Blending the clinical and the statistical

Early in his career, Lee Goldman saw the value of applying epidemiology to clinical practice.

For more than two decades physicians have carried in their pocket copies of the Goldman Index, a list of factors to determine whether a patient undergoing surgery for noncardiac reasons is at risk of a heart attack or another major cardiac complication. The index is named for Lee Goldman, M.D. ’73, M.P.H. ’73, FW ’78, who developed it during his medical residency and published it during his cardiology fellowship at Yale by applying techniques derived from epidemiology and clinical practice.

In recent years Goldman has also achieved renown for his leadership of the department of medicine at the University of California, San Francisco (UCSF), which he joined in 1995. In July 2006 Goldman moved to Columbia University’s College of Physicians and Surgeons as executive vice president for health and biomedical sciences and dean of the faculties of health sciences and medicine.

Goldman traces his interest in statistics to a class he took during his first semester at the School of Medicine with John D. Thompson, R.N., M.S., the legendary director of the program in hospital administration at the Department of Epidemiology and Public Health. That course convinced Goldman to enroll in Yale’s master of public health program, and a study he undertook there cemented his love of numbers and other data. In 1971, President Richard Nixon was pushing a plan for national health insurance. Goldman surveyed Yale medical students and faculty, deconstructing this bill and competing pieces of legislation to determine how his colleagues should perceive each proposal. Goldman then took his programming textbook to the beach over Labor Day weekend and came back ready to crunch numbers in the giant computers of the day. As the analysis came together, he was hooked. “I ended up publishing five papers out of my thesis,” he said, “and kind of got the bug.”

He soon began to apply his new-found statistical and programming savvy to studies of cardiac risk. After an internship and residency at UCSF and a second residency at Massachusetts General Hospital, Goldman became a cardiology fellow at Yale. As his fellowship ended, Goldman said, his interest in epidemiology propelled him toward nontraditional applications of cardiology. “Cardiology divisions weren’t really interested in me, and I didn’t really want to run an echo [cardiogram] lab,” he said.

In the division of general internal medicine at Harvard’s Peter Bent Brigham (now Brigham and Women’s) Hospital, where he stayed for almost two decades, Goldman continued to focus on combining epidemiology with clinical care in cardiology. “Most of my work used the same kinds of methods an epidemiologist used, but applied it to patients we actually touched,” he said, describing his efforts to determine risk factors for heart attacks after surgery and among patients who came to emergency rooms with chest pain. “There were so many factors to consider that clinicians did not have a way of determining which ones were the best predictors of a patient’s risk,” he said. “The concept was always to gather comprehensive data and to whittle it down to what might be important.”

One of Goldman’s most enduring contributions was the Goldman Index. “It was the first systematic approach to that question,” said Lawrence S. Cohen, M.D., HS ’65, special advisor to the dean. “It has remained a benchmark for the care of patients that are undergoing noncardiac surgery, and it has stood the test of time over three decades.”

Goldman and his colleagues also started one of the first chest pain evaluation units at Harvard. Today, these are common at many hospitals nationwide. And Goldman developed the Coronary Heart Disease Policy Model, which sets priorities for preventing and treating heart disease. At Harvard, he also codeveloped the Program in Clinical Effectiveness, which has trained over 1,000 young physicians in the basics of clinical research.

“He really has been a pioneer,” said Harlan M. Krumholz, M.D., M.Sc., the Harold J. Hines Jr. Professor of Medicine and professor of epidemiology and public health, and of investigative medicine, one of Goldman’s advisees at Yale. “He was one of the first people to develop large observational studies that drew knowledge from the real world and could be fed back into practice.”

