providing detailed annual updates, and in the process have created an extraordinary trove of medical information. This mother lode of data has yielded some fascinating and important results over the years, including landmark studies correlating high cholesterol in early adulthood with later heart disease, as well as links between mental depression and heart attacks. Hopkins scientists using the data were also able to show links between coffee drinking and heart disease, and youthful obesity and later diabetes.

"The study is able to integrate health information over the course of a lifetime--to look at characteristics of young people and trace how they affect health in later life. It's just incredible," says Michael Klag, professor of medicine and interim chair of Medicine, who's been director of the study since 1988.

The Precursors Study isn't the most famous prospective, long-term study of disease risk factors and health outcomes, nor is it the largest, or even the most applicable to the general population (it's too white, male, and upper-class for that). But Precursors was the original, and it is considered the longest continuous study of its kind in the nation. Many of the studies with greater name recognition, like the Framingham Heart Study, the Harvard Physicians Health Study, or the national Nurses Study, have used the pioneering Precursors model as a guide.

Over the years, results from the study have also found their way into the public's imagination. Articles in Newsweek, Time, Parade, Cosmopolitan, and even Playboy have helped to popularize scientific findings spawned by the Precursors Study, putting mind/body connections--such as personality type as a predictor for heart disease--in the spotlight. Caroline Bedell Thomas, the study's founder, even appeared on TV's "Today Show."

"What makes the Precursors Study so special," explains Klag, "is this group of people who've been collaborators for over 50 years, who've been followed from the age of 23 to over 70 now--there's no other data set like that."

In 1946, a feisty School of Medicine professor named Caroline Bedell Thomas (MD '30) began roping medical students into her tiny office in the Physiology Building to sit through a battery of tests. She measured, poked, and pricked them, and peppered them with some rather unusual personal questions. Thomas, who had interests in cardiology and physiology, had already done some groundbreaking work in using the antibiotic sulfanilimide to prevent the recurrence of rheumatic fever. Now she had become intrigued by the possible connections between a person's genetic, physical, and psychological makeup and his or her susceptibility to cardiovascular disease--an idea that was quite forward-thinking for the time. (The original name, and focus, of the study was "Precursors of Essential Hypertension and Coronary Artery Disease.")

Right under her nose was a self-replenishing supply of healthy, scientifically minded young men (and a few women) who could be examined closely for four years, wouldn't dare protest being subjected to uncomfortable tests, and could be followed even after they graduated. As future physicians, they could also be relied upon to supply accurate follow-up information. And Caroline Thomas was not one to take no for an answer.

She didn't waste time on subtle persuasion: She hired two or three student recruiters and paid them $5 a week to deliver their classmates to the study's offices. "It was very convenient," recalls endocrinology professor Simeon Margolis (MD '57). "The study's offices were located above a drugstore at the corner of Monument and Wolfe streets, right across from the basic sciences lab, where we spent a lot of time anyway. So we could just drop in."

The Class of '51: a "data set" that's been collaborating for half a century. Peer pressure, Thomas's zeal, and perhaps some mild arm twisting worked well. Over the next 17 School of Medicine classes, 95 percent of students participated in the study. Even more striking, the study, now entering its 55th year, boasts an annual response rate of close to 80 percent.

Thomas subjected the young volunteers to a barrage of tests, from a basic physical exam to advanced cardiovascular and metabolic tests--even some rather exotic psychological surveys. The baseline exam included electrocardiograms, step stress tests, tilt-tests measuring blood pressure, and everyone's least favorite, the cold-pressor test, in which students had to hold one hand in a bowl of ice for over a minute while their circulatory response to temperature extremes was measured.

Volunteers also had to inhale an oxygen-nitrogen gas mixture until their arteries were saturated, so that Thomas could measure the resulting stress on their system. And long before it was standard procedure, Thomas measured the serum cholesterol levels of the study participants; not until many years later would the data enable researchers to make the connection between high cholesterol and heart disease. Thomas also measured the response to eating varying amounts of salt, for correlations with hypertension, and even tested for cardiovascular inflammations, "which is a very hot issue in cardiovascular research today," says Klag, whose own research interests are in this field.

"Pick any of the current issues in cardiovascular epidemiology," says Klag, "and she hit them all. What she asked in 1946, we're very interested in now. She hit all the high points."

Volunteers also had to fill out 11 pages of questions about their parents and siblings, their childhood, relationships, and even their work, play, and eating habits. Questions about smoking; coffee, tea, and alcohol consumption; and fat and salt intake were novel at the time but proved to be valuable in the long run.

