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ince its founding, UNC’s school of public health S has encouraged innovators who developed new ways of collecting and analyzing information and solving problems. At the heart of that effort has been a synergistic collaboration of the School’s basic measurement science departments—, , and environmental sciences and engineering—along with other departments that have strong methods and measurement science foci. These include the School’s departments of health policy and management, health behavior, maternal and child health, and nutrition, as well as others outside the School. Data Driven by Caring and Change

48 | carolina public health Data Driven by

Caring If you always do what you’ve always done, you’ll always and get what you’ve always got. Change —Henry Ford

fall 2014 | 49 [Above, left to right]: Drs. Jim Grizzle, Bernard Greenberg, Dale Williams and Michel Ibrahim discuss plans for renewal of their research grant on lipids; Drs. Gary Koch and Dennis Gillings conducted clinical trials work from a trailer on School grounds; Dr. Gillings, as a faculty member in 1971.

Development mathematical department at drugs. Under Greenberg’s leadership, UNC-Chapel Hill. In 1949, less than the department developed a roadmap of biostatistics a decade after the School began, she for evaluating new drugs for efficacy. helped establish the Department of Without the clinical trials methodol- methods Biostatistics in the UNC–Chapel Hill ogy and infrastructure developed by School of Public Health, selecting her UNC’s biostatisticians, many advances former student, Bernard Greenberg, that benefit individuals might nev- In 1940, UNC system president Frank PhD, to lead it. er have been made. Members of the Porter Graham took a chance in hiring Greenberg, who later became the biostatistics faculty continue to make Gertrude Cox, MS, as the first woman department’s first Kenan Distinguished innovations in clinical trials. professor and department head at Professor, was awarded a National In 1967, NIH’s National Heart N.C. State University. Cox, professor of Institute of General Medical Sciences Institute commissioned Greenberg statistics and head of the Department grant, “Multivariate Analysis for the to develop procedures for conducting of Experimental Statistics, likely met Health Sciences,” with co-principal large, multicenter clinical trials. His Graham’s highest expectations; her investigator S.N. Roy, MSc. With Greenberg Report (see tinyurl.com/ hiring certainly set in motion a series of support from Hotelling and others Greenberg-report) is still a respected events that resulted in one of the finest in the UNC–Chapel Hill statistics document, having established methods biostatistics departments in the world. department, Greenberg also competed to evaluate new drugs and cancer As the UNC system’s graduate successfully for one of the first National treatments that have been used for program in statistics was housed at Institutes of Health (NIH) grants to nearly 50 years. N.C. State, it was incumbent upon Cox train biostatisticians and pioneered The tradition of statistical to develop any additional statistics efforts to establish the practice of innovation for the betterment of programs on other campuses. In 1946, cooperative multicenter trials. humankind continues in a program led she recruited Harold Hotelling, PhD, This groundbreaking, transforma- today by Michael Kosorok, PhD, W.R. formerly on the faculties of Stanford tional research changed the course Kenan Jr. Distinguished Professor and Columbia, to head the new of practice for the evaluation of new and chair of biostatistics, who

