Infectious Diseases and Hospital Medicine Act Swiftly to Launch Clinical Trials for Remdesivir

by | Feb 26, 2024 | 2021, all stories 2021

Infectious Diseases and Hospital Medicine Act Swiftly to Launch Clinical Trials for Remdesivir

Less than two months after the World Health Organization characterized COVID-19 as a pandemic, the U.S. Food and Drug Administration (FDA) approved emergency use of remdesivir for the treatment of the virulent disease. Later, the FDA gave full approval to remdesivir, which remains the standard of care for hospitalized patients with COVID-19.

Clinical trials, which took place at Stanford and dozens of other sites, yielded convincing data that led to the FDA’s emergency use authorization.

Department of Medicine researchers began recruiting participants for the trials in early March 2020. One pair of trials was sponsored by Gilead Sciences, a company based in Foster City, California, that makes the drug. The other was by the National Institutes of Health (NIH) and one of its institutes, the National Institute of Allergy and Infectious Diseases (NIAID).

The Gilead Trials

Aruna Subramanian, MD, clinical professor of infectious diseases, was the principal investigator of the Gilead trials at Stanford. Subramanian was joined by co-principal investigator Philip Grant, MD, assistant professor of infectious diseases, who helped enroll 46 participants at Stanford and execute these studies. Results were published in the New England Journal of Medicine and the Journal of the American Medical Association.

In results reported April 29, Gilead announced that a five-day treatment course with remdesivir was potentially as effective as 10 days of treatment in its trial of severely ill patients. Later that same day, the NIH reported that early data from its remdesivir trial indicated that the drug helps to accelerate the time to recovery in severely ill patients.

On June 1, results from the remdesivir trial for people with moderate disease stated that a five-day treatment course of remdesivir resulted in a significant clinical improvement over standard of care.

Subramanian says the results from both trials were reassuring to her, both as a scientist and as a doctor who treats patients in the hospital with COVID-19.

“To at least have something that we can potentially use as a treatment for this virus was very assuring,” she says. “In the early course of the pandemic, we were all so scared and disheartened by patients going downhill and needing to be on a ventilator for so long. To see that even those people could potentially be turned around was very encouraging.”

“To at least have something that we can potentially use as a treatment for this virus was very assuring”

Philip Grant, MD (left) and Aruna Subramanian, MD (right)

“To at least have something that we can potentially use as a treatment for this virus was very assuring”

Philip Grant, MD (left) and Aruna Subramanian, MD (right)

The NIH Trial

The process of setting up an infrastructure for clinical trials, slow-moving and deeply complicated under normal circumstances, was accelerated with the outbreak of COVID-19. A team of researchers needs to be assembled, patients need to be recruited, and sites need to be established.

But in a matter of weeks, the division of hospital medicine organized an infrastructure at both Stanford Hospital and Stanford Health Care – ValleyCare and implemented Phase 1 of their first trial—to explore the effectiveness of remdesivir—with impressive results.

Neera Ahuja, MD, chief of the division of hospital medicine, was the principal investigator for the global NIH/NIAID Adaptive COVID-19 Treatment Trial (ACTT) at Stanford. The work was greatly facilitated by Kari Nadeau, MD, PhD, the Naddisy Foundation Endowed Professor of Medicine and Pediatrics and hospital medicine’s senior director of clinical research.

Stanford Hospital and SHC – ValleyCare were among the more than 65 sites around the world hosting the ACTT, a randomized, double-blind, placebo-controlled study that included 1,063 patients for its first phase.

Ahuja and Nadeau worked with clinical associate professor Nidhi Rohatgi, MD, MS; associate professor Sharon Chinthrajah, MD; and clinical assistant professor Rita Pandya, MD, to enroll patients quickly at the Stanford Hospital location. At the other location, David Svec, MD, MBA, clinical associate professor of medicine and chief medical officer at SHC – ValleyCare, was instrumental to the process, along with Minjoung Go, MD, clinical assistant professor of medicine, and Evelyn Ling, MD, MS, clinical assistant professor of medicine and SHC – ValleyCare physician research co-champion.

From left: Evelyn Ling, MD, MS; David Svec, MD, MBA; Minjoung Go, MD

The intense time frame put a great deal of pressure on everyone at Stanford Hospital and SHC – ValleyCare, from the physicians to the staff to the lab workers. When the first trial began, there was no real infrastructure for clinical trials.

