On Sept. 29, Wesley Self, MD, MPH, who oversees clinical and translational research at Vanderbilt University Medical Center, ended his address to an international gathering of biomedical researchers and trainees by thanking VUMC’s biostatisticians.
“Thank you for being rigorous. Thank you for being innovative. Thank you for changing (the) practice (of medicine),” said Self, an established clinical investigator who this year was appointed VUMC Senior Vice President for Clinical Research, and director of the Vanderbilt Institute for Clinical and Translational Research (VICTR).
Biostatisticians develop and apply mathematics and statistical methods to answer urgent questions in medicine and public health. At VUMC, they have played a pivotal role in the redesign of clinical trials that rigorously and rapidly determine the effectiveness of life-saving treatments for acutely ill patients.
Traditional randomized clinical trials require the recruitment of hundreds, if not thousands, of patients into studies that compare potential treatments against inactive placebo. These studies can take months, if not years, not to mention millions of dollars, to complete.
Patients in the intensive care unit can’t wait, Self said during a symposium celebrating the 20th anniversary of the Department of Biostatistics. The acuity of their illness also makes it difficult to enroll ICU patients into traditional clinical trials.
Eight years ago, Self and his colleagues set out to settle a long-standing medical conundrum. Which is the better intravenous fluid to give patients on admission to the ICU—regular saline, which contains sodium chloride (salt), or balanced crystalloids, which more closely resemble the liquid part of blood?
Intravenous saline, which has been used in medicine for more than a century, has been linked to an increased risk for acute kidney injury and death. However, prior studies had failed to prove that the risk could be lowered by giving balanced crystalloids instead.
“The problem with studying something so routinely used in clinical care is that … you can get an IV fluid bag within seconds of admission to the ICU,” Self said. “People are getting fluids too rapidly for us to randomize them.”
So, Vanderbilt biostatisticians Li Wang, MS, and Dan Byrne, MS, helped design a pragmatic, cluster-randomized, multiple-crossover trial, in which five ICUs at VUMC were randomly assigned to use saline during even-numbered months and balanced crystalloids during odd-numbered months.
The trial, which enrolled nearly 16,000 patients over 23 months, found that patients in the balanced-crystalloid group had a significantly lower incidence of adverse kidney events or death within 30 days of admission compared to the saline group.
Then came COVID-19. As the pandemic swept into the United States, the National Institutes of Health and Foundation of the NIH set up a public-private partnership called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) to evaluate potential treatments and vaccines, streamline clinical trials, and expedite rapid approval and production.
In early 2021, VICTR was selected to lead a national trial of treatments targeting the Renin Angiotensin Aldosterone System (RAAS) in patients hospitalized with COVID-19 under the ACTIV-4 Host Tissue platform.
Composed of three hormones, renin, angiotensin, and aldosterone, RAAS is essential for the regulation of blood pressure and fluid balance. SARS-CoV-2, the virus that causes COVID-19, can disrupt this system, resulting in life-threatening complications, including fluid in the lungs, blood clots, and severe cardiac injury.
“This is a brand-new world, right?” said Self, who helped lead the ACTIV-4 RAAS Clinical Coordinating Center at VUMC. The urgency of the situation required a different approach to clinical trials.
“We need to know, and we need to know very quickly what drugs might help people survive.,” he said. “We want rapid, efficient, and rigorous clinical trials maximizing knowledge generation with lowest possible sample size.”
Biostatistics again came to the rescue. Matt Shotwell, PhD, and colleagues in the ACTIV-4 RAAS Data Coordinating Center at VUMC decided to use a new outcome measure for judging the effectiveness of potential therapies.
Rather than mortality, the historical endpoint for many clinical trials, they chose oxygen-free days, which measures the time hospitalized patients with acute lung injury require supplemental oxygen. It enabled them to detect signs of recovery earlier, and in smaller groups of patients.
Among the first drugs to be evaluated were two that were thought to help the body recover from a pathological imbalance caused when SARS-CoV-2 binds to and interferes with ACE2, a vital enzyme which controls blood pressure and blood flow to multiple organs.
The study, conducted at 35 sites in the United States between July 2021 and April 2022, found that neither drug was effective for treating severe COVID-19. While the findings, published last year, were disappointing, they also were important.
“We now understand that giving these drugs, which would seem very logical from a mechanistic perspective, should not be done,” Self said at the time.
Earlier this year, VUMC was chosen to lead a national effort to better understand acute respiratory distress syndrome (ARDS), pneumonia, and sepsis, which together kill hundreds of thousands of people in the United States each year.
Pneumonia currently is defined by symptoms such as fever, cough, and shortness of breath. But the same cluster of symptoms may have entirely different root causes in different patients. That’s why a treatment aimed at a broadly defined disease may benefit only a percentage of patients.
“We need to identify mechanisms of disease,” Self said, “and target therapies at those underlying mechanisms to advance clinical care.”
Thus, the ARDS, Pneumonia, and Sepsis (APS) Phenotyping Consortium was born. VUMC biostatisticians Frank Harrell, Jr., PhD, and Bryan Blette, PhD, help lead the consortium’s Design, Data, and Statistical Analysis Unit, which will oversee collection and analysis of laboratory tests and imaging studies from thousands of patients nationwide.
The goal is to link phenotypes, observable characteristics (symptoms), to specific genetic or physiological mechanisms (causes), and thus define the three syndromes more precisely.
““Our core principles as a department and as individual practitioners are rigor and reproducibility,” said Yu Shyr, PhD, the Harold L. Moses Chair in Cancer Research, and professor and chair of the Department of Biostatistics.
“The biostatistician stands as the gatekeeper of meaningful experimental results, which are a function of careful study design and appropriate methods of analysis,” Shyr said. “Our commitment to these core principles has allowed us to make the sort of impact that, ultimately, saves lives.”