Then there was the psychological testing. Thomas was intrigued by the possibility that personality and mental state could have long-term impact upon the development of disease. She administered Rorschach inkblot and figure drawing tests to illuminate characteristics of aggression, passivity, or anxiety, and had students interviewed by a psychiatrist.

Using the study results, Thomas developed theories regarding the young volunteers' reactions to the Rorschach test and those who later in life experienced emotional disturbances, committed suicide, or even developed cancer. Thomas found that medical students who ascribed to the inkblots sinister or morbid meanings--or who used words involving "whirling" movements--were more likely to develop mental and physical illnesses prematurely in their life. Her findings led to several scientific papers and received lots of attention in the popular press.

More conventional results using the data have found correlations between clinical depression and the later development of cardiovascular disease, heart attack, and stroke.

Study director Michael Klag and associate director Lucy Meoni, seen here with the Osler chair, are now querying the physician cohort about issues related to aging, including physical and mental impairments, quality of life, and even end-of-life choices.
Photo by Tracey Brown
From the baseline data, Thomas assembled a detailed portrait of each participant, one she hoped would prove to be predictive, perhaps containing early warning signals that could eventually be used to prevent disease. Sometimes her analysis of the data was off base. As she once said to participant William Fritz (MD '49) when he was close to retiring from his wonderfully long medical career: "You know Bill, we had you pegged to be dead by now."

After the students left medical school, Thomas took a personal interest in keeping tabs on them. She scanned medical journals for familiar names, looked for mentions in the social columns of the Baltimore newspapers, and wrote notes to those who lived far away. "It would take us three months to mail out the questionnaires, because she had to write a personal note on almost every one," says Lucy Meoni, associate director of the study, who joined the staff in 1984.

"She called the cohort her children," Klag recalls, though Thomas had three children and five grandchildren of her own.

Thomas was hardly the cuddly sort. "She was very brusque; you couldn't let it bother you," Meoni explains. A severe taskmaster, Thomas frowned on office chatter and was notorious for not accepting illness as a valid excuse for absence from work. She'd drive over to your house and pick you up, if necessary.

"She had an incredible mind," says Klag. "She was truly ahead of her time. She used something like 6,000 variables at baseline, which is amazing. Remember, this is before computers, before Xerox machines. Even now, we realize she anticipated so many things. The methods hadn't been worked out yet, but she knew what she wanted to find out--what are the underlying reasons for disease--and she asked the important questions."

The popular press jumped on findings linking personality to illness.
Courtesy the Alan Mason Chesney Medical Archives
Today, the nerve center of the Precursors Study is a suite of offices on Monument Street. The staff includes biostatistician Meoni, a research nurse, a follow-up coordinator, a part-time statistician, data entry clerks, a secretary, and an epidemiology graduate student. They work surrounded by the big green military-surplus filing cabinets in which Thomas stored the study files. Her thousands of keypunched cards that held the study's data have been replaced by many million bytes on mainframe computer servers, PCs, and Zip disks. But Evelyn Severn, the study's keypunch expert hired by Thomas in 1956, is still working in the office. She recently celebrated her 80th birthday.

As the study's cohort ages, more questions about retirement have been popping up on the questionnaire, and about prostate and other cancers, gout, arthritis, physical and mental impairments, quality of life issues, even end-of-life choices.

Fruitful Links
By following the Precursors cohort of doctors over their lifetimes, researchers have been able to identify a slew of predictors of later disease. Some findings have proved to be landmark. A sampling...
How accurate are the self-reported responses? Klag has conducted experiments to find out. At the Centennial celebration of the founding of the School of Medicine in 1989 and at some class reunions, the Precursors staff turns a meeting room into a clinic, inviting cohort members to drop by and have their blood pressure and pulse taken, perhaps have a blood test and an EKG. These results are compared with the latest annual survey the participant has mailed in. Klag has found that the accuracy of the self-reports is striking.

Still, the fact that all of the Precursors Study data is based upon only one initial set of physical exams, conducted decades ago, with all subsequent follow-ups self-reported and not consistently validated, is often cited as a shortcoming of the study. So are its relatively small size of 1,337 research subjects (Framingham boasts some 10,000 participants, the Nurses Study over 100,000), and the homogeneity of the cohort.

Klag readily admits that the Precursors has its disadvantages as a research source. "It's small, it's homogeneous--almost all white men--but that's the price you pay for this incredibly loyal, cohesive cohort."