50 | carolina public health collaborates with colleagues at UNC, continuously funded NIH coordinating “With that,” Grizzle says, Duke and N.C. State universities, and center in the U.S., having coordinated “biostatisticians changed the world.” SAS (SAS.com), a business analytics studies with hundreds of clinical centers Williams, who succeeded Grizzle software and services company. in the U.S. and abroad. The late H.A. as principal investigator for the study, The National Cancer Institute Tyroler, MD, Alumni Distinguished says that trial “set the stage for the drug (NCI)-funded program, “Statistical Professor of epidemiology, was a vital development that led to statins and Methods for Cancer Clinical Trials,” is contributor to the study group and lipid-lowering compounds.” pioneering new methods that will help provided much insight into the tools Grizzle’s methodology for crossover researchers more effectively discover and methods used by the CSCC. Grizzle, trials is still referred to today, some 50 and evaluate cancer treatments, as well Clarence (Ed) Davis, PhD, retired years later. Another paper by Grizzle, on as treatments for other diseases, and former chair of biostatistics and director analyzing categorical data and whose to more quickly deliver effective new of the CSCC, and Dale O. Williams, co-authors included Frank Starmer, therapies to patients. PhD, took the lead in the first study, PhD, now with the Duke University- The biostatistics department was which found that lowering cholesterol National University of Singapore successful from the start in attracting reduces the risk of heart disease. Graduate Medical School, and financial support through contracts biostatistics professor Gary Koch, PhD, and grants, says Jim Grizzle, PhD, is among the most-cited biostatistics who chaired the department from papers in the world. 1972 to 1987. In 1958, Greenberg undertook In 1955, the NCI awarded the another landmark epidemiological department a contract to become the study—the first large study of statistical coordinating center for the cardiovascular disease that included Southeastern Cooperative Cancer African-Americans. All other large Chemotherapy Study Group (SCCC), trials in the U.S. at the time had only believed to be the first large-scale white participants. The Evans County, clinical trials group in the U.S. (The first Ga., study continued through the such study was published in England 1990s. (See tinyurl.com/evans-county.) in 1949.) Faculty members from 10 “All of these studies had a real medical schools and the coordinating impact on the health of society,” says center collaborated to investigate the Ed Davis. The studies led to insights effectiveness of chemotherapy agents. and treatment options for widespread The department developed some of health problems, such as high the new necessary to an- cholesterol and congestive heart failure. alyze data from these large-scale, mul- The impact continues with research ticenter trials. In 1957, Greenberg hired in progress now, including the Hispanic

Grizzle as a graduate research assistant. Dr. Gary Koch, in the 1980s, stands Grizzle led the Lipid Research Clinics outside his office in ‘Trailer 39.’ Coordinating Center, established in 1971, which was among the first groups to perform distributive data entry. The unit was renamed the Collaborative Studies Coordinating Center (cscc) in 1986, and is now the oldest,

fall 2014 | 51 Community Health Study/Study of and Drug Administration, both for- the CSCC in 1991, had cumulative Latinos, the largest, long- study mer biostatistics professors and CSCC oversight of $35 million in grants. to date on this population. An original directors, and is currently overseen by UNC’s School of Public Health $22 million grant from the National Jianwen Cai, PhD, professor and vice extended its international reach, Heart, Lung and Blood Institute chair of biostatistics. Twelve faculty particularly in the 1960s after supported the multi-center study of members, 24 staff members and four Pranab K. Sen, PhD, DSc, Cary C. more than 16,000 Hispanic adults to students from UNC are involved in Boshamer Distinguished Professor, examine the role of acculturation in the study. joined the faculty and strengthened the prevalence of disease. A six-year, Grant funding reflected the ties to universities in India. Sen $21.7 million federal contract was biostatistics department’s success. has contributed significantly to also awarded to conduct a second Grizzle recalled that his department’s methodological studies related to examination of study participants, budget hovered close to $6 million diabetes, environmental health and beginning in October 2014. annually, but the state contributed , as well as clinical trials. The study was initiated by Lloyd only $90,000. The rest came from The lipids study also fostered a Chambless, PhD, now retired, and Lisa grants and contracts. Dale Williams, stream of global interactions, including LaVange, PhD, now at the U.S. Food who succeeded Grizzle as director of ones with eastern European countries,

Speeding up drug development, improving clinical trials

Data pile up fast in large-scale, long-term, multisite clinical trials. As methods evolve, so too must the by which data are analyzed. Early on, the Gillings School’s biostatistics department developed a reputation for its program in Bayesian statistics, an analysis paradigm that involves determining probability of something based on particular pieces of evidence. The program is led by Alumni Distinguished Professor Joseph G. Ibrahim, PhD, who also directs the UNC Center for Innovative Clinical Trials (CICT) and the department’s graduate studies program. Ibrahim and colleagues in the CICT have conducted leading- edge research on innovative Bayesian clinical trials design, including development of new statistical methods to determine the odds that a large future will be successful.