After becoming the chair of medicine at UCSF, Goldman and his colleague Robert M. Wachter, M.D., in 1996 coined the term hospitalist for inpatient physicians, a concept that quickly produced a major movement in medicine. (Goldman and Wachter started the first hospitalist program in the country at UCSF.) With inpatient care changing rapidly, they argued, office-based doctors simply do not have time to monitor their hospital patients the necessary three or four times a day. Establishing a separate specialty of hospital medicine, they argued, would increase hospital efficiency and benefit patients. “The board is about to recognize it as a distinct discipline,” he said, referring to the American Board of Internal Medicine, which certifies subspecialties in internal medicine.

“Columbia is fortunate,” said his former advisee Krumholz, recalling his mentor’s seemingly limitless capacity to inspire students and colleagues. “When he walked into a room, the energy would just increase, the quality of conversation would go up. I think a whole generation of people was drawn to research because of their association with him.”

—Alla Katsnelson

From sleepless nights and a study of narcolepsy to chairing a leading program

When most lights in the dormitory went out, David Kupfer’s stayed on. A history and economics major at Yale College, Kupfer, M.D. ’65, couldn’t understand why his peers needed so much sleep. At the time, he didn’t realize sleep would influence his career—that he would become a leader in sleep, depression and bipolar disorder research—and that observing two cases of narcolepsy would set him on this path.

While in medical school and still undecided about a specialty, Kupfer saw two patients at Yale-New Haven Hospital (YNHH) who suffered from an extreme exhaustion called cataplexy that results in a complete loss of muscle control. Both were also diagnosed with narcolepsy.

Seeing these two patients solidified Kupfer’s decision to study sleep, but two encounters with a Yale professor molded his career. As a second-year student he met Thomas Detre, M.D., then chief of psychiatry at YNHH, whose interests included recurrent depression, violence and aggression in children, biologic aspects of mental disorders and the budding fields of psychobiology and psychopharmacology. At a time when there was little understanding of mental diseases, Detre felt that understanding the body could lead to better treatment of mental illness.

During Kupfer’s third year, a last-minute trade with a classmate led to a chance reunion with Detre and solidified Kupfer’s decision to pursue psychiatry. The night before beginning his psychiatry rotation at the VA hospital in West Haven, Kupfer agreed to switch rotations with a classmate who wanted to work at the VA. Kupfer was back at YNHH with Detre. They soon realized they had a lot in common—both were high-energy and stayed up late. Detre expected diligence and Kupfer delivered.

“Some people have considered [Detre] a tough taskmaster because he was so persistent. I found him loyal and supportive and clever. He gave me freedom,” Kupfer said.

After medical school, Kupfer trained at the National Institute of Mental Health (NIMH), then returned to Yale in 1969 as an NIMH investigator and assistant professor of psychiatry. Kupfer’s career was blossoming at Yale, but Detre asked him to join him at the University of Pittsburgh and its Western Psychiatric Institute and Clinic (WPIC), which Detre felt he could transform to better treat patients with mental illness. In 1973, Kupfer went to Pitt as an associate professor of psychiatry and director of research. In 1983, he became director of the WPIC and chair of the Department of Psychiatry when Detre became senior vice chancellor for health sciences. In 1994, further cementing the connection between these remarkable colleagues, Kupfer was named the first Thomas Detre Professor of Psychiatry.

Finally retired from his 23-year career as vice chancellor, Detre now serves as a professor emeritus of psychiatry and is teaching a course to residents on psychiatric diagnosis. He sits on the boards of two software companies in Pittsburgh and is also on the scientific advisory board of PsychoGenics, a New York-based company that tests neurological drugs.

At Pitt, Kupfer stressed the importance of determining the biological underpinnings of psychiatric disease and led a research revolution by earning a number of NIMH grants for research on sleep disturbances, depression and bipolar disorder. The number of faculty and beds increased, along with the reputation of Pitt’s psychiatry program. “From 1983 to 1993 the department went from Number 4 to Number 1 in federal research funding,” Detre explained.

With his wife, Ellen Frank, Ph.D., Kupfer co-directs the Bipolar Disorder Center for Pennsylvanians, created with a $5 million grant from the commonwealth. He is principal investigator of several studies, including one on the pharmacogenetics of bipolar disease.