Ironically enough, the study's limitations have also proven scientifically useful. Back in 1958, John Thomas, a professor at the historically black Meharry Medical College in Nashville, Tennessee, came to Hopkins to work with Thomas to learn the methodology of the Precursors Study and take it back to his own campus. He enrolled eight classes of Meharry doctors (1958-1965), and the two institutions have worked together on projects. Since 1984 the two cohorts--one made up almost exclusively of white physicians, the other of black physicians--have received the exact same set of annual follow-up questions. Comparing results has been a fruitful enterprise.

"Pick any of the current issues in cardiovascular epidemiology and she hit them all," says Klag of Thomas. "What she asked in 1946, we're very interested in now. She hit all the high points." What emerges clearly is that while the cohorts are similar in generational and educational background, as well as socioeconomic standing, the racial differences seem to account for a 60 percent higher risk that Meharry doctors will die prematurely from cardiovascular diseases. The collaboration with Meharry is in limbo at the moment, as John Thomas died recently, and the future of the Meharry study's administration is still uncertain.

An oil portrait of Caroline Thomas hangs on the wall of the Precursors Study conference room, next to a portrait of her husband, Hopkins physician Henry Thomas. On another wall hangs a classical Greco-Roman tableau of a woman driving a chariot--a very fitting illustration of how Caroline Thomas piloted the Precursors Study for 40 years.

"She devoted her life to it, at considerable personal and career sacrifice," says Klag.

For Thomas, attracting funding to maintain the study was a constant challenge. She scraped by in the lean times by taking no salary for herself. In 1964 she had to end the cohort enrollment for lack of funds, which is why the Class of '64 was the last. When funding for the study became shaky, as it did periodically over the years, she would offer to give a treasured family heirloom--the ornate wooden chair that once belonged to William Osler, Hopkins's first chief of medicine, and a founding faculty member of the medical school and hospital--to a donor who would agree to endow the study with a large gift. She never found that donor.

Thomas finally stepped down from the director's chair in 1986, when she was 82 years old. Klag took up the reins two years later, following the brief directorship of Thomas Pearson. In many ways Klag is the perfect modern successor. "I love this kind of stuff," he says. "When I was a kid, we lived in an old Victorian house with an attic, and I loved going up there and going through all the old family books and papers and photos. So when I took over the study, I physically went through every file--that was a wonderful, bonding experience for me."

Klag is also the study's biggest booster; he plugs its virtues in his Methods of Epidemiology course, making sure new research fellows are made aware of its treasures, and he talks it up among his colleagues. Over the years, Hopkins researchers have embarked on collaborations with teams from Columbia, the University of Pittsburgh, the University of Maryland, and others.

Caroline Bedell Thomas and her husband, physician Henry Thomas, were fixtures on the Hopkins medical campus.
Photo courtesy Alan Mason Chesney Medical Archives
"It's a great resource for students and fellows," he says. "It teaches them all the basics about formulating research questions and data analysis." The Precursors data is well-mined by the faculty and staff of the Welch Center for Prevention, Epidemiology, and Clinical Research. Hopkins rheumatologist Allan Gelber has been asking cohort members about their experiences with osteoarthritic conditions, and internist Daniel Ford has explored the relationship between various temperamental and behavioral risk factors and the development of disease. Each new generation of researchers brings new, creative approaches and questions.

"The hardest part of this job is keeping the study funded," says Klag. Today the core of the study's funding, about $250,000 a year, comes from the National Institute on Aging of the National Institutes of Health; this is supplemented by support from the Office of the Dean of Medicine and various training grants.

One thing is for certain, though--Hopkins has no intention of following the ill-fated lead of the Framingham Study, which last year announced plans to sell data to pharmaceutical and genomics companies. Boston University, which administers the Framingham study, had already formed a for-profit spin-off corporation to market the data but encountered such flak from the NIH and the medical community that it canceled the entrepreneurial venture within weeks. That's simply not territory where Hopkins cares to tread, says Klag. Though there are tentative thoughts of making parts of the study data more readily available via the Internet, the data itself will never be for sale.

Caroline Bedell Thomas died in 1997. In bequeathing the Osler chair to Hopkins, she made sure to protect her beloved study: The chair can stay at Hopkins only if it resides in the office space of the Precursors Study. If the study ever loses its lease, the chair goes back to Thomas's children.

"There are a lot of papers left to be written" using the Precursors data, asserts Klag. "We've a lot of life left."

Elaine F. Weiss is a freelance journalist living in Baltimore.

Fruitful Links By following the Precursors cohort of doctors over their lifetimes, researchers have been able to identify a slew of predictors of later disease. Some findings have proved to be landmark. A sampling...

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