Drs. Danyu Lin (foreground) and Joseph Ibrahim

52 | carolina public health China, Brazil, Israel, Poland and India. In 2014–2015, he will be a Fulbright Excellent networks of UNC-trained Scholar in Chile. Dr. Ed Davis statisticians in Brazil and Chile have Some faculty members have recalls attending a opened the door to collaborations in established global corporations to conference in the 1960s teaching and training for UNC’s bio- expand the reach of their work. in Chile. “There were only statisticians. Visiting professors and In the 1970s, Gary Koch partnered seven biostatisticians in scholars from developing countries with another faculty biostatistician, the country,” he said, have added greatly to the development Dennis Gillings, PhD, CBE, to “and five of them of biostatistics methodology, including develop Quintiles, a contract had been trained clinical trials. Professor Kant Bangdi- research organization (CRO) at UNC.” wala, PhD, whom Sen calls “our am- that now employs some 30,000 bassador to Latin and South America,” people worldwide. Gillings led the has taught biostatistics classes around organization; Koch remained in the world, including as visiting profes- academia, directing UNC’s Biometric sor at Chile’s University of Valparaiso Consulting Lab, mentoring students and University of Chile at Santiago. and publishing. Quintiles provides (continued on page 56)

Speeding up “Bayesian methods are a powerful paradigm for complex in many areas, particularly and clinical trials design and analysis since they can produce statistical genomics. drug development, very efficient designs that potentially yield large reductions In a word, Lin says, “We do statistical research to create in the number of patients needed for a trial, and hence yield new tools for clinical trials.” improving major in resources,” Ibrahim says. Survival analysis is indispensable to clinical trials. Many Ibrahim and his team also have developed new statistical patients remain alive at the end of a trial, so their total clinical trials methods for data analysis, especially for cancer research. survival times are unknown. Lin has developed survival One such method assesses efficacy of a patient’s treatment analysis methods that are widely used in clinical trials. when that course of treatment changes, as when the patient Many of them have been incorporated into standard crosses over to an experimental treatment. software packages, such as SAS. are a big problem in research, especially Lin received the prestigious Merit Award from the in longitudinal studies, where patients drop out before National Institutes of Health from 2005 to 2015, and the study completion. Ibrahim devises statistical models Royal Statistical Society selected one of his papers to be to understand why data go missing, so as to efficiently read and discussed at its meeting in 2007. incorporate all the cases with missing values. CICT In recent years, he has devoted considerable energy to personnel also aim to develop user-friendly statistical the development of statistical and computational tools for software for the design and analysis methods they construct. analyzing genomic data. Ibrahim has received funding from several pharmaceutical “Eventually, we want to use this information to guide the companies to carry out this joint research with the CICT, selection of treatments for personalized medicine,” Lin says. and several National Institute of Health grants support “It’s not clear how successful we’ll be, but whatever happens, his research. statistics will be an important part of it.” Danyu Lin, PhD, the Dennis Gillings Distinguished Professor of Biostatistics, has led cutting-edge research —Nancy Oates

fall 2014 | 53 Dr. Michael Kosorok (far left) posed recently with former CSCC directors (l-r) Drs. Lisa LaVange, Lloyd Chambless, Ed Davis, Dale Williams and Jim Grizzle.

(continued from page 53) training opportunities for students doctoral degree from the Gillings that makes students nimble and able and real-world experiences for faculty School, launched SciMetrika, a leading to adapt to ever-changing technologies members. CSCC director Sonia population health research company and new problems in public health. Davis, DrPH, Julie MacMillan, MPH, based in Durham, N.C. “Students benefit from the mentored managing director of the School’s “Our biostatistics faculty members hands-on experiences they get Research and Innovation Solutions, carry out absolutely groundbreaking working with top-notch investigators and clinical professor and former theoretical work,” says Dean Barbara on high-impact research across Public Health Leadership Program K. Rimer, “but another great strength multiple domains of public health and director William Sollecito, DrPH, is their commitment to finding medicine,” she says. are among those who held leadership solutions to important health Herring, with Rebecca Fry, PhD, positions at Quintiles. problems. They show that outstanding associate professor of environmental In 1984, biostatistics professor Ron faculty members can excel at both sciences and engineering, and Helms, PhD, founded Rho, a CRO theoretical and applied research.” Marilie Gammon, PhD, epidemiology focused on clinical data management Amy Herring, ScD, professor and professor, leads a National Institute that now employs more than 300 associate chair of biostatistics, lauds of Environmental Health Sciences people in the Triangle. In 2001, Jean her department’s highly rigorous (NIEHS) grant to train postdoctoral Orelien, DrPH, who received his training in the foundations of statistics scholars in biostatistics, epidemiology and environmental sciences. The training award, renewable every five years, has been held by UNC’s public health school continuously since it was awarded first to Dr. Bernard Greenberg in 1971. Larry Kupper, PhD, retired former Alumni Distinguished Professor of