As physician research champions, both Go and Ling were leaders on the ground at SHC – ValleyCare, although this was the first clinical trial that either of them had taken such a large part in.

“I was on the night shift, so trying to attend all the daily meetings was a little bit challenging,” Go admits. “It felt a little like trying to fly a plane while you’re building it. But it was a really, really rewarding experience. I got to learn a lot of the process of clinical trials and how to operationalize them.”

Results

That study’s trials showed that recovery time for patients infected with COVID-19 was reduced from 15 days to 11 days with the use of intravenous (IV) remdesivir.

“Data shows remdesivir has a clear-cut positive effect in diminishing the time to recovery,” said Anthony Fauci, MD, director of the NIAID, in a televised meeting at the White House on April 29, the day the results were announced. “What this has proven is that a drug can block this virus,” he said.

“This trial represents the fusion of the Stanford mission, bringing

the kind of research that’s typically only at academic centers to a

community center, but still being able to use our local nurses,

pharmacists, and lab”

“This trial represents the fusion of the Stanford mission, bringing

the kind of research that’s typically only at academic centers to a

community center, but still being able to use our local nurses,

pharmacists, and lab”

“I was very excited by the trial results,” says Ahuja. “Still, this is not a panacea. We don’t know if this is the best treatment. We still need to look for the most effective drug. Here we are in May 2021, a year later. We have the benefit of vaccines, but we still do not have the ideal combination of treatments to rapidly abate the virus.”

Ling says that “this trial represents the fusion of the Stanford mission, bringing the kind of research that’s typically only at academic centers to a community center, but still being able to use our local nurses, pharmacists, and lab. It was a really meaningful first trial. ”

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

by | Feb 26, 2024 | 2021, all stories 2021

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.

Lung Organoids: A Novel Way to Model COVID Infection

by | Feb 26, 2024 | 2021, all stories 2021

Lung Organoids: A Novel Way to Model COVID Infection

A year into the pandemic, we’ve all heard the stories. A patient is a little short of breath but appears to have a mild case of COVID-19. The next day, she deteriorates so rapidly that she’s rushed to intensive care, put on a ventilator, and hooked up to a dialysis machine to prevent kidney failure. Her overzealous immune system has gone rogue, attacking healthy cells instead of just fighting off the virus.

What triggers this devastating immune response, called a cytokine storm? Researchers are still struggling to identify the underlying processes that initiate a COVID infection and subsequent cytokine storm.

Biologists use advanced technologies and cell cultures in petri dishes to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus strain responsible for COVID-19, identifying its key characteristics such as the famous crownlike spikes on their surfaces. But these short-lived cultures don’t act like real organs. And scientists are limited by their samples.

“When you analyze samples from patients, they’re often at the end stage of the disease, and many of the samples are from autopsy. You can’t understand the initiation process because the tissue is essentially destroyed,” says Calvin Kuo, MD, PhD, professor of hematology.

Understanding how the disease develops and testing potential treatments require better ways to model this coronavirus.

Miniature Organs in a Dish

Kuo’s laboratory develops organoids—three-dimensional miniature organs grown in a petri dish that mimic the shape, structure, and tissue organization of real organs.

Grown from human tissue samples using precisely defined ingredients, these organoids are little spheres of gel up to 1 millimeter in diameter. Healthy tissue samples are mechanically minced and enzyme digested to get to single cells, and then the organoids are grown from single stem cells. They last about six months, significantly longer than the few-weeks lifetime of traditional cell cultures.

Kuo initially developed organoids to study stem cell biology and model cancer. His team was the first to use organoids to convert normal tissues to cancer, as previously reported in Nature Medicine.

Calvin Kuo, MD, PhD, with Shannon Choi, MD, PhD, a student in the Kuo lab. Courtesy Steve Fisch

But he was passionate about using organoids to model infectious diseases. In 2015, he led a National Institute of Allergy and Infectious Diseases U19 research program, recently renewed for an additional five years, in collaboration with Stanford researchers Manuel Amieva, MD, professor of pediatrics and of microbiology and immunology; Harry Greenberg, MD, the Joseph D. Grant Professor in the Stanford University School of Medicine and professor of microbiology and immunology; Elizabeth Mellins, MD, professor of pediatrics; and Sarah Heilshorn, PhD, professor of materials science and engineering. Focusing mainly on the gastrointestinal tract, this multidisciplinary team provided proof of principle that organoids could model infectious diseases.

