Team Science Initiatives Aim to Investigate ‘Long-Haul COVID’

Two multidisciplinary teams led by Department of Medicine faculty have applied for support to investigate why some people fully recover from COVID-19 while others have long-term effects months later, a condition commonly known as “long-haul COVID.” The groups are taking a team science approach—collaborating across different fields—to understand COVID-19’s myriad effects on the body.

“To solve complex problems, we need teams that bring different expertise to the table,” says Hannah Valantine, MD, professor of cardiovascular medicine and a member of one of the teams who has worked to encourage more team science initatives in the Department of Medicine. “To rapidly translate discoveries that impact the health of patients—that’s when we need the team science approach.”

Large, collaborative clinical research projects are a powerful way to build on the infrastructure established in the last year for COVID-19 clinical trials at Stanford. These include smaller independent trials and collaborations with pharmaceutical companies and the National Institutes of Health (NIH) Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program.

Demystifying Long-Haul COVID

At the new frontier of COVID-19 research is the question of why so many coronavirus patients suffer from a diverse collection of long-term symptoms, called post-acute sequelae of COVID-19 (PASC). Patients with PASC report shortness of breath and levels of fatigue that mirror chronic fatigue syndrome. Some experience a neurological symptom called “brain fog” and metabolic changes, including new-onset diabetes. Myocarditis is another frequent consequence of COVID-19, which can lead to arrhythmia or even sudden death. Some researchers suspect that a patient’s immune response may be to blame for the varied symptoms.

Upinder Singh, MD, professor and division chief of infectious diseases, is the lead for one team that applied for NIH funding to understand this complex condition. She has been involved with several multicenter COVID-19 clinical trials. Her co-investigators include PJ Utz, MD, professor of immunology and rheumatology; Catherine Blish, MD, PhD, professor of infectious diseases; and Yvonne Maldonado, MD, professor of pediatrics (infectious diseases) and of epidemiology and population health. Additionally, a steering committee composed of leaders from across the Department of Medicine and the Department of Epidemiology and Population Health will advise the project.

“This is a project that requires a team science effort, not only because you need large cohorts, but because the virus results in many different syndromes, and that expertise lies in various domains”

Hannah Valantine, MD

“This is a project that requires a team science effort, not only because you need large cohorts, but because the virus results in many different syndromes, and that expertise lies in various domains”

Hannah Valantine, MD

The team has already identified more than 2,500 patients who received care at Stanford to be included in study cohorts. Pregnant women and children will be included, as well as patients from Stanford’s transplant program. Since transplant patients receive immune-suppressing drugs, results from this cohort may offer insights into whether these drugs prevent or worsen the chances of a patient developing PASC, and if they interfere with a patient’s response to the vaccine. Researchers will also make use of the biorepository of COVID-19-related specimens, overseen by Blish.

Ultimately, the group hopes to answer basic questions about PASC, such as its incidence, its prevalence, and the full spectrum of symptoms. Moreover, by understanding the immune response, genetics, and life history of patients with PASC, they aim to tease out which factors cause one person to recover completely while another develops chronic effects.

“This is a project that requires a team science effort, not only because you need large cohorts, but because the virus results in many different syndromes, and that expertise lies in various domains,” says Valantine.

Transforming Clinical Research Through Team Science

Historically at Stanford, this type of large, multidisciplinary project has been rare. “There has been incredible clinical research over the decades here, but it has largely been done by relatively small groups or individual faculty members,” says Kenneth Mahaffey, MD, professor of cardiovascular medicine and director of the Stanford Center for Clinical Research (SCCR). Increasingly, however, the culture is shifting to recognize the value of collaborating with researchers across divisions and departments. These collaborations yield innovative, interdisciplinary discoveries that advance medicine and improve outcomes for patients, says Mahaffey. “Transformative clinical research that is going to alter how we deliver care and improve patient outcomes needs large, impactful science, and that requires large teams and large projects.”

To support faculty in performing large multicenter clinical trials, the Department of Medicine, through the efforts of Nancy Lonhart, associate director of finance and administration, has invested in a number of resources to help realize these projects.