56 | carolina public health biostatistics, was instrumental in recognized by Thomson Reuters as one richer understanding of issues such as obtaining that original NIEHS grant of the most cited researchers in the genetic susceptibility to diseases. The and led it from 1972 through 2006. world.” (See sph.unc.edu/most-cited). epidemiology department now has labs Kupper studied the development and An excellent history of the UNC for molecular biology, genotyping and application of innovative statistical biostatistics department, compiled by immunohistochemistry. methods for design and data analysis Drs. Jane Monaco, Jianwen Cai, Lisa In the health policy and manage- of public health studies, with LaVange and Michael Kosorok is at ment department, associate professor particular emphasis on environmental, tinyurl.com/unc-bios-history. Bryce Reeve, PhD, concentrates on occupational and women’s health patients’ experiences of risks, diseas- issues. His work led to improved es and illness. Reeve designs Web- statistical methods for quantifying based that integrate human health risks due to harmful Epidemiological patient-reported data into electronic substances in the workplace and medical records systems to give clini- external environment. and cians real-time feedback from patients Today, the biostatistics department to improve the and of is the statistical home for many other tools the clinical encounter. Patients’ data studies in the UNC schools of also may be a better way of under- medicine and nursing and provides standing issues such as adverse events The Gillings School’s expertise in statistical support for UNC Lineberger experienced by patients in clinical tri- clinical methodologies extends beyond Comprehensive Cancer Center and als and how different medication regi- biostatistics. the N.C. Translational and Clinical mens affect patients’ quality of life. Barbara Hulka, MD, MPH, joined Sciences Institute (NC TraCS). “It’s the wave of the future,” Reeve the epidemiology department in Educational preparation for the says. “We’re not replacing what doctors 1967. In a discipline that traditionally next generation is assured through already do, but rather facilitating analyzed medical records and surveys a biostatistics leadership course, the their discussions with patients. We’re for disease prevalence and causes, first of its kind in the U.S., which has trying to identify what’s going on in the Hulka was among the first to integrate received national attention for its patient’s life, what’s most important to molecular biology into the field, timely and meaningful content. (See him or her, so clinicians can respond a transformation that shifted the tinyurl.com/BIOS-leadership-course.) quickly and thus improve the quality emphasis of discoveries. Kosorok says the development of of care.” Kenan Distinguished Professor data tools and methodologies begun in In preparing the next generation Gerardo Heiss, MD, PhD, who joined his department seven decades ago is of researchers, Reeve deliberately the epidemiology faculty in 1974 and is still thriving. allows large classes to include diverse one of the most cited researchers in his “A number of leaders in the expertise, backgrounds and . field, is a CSCC investigator who has department are doing excellent work,” Medical students, residents, fellows made a huge impact in multicultural he says. “I’d mention Drs. Jianwen and students from the schools of collaborations. (See page 25.) Cai, Jason Fine, Amy Herring, Joseph pharmacy, nursing and public health Today, epidemiologists often Ibrahim, Danyu Lin, Hongtu Zhu, approach the same patient from augment self-reported participant data Haibo Zhou, Fei Zou, Donglin Zeng, different perspectives. with biological data (e.g., from blood Michael Hudgens, Wei Sun, Yun Li or cheek swabs) and combine genetic and others, whose methodology is —Nancy Oates analyses with other data to get a being widely used. Dr. Yun Li has been

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