“With an organoid system, you can start at the infection and look at the very earliest events that occur after infection. And those can give insights as to what needs to be blocked therapeutically,” Kuo explains.

Distal Lung Organoids

After the initial success with gastrointestinal organoids, Ameen Salahudeen, MD, PhD, a hematology and oncology postdoctoral fellow working in Kuo’s lab, led efforts to expand this work by developing distal lung organoids. He partnered with lung stem cell expert Tushar Desai, MD, associate professor of pulmonary, allergy, and critical care medicine at Stanford.

The distal lung is composed of terminal bronchioles and alveolar air sacs, where inhaled air passes through the tiny ducts from the bronchioles into the elastic air sacs. It performs essential respiratory functions that can be compromised by inflammatory or infectious disorders, such as COVID-19 pneumonia.

“Growing distal lung cultures in a pure way that doesn’t require any supporting feeder cells and is in a chemically defined media had not been possible,” Kuo says. “We were able to do this very beautifully—to grow alveoli at the terminal bronchioles as long-term human cultures.”

The team developed two types of distal lung organoids. Both were made from human distal lung samples provided by Stanford cardiothoracic surgeon Joseph Schrager, MD.

They grew the first type, alveolar organoids, from single alveolar type 2 (AT2) stem cells. AT2 cells have several important functions that together help control the immune response to decrease lung injury and repair. The scientists then induced the AT2 cells to produce alveolar type 1 (AT1) cells, which are the thin-walled cells lining the alveolar air sacs; they are essential for the lung’s gas-exchange function.

“The second type are the basal organoids, which grow from single basal stem cells. They give rise to the mucus-secreting club cells and the ciliated cells with beating hair. And we can see the beating hair under the microscope—it’s quite dramatic,” describes Kuo. “That’s a very nice reproduction of the differentiation and function of the lung.” The team also grows a mixture of alveolar and basal organoids.

They selected these organoid types to determine which cell types in the bronchioles and alveoli were infectible—in hopes of identifying the different mechanisms for how viruses cause respiratory compromise.

Initially, they tested the distal lung organoids using the H1N1 influenza virus, collaborating with Stanford molecular virology expert Jeff Glenn, MD, PhD.

The team fluorescently labeled the virus and infected the lung organoids, demonstrating that the virus replicated in both basal and alveolar organoids. Next, they did more sophisticated PCR-based testing to show that the virus replicated its genome.

COVID-19 Model

“But then the COVID-19 pandemic hit, so we initiated a fabulous collaboration with infectious disease expert Catherine Blish, MD, PhD, in the Department of Medicine, to infect our lung organoids with SARS-CoV-2. This was driven by a talented MD-PhD student in my lab, Shannon Choi,” says Kuo. “She worked with Arjun Rustagi, an infectious disease fellow in Catherine Blish’s lab, who infected the organoids in a biosafety-level-3 lab.”

Another partnership was critical, though. An important coronavirus receptor, called angiotensin-converting enzyme 2, or ACE2, resides inside the lung organoids. But ACE2 needed to be on the outside of the organoid to get the infection going.

“We discovered an unknown basal cell

subpopulation containing the stem cell activity.

And then we showed this subpopulation

actually existed in human lungs in very

interesting anatomic locations”

“We discovered an unknown basal cell

subpopulation containing the stem cell activity.

And then we showed this subpopulation

actually existed in human lungs in very

interesting anatomic locations”

Luckily, Amieva previously devised a way to flip intestinal organoids inside out. Working together, Choi and Amieva turned the lung organoids inside out.

As reported in Nature in November 2020, the team demonstrated that the coronavirus infected their distal lung organoids, including the alveolar air sacs, where COVID-19 pneumonia originates. They also identified a new airway subpopulation as a COVID-19 virus target cell.

“Everyone knew basal cells were stem cells in the lung, but they thought they were all equivalent. Using our organoids, we discovered an unknown basal cell subpopulation containing the stem cell activity. And then we showed this subpopulation actually existed in human lungs in very interesting anatomic locations,” Kuo says.

COVID-19 Applications

According to Kuo, their distal lung organoids have three major applications for COVID-19.

They are using them to screen potential coronavirus therapeutic antibodies and to understand how these treatments work. Although initially focused on COVID-19, this screening will likely expand to other kinds of lung infections in the future.