Under the directorship of Mahaffey, SCCR has grown to almost 100 people dedicated to designing and running multicenter research programs. They can enroll Stanford patients in clinical trials, create opportunities for educational events, and assemble teams of faculty, project managers, and – through partnership with the Quantitative Sciences Unit (QSU) – data scientists, biostatisticians, and bioinformaticians for team science research.

The QSU includes practicing data scientists at the faculty, PhD, and master’s levels who can become fully integrated into a collaborating faculty member’s team to leverage all perspectives for effective study design and analysis. Through partnerships with other clinical departments within the Stanford University School of Medicine, the QSU is able to create teams that bridge multiple disciplines to solve particularly complex biomedical problems.

For researchers interested in the interface between health care and digital technologies, the Stanford Center for Digital Health, run by executive director Mintu Turakhia, MD, associate professor of cardiovascular medicine, can foster industry collaboration and help researchers develop innovative mobile and digital health projects.

While individual science will always be necessary for discovery, says Valantine, team science approaches can transform those discoveries into solutions that improve the health and well-being of patients. She credits Bob Harrington, MD, chair of the Department of Medicine, for creating the infrastructure necessary for faculty to participate seamlessly in this type of large, collaborative project. “This is his vision, to have team science as a core element of the research agenda for the Department of Medicine.”

Finding Answers From Data ‘in the Wild’

Another team, led by Melissa Bondy, PhD, professor of epidemiology and population health, and Manisha Desai, PhD, professor of biomedical informatics and director of the QSU, is applying for a second NIH PASC funding opportunity. Their project will ask similar questions and develop new inquiries using real-world data not collected for research purposes—electronic health records, claims information, and data collected “in the wild” from phones, smart watches, and other mobile devices.

As part of a larger research consortium, the team will use these unconventional data sources to understand the incidence and prevalence of PASC and who is at risk of developing the condition. They are also interested in the trajectory of the symptoms and whether those symptoms vary in relation to socioeconomic and demographic factors.

“It’s really an opportunity for us at Stanford to show off our team science skills and our willingness to play in the sandbox with other institutions,” says Desai.

Manisha Desai, PhD

The multiple principal investigators on the project include David Rehkopf, PhD, MPH, associate professor of primary care and population health; Steven Goodman, MD, MHS, PhD, professor of primary care and population health and co-director of the Meta-Research Innovation Center (Metrics); and Abby King, PhD, professor of epidemiology and population health and medicine at the Stanford Prevention Research Center.

The team will use data from a number of real-world data resources, including the American Family Cohort, which comprises 6 million people with diverse backgrounds and was gathered by the Stanford Center for Population Health Sciences, which Bondy and Rehkopf co-direct.

“From a statistical standpoint, these resources are appealing because we love having lots and lots of data,” says Desai. “But it often comes with a price.” Real-world data tend to be noisy and messy, because often they are collected for reasons other than research, but Desai’s QSU group has data scientists who are well-versed in study design, data management, and analysis for biomedical studies that leverage real-world data.

The Impacts of COVID-19 on the Community

Both projects will involve a strong community engagement piece, led by King, to gain perspectives and insights from affected individuals, especially those from the communities of color who have been so disproportionately impacted by the virus. Lisa Goldman Rosas, PhD, MPH, assistant professor of epidemiology and primary care and population health, will also be involved as the faculty director for the School of Medicine Office of Community Engagement.

“In taking a team science approach, we have learned that it is critical to bring in the knowledge and perspectives of community members themselves—those who are living day-to-day with COVID-19 and its longer-term effects,” says King. “They can contribute a wealth of knowledge concerning the real-world impacts of this disease and how we may be able to address those impacts.”

“In taking a team science approach, we have learned that it is

critical to bring in the knowledge and perspectives of community

members themselves—those who are living day-to-day with

COVID-19 and its longer-term effects”

“In taking a team science approach, we have learned that it is

critical to bring in the knowledge and perspectives of community

members themselves—those who are living day-to-day with

COVID-19 and its longer-term effects”

For both projects, King proposes to use a community-engaged citizen science method called Our Voice. This includes a mobile app available in multiple languages, called the Discovery Tool, to capture aspects of the users’ daily lives that impact their health and well-being.

If funded, these team science initiatives have the potential to vastly improve our understanding of the potential long-term effects of coronavirus infection. These answers may inform the development of more effective therapies or even strategies for preventing PASC.