“You’re going to laugh when I say this—writing is very difficult for me,” he said. He has written 800 articles, books and book chapters. His latest book, written for a general audience with Helena Chmura Kraemer, Ph.D., and Karen Kraemer Lowe, M.S., is titled To Your Health: How to Understand What Research Tells Us About Risk, and stresses the importance, throughout medicine, of designing more rigorous clinical trials and clearly defining the results. As a case in point Kupfer cites media reports of studies that appeared to show a high risk of suicide among young children on antidepressants. According to Kupfer, many of the studies poorly defined the risk.

Kupfer hopes that someday more physicians will value the relationship between mental and physical illnesses. Research has shown that depression, for example, makes people more susceptible to other illnesses, like diabetes. Kupfer feels that many doctors treat the diabetes rather than exploring the link between the depression and diabetes. He hopes this paradigm changes soon—patients who receive poor mental health treatment face serious health risks, just like patients who receive the wrong medical care.

It might keep Kupfer up at night, but that’s when he does his best work.

—Meghan Holohan

A rebel with “medicine in his veins” becomes a scientific researcher in India

When Manohar V.N. Shirodkar, Med ’54, M.D., initially rebelled against a family tradition and rejected medical practice, his father, a famed gynecologist in Mumbai, India, despaired. The young Shirodkar knew he had “medicine in his veins”—his father had developed the Shirodkar stitch, which is still used to treat cervical incompetence. But Shirodkar wasn’t interested in being a clinician.

Shirodkar, however, found something more exciting—the viral causes of illness. When he learned that his grandmother had died of cervical cancer, Shirodkar was hooked. How did she get sick? Why would she have cancer when others do not? Today, the medical community knows that some types of the human papilloma virus can cause cervical cancer, but at that time the young man simply knew that one way to understand illness was to study oncogenic viruses.

To his father’s delight, Shirodkar begged to study medicine in the United States. After he completed his undergraduate work at Johns Hopkins University, he headed to the Yale School of Medicine in 1950. His clinical studies were interrupted when Shirodkar learned his wife was pregnant. The couple returned to Mumbai, where their daughters, Renée and Diane, were born. With a growing family, Shirodkar didn’t have the funds to complete medical school. He accepted a position at Johns Hopkins’ school of public health, which gave him a stipend to pursue an Sc.D.

His detour from a traditional medical education gave Shirodkar the opportunity he wanted. (He finished his M.B.B.S. in 1970 at the Seth G.S. Medical College in Mumbai.) And throughout a career filled with many twists and turns, his drive to understand viruses remains constant.

As a graduate student at Hopkins in 1958, Shirodkar began investigating the Rous sarcoma virus in chickens, the first virus discovered to cause a solid cancer. His research took him from Hopkins to the Virus Research Center of the Rockefeller Foundation in Pune, India, where he completed his doctoral thesis. In 1978 he found that West Nile virus, and later, rabies, blocked the Rous-produced sarcoma, and that the underlying mediator was not interferon, but his newly discovered anti-sarcoma, antiviral protein, called plasma factor. His research findings appeared in The Journal of Immunology in December 1965, the Journal of General Virology in 1973, The Indian Journal of Medical Research in 1978 and the Indian Journal of Experimental Biology in October 2006.

“The most gratifying aspect of my career,” Shirodkar said, “is the fact that I have been a perpetual student—quite literally—and have been able to pursue, with some success, ... the search for scientific truth.”

As a young man, Shirodkar turned away from a career as a clinician, yet he always admired his father. In 1976, Shirodkar and his wife, Sudha, founded the Dr. V.N. Shirodkar Memorial Research Foundation, an organization that embodies the dreams of both Shirodkar and his father. The organization screens underprivileged women for cervical cancer and investigates novel antiviral biological agents to treat virus diseases.

—M.H.


			Originally published in Yale Medicine, Spring 2007. Copyright © 2007 Yale University School of Medicine. All rights reserved.