Because the distal lung with the alveoli is the site of the COVID-19 pneumonia, they also plan to use the organoids to identify the underlying biological mechanisms behind coronavirus infection. Finally, they plan to extend their organoid system to incorporate immune cells and understand more complex processes. In particular, they plan to model the dreaded cytokine storm.

Overall, Kuo emphasizes that this organoid research represents a huge team effort involving many investigators with wide-ranging expertise from various departments at Stanford, as well as an “interesting evolution of events.”

“Now we have a human experimental system to model SARS-CoV-2 infection of the distal lung with alveoli, which is the site of the lung disease that kills patients,” he summarizes. “We know patients die because of severe pneumonia and lung failure. We can now recapitulate this in the dish. So, we can study how it works, and also test drug treatments.”

Biomedical Informatics Research: High Schoolers Show How Data Analysis Can Shape Public Health Policy

by | Feb 26, 2024 | 2021, all stories 2021

Tofunmi Omiye

High Schoolers Show How Data Analysis Can Shape Public Health Policy

Tofunmi Omiye

High Schoolers Show How Data Analysis Can Shape Public Health Policy

Remember the game where you’re given several disparate items and you get two minutes to make up a skit using all of them? Well, that’s not too different from what happened to Nigam Shah, MBBS, PhD, during late spring 2020.

Shah is professor of biomedical informatics at the Stanford University School of Medicine and associate chief information officer for data science at Stanford Health Care. In June, he received emails from four high school students looking for research experience during their summer vacation. The students approached Shah because the pandemic forced a temporary shutdown of programs such as the Stanford Institutes of Medicine Summer Research Program (SIMR), which is the primary mechanism by which faculty accept high school interns.

At the same time, Shah was in touch with Tofunmi Omiye, a physician in Nigeria, who had been admitted to a master’s degree program in health policy at Stanford but was delayed entrance because of the pandemic. Omiye said he was seeking a research assistant position to help fund his Stanford education and asked if Shah had a research project he could work on.

“At that point, I wondered if I could combine these two problems: Here’s a master’s student doing a research project, and here’s a bunch of kids wanting to do something so they’re not bored out of their minds sitting at home all summer long. So I asked each of them if they would be OK working on a team project as opposed to me working with them one-on-one, and they all said yes,” Shah says.

The result exceeded all expectations and led to a March 2021 presentation during the American Medical Informatics Association (AMIA) 2021 Virtual Informatics Summit.

The Backstory

The four students had written to Shah completely on their own to inquire about summer research opportunities in his lab. Logan Pageler (son of clinical professor of biomedical informatics research Natalie Pageler, MD) and Nikhil Majeti (son of professor and division chief of hematology Ravi Majeti, MD, PhD) were given Shah’s name by their parents. The other two—Ron Nachum and William Ding—found Shah independently.

As Ding says, “I first saw Professor Shah in one of Stanford Medicine’s virtual town hall videos about COVID-19. I then found his various projects on Stanford’s website and reached out to him to see what I could help with.”

Not long after that, Omiye, who holds the equivalent of an MD degree from the University of Ibadan in Nigeria, approached Shah and several other Stanford faculty to ask about serving as a paid research assistant. Omiye noted that Shah’s focus coincided with Omiye’s interests in big data and medicine.

When Shah asked if Omiye was willing to serve as an unpaid mentor to four high school students on a project he was thinking about, the master’s candidate jumped at the opportunity.

The Assignment

Shah gave his “assignment” to Omiye and the four high school students during June 2020, when COVID-19 cases were decreasing and some states were beginning to loosen shelter-in-place orders.

“I posed a research question to them, asking if we could use public data to identify the effect of various states’ reopening orders. That is: ‘Using public data, can we identify which reopening orders are good and which are bad?’” Shah says.

Shah gave a few hints at how to approach the problem and then left the mentor and the four students alone.

“I pointed them to a few data sets and told them that the best way to figure out whether a policy like masks, distancing, curfew, or whatever is working or not working is to look at how many people are going into hospital beds, because an increasing number of inpatients puts a burden on the entire system. So we figured we would count hospitalizations and ask questions like ‘If people are ordered to wear masks, what happens to hospitalizations?’ and ‘If you allow restaurants to reopen, what happens to hospitalizations?’” he says.

Omiye, who was working full-time as a medical intern in Lagos, Nigeria, created a framework with milestones for the project, and he arranged weekly meetings by Zoom so that he and the teenagers could discuss accomplishments and challenges in real time from their locations in California, Virginia, and Nigeria.

The students devised and maintained schedules for completing the work, they created a WhatsApp group where they would post daily progress notes, and they used Google Docs to keep meeting minutes that they would share with Shah.

Working Quickly

Less than two months later, the team had developed a presentation for the members of Shah’s lab.

Using their own computers and publicly accessible data, they learned how to figure out how long it takes for a policy decision made today to affect the rate of hospitalizations down the road.

Specifically, they investigated the effect of reopening orders on COVID-19 hospitalizations in the U.S. They discovered that reopening restaurants/bars and houses of worship correlated with the most significant spikes in hospitalization cases. “In the end, they determined that if you open up restaurants, that’s bad; and that’s exactly what all the famous public health scientists concluded four to six weeks later! So some kids who knew nothing about epidemiology used their computers and some data sets to match wits with the best in the field,” Shah boasts.

Furthermore, Omiye taught his mentees the basics of writing a scientific research paper and led the team into expanding the presentation into a paper worthy of submission to a peer-reviewed journal.

“These kids had never written a paper before in their lives,” Shah says, “but just a few weeks after the presentation to my lab, they completed a paper that was submitted to AMIA, and it was accepted.”

“In the end, they determined that if you open up restaurants,

that’s bad; and that’s exactly what all the famous public health

scientists concluded four to six weeks later! So some kids who

knew nothing about epidemiology used their computers and some

data sets to match wits with the best in the field”

“In the end, they determined that if you open up restaurants,

that’s bad; and that’s exactly what all the famous public health

scientists concluded four to six weeks later! So some kids who

knew nothing about epidemiology used their computers and some

data sets to match wits with the best in the field”

William Ding ponders comments made during a Zoom teleconference call with his fellow high school research colleagues and mentor Tofunmi Omiye

Camaraderie

Among the benefits for the high school students was the experience of teamwork.

“I really enjoyed working together with the team, with the virtual setting allowing us to work together from different parts of the country and share our knowledge in computer science, data analysis, epidemiology, and more,” Nachum says.

“I was so impressed at how hardworking these students were,” Omiye adds. “They were willing to respond to every comment from me, Dr. Shah, and the AMIA reviewers.

”What’s more, says Omiye, the reviewers were “really impressed by the quality of the project, and the feedback was overwhelming.”

Among the comments:

“I noticed that the authors are in high school. Well done! And kudos on a great effort on a very interesting study.”

“Analysis in this paper is clearly conducted and easy to digest as well as the limitations of the study.”

“The submission clearly presents how the methods are structured. The submission follows standard scientific writing.”

Summing up the experience, Omiye says that “we were five strangers from different parts of the world, and we just connected to build an impactful project.”

Talented Women at Every Level of Nephrology

by | Feb 26, 2024 | 2021, all stories 2021

Talented Women at Every Level of Nephrology

A glance at the website for the division of nephrology brings a short paragraph into focus. It includes these three sentences, which could easily be considered a vision statement: “We are devoted to training the next generation of nephrologists in a supportive environment that cultivates their individual passions. We are dedicated to creating and maintaining a diverse and inclusive community. We are Stanford Nephrology.”

A New Division Chief

When associate professor Tara Chang, MD, MS, assumed the position of chief of the division of nephrology in early 2021, she was following directly in the footsteps of her mentor, Glenn Chertow, MD, MPH. Chang has only good things to say about Chertow: “He had a critical role in shaping my career. And it’s really through his efforts that our division is so diverse with regard to women and with regard to race and ethnicity, both at the faculty level and at the fellowship level.”

Tara Chang, MD, MS

Tara Chang, MD, MS

The way Chang ended up with nephrology as her specialty reflects her approach to many things: “I was never one of those people who had a grand plan for life. Opportunities arose and I took them as they came. As an example, UC-San Francisco wasn’t actually my first choice for residency but matching there changed my trajectory. I met fantastic faculty in nephrology there, so I decided to specialize in this field.”

Her research program covers almost everyone with kidney disease, which has a great deal of overlap with cardiovascular disease. Chronic kidney disease is a risk factor for many cardiovascular diseases, including premature coronary disease, hypertension, and atrial fibrillation. “What has been cool in recent years,” she says, “is that more and more the cardiology community is recognizing the importance of the kidneys. While cardiology is still ahead of nephrology in terms of clinical trials, we are seeing more and more studies with a primary kidney outcome and a secondary cardiovascular outcome. It’s an exciting time for us to partner with the cardiovascular community because there are many new therapies coming down the pike.”

Race, Ethnicity, and Kidney Disease

Kidney disease disproportionately affects people who are Black or of Hispanic ethnicity and those in lower socioeconomic groups. A lot of the reason is a lack of access to care, risk factors such as diabetes, and a scarcity of options for food. The kidney community is trying to understand how to do better.

The estimated glomerular filtration rate (eGFR) is an important basic way to assess a patient’s kidney function. The formula used to calculate it includes factors such as age, gender, and race, for which the choices are Black or non-Black. The use of racial data is of enough concern that the National Kidney Foundation and the American Society of Nephrology have appointed a task force to look into it and report back.

Chang notes that “there’s been a lot of scrutiny into how we include race in clinical care, including how we calculate the eGFR. Changing the way we calculate it is just the tip of the iceberg, but it may spur more of us to think more deeply about issues of race and ethnicity and medicine.”

Establishing Goals

Goal setting is an important early step for a person in a new position of responsibility. Chang feels that she ascended to become chief of a division that already had a number of strong goals in place, causing her to want “to continue a lot of the things that Glenn prioritized: investing in training fellows and taking care of them and trying to have fellows and faculty in the division who look like the patients we serve. I have other evolving goals, but I want input from faculty in the division on such matters. We have an awesome faculty, and I want them around me forever. I need their help to set the course.”

Adetokunbo Adenike Taiwo, MD, MS

One of those faculty members is clinical assistant professor Adetokunbo Adenike Taiwo, MD, MS, whose path into nephrology was similar to that of her chief. “When I started my residency, I was uncertain what specialty I would choose. Nephrology was not at the top of my list. During my training at the University of Chicago, we took care of a predominantly African American population. The burden of kidney disease in the community made a deep impression on me. Every time I was on call, I admitted several patients with either acute or end stage kidney disease.”

Kidney Transplantation at Stanford

Caring for patients with kidney failure was challenging. Taiwo explains why: “They were often the sickest patients in the hospital. I spent the bulk of my residency taking care of very sick people and trying to get them to feel well enough to return home to their family. Many of these patients were hospitalized frequently with complications related to kidney disease. It just seemed like they never had a great quality of life.”

Getting the sickest patients to life saving transplant is a long, bumpy, uncomfortable path, and it often ends with patients being short of their goal. Dialysis saves them from immediate death, but it takes a long time to get a kidney transplant; the standard waiting time is seven to 10 years in the San Francisco Bay Area. With kidney transplantation, unlike transplantation of other organs where the sickest patients are the ones who are prioritized for transplant, “you have to be fit enough to be transplanted,” says Taiwo. After 10 years on dialysis, the sad reality is that many patients are not healthy enough or have developed complications such as severe vascular disease that make them ineligible for transplantation.

When Taiwo rotated through the kidney transplant service, she encountered a very different set of patients.

“I love asking patients the first time they show up to my clinic

after transplant, ‘What’s different?’ Hearing how much better

they feel makes this field so fulfilling”

“I love asking patients the first time they show up to my clinic

after transplant, ‘What’s different?’ Hearing how much better

they feel makes this field so fulfilling”

Her story continues: “Here I was on a rotation where I was seeing end stage kidney disease patients coming in for follow-up after their kidney transplant, and they looked so well. Knowing that these patients were similar to patients I took care of in the hospital setting really changed my view. I went into medicine to make a difference, to see people get better, to see people go from sick to well. When I saw how much kidney transplantation changed quality of life, it simply blew me away.”

Taking care of transplant patients, she says, “is rewarding every single time. I love asking patients the first time they show up to my clinic after transplant, ‘What’s different?’ Hearing how much better they feel makes this field so fulfilling.”

A Fellow Also Drawn to Transplant

Unlike Taiwo and Chang, Ruth Romero, MD, a second-year fellow, says she “actually wanted to do nephrology since I was in medical school when I learned about electrolytes and fluid balance. It’s very interesting, and it’s challenging to learn it very well.”

Adetokunbo Adenike Taiwo, MD, MS (left) and Ruth Romero, MD (right)

Romero says that she chose “Stanford for my fellowship first because of the faculty. I feel like there is a very good balance here between clinical work and teaching. A lot of the faculty take much of their time to teach us every day when we are rounding. We also have teaching conferences almost every day.”

Romero is also interested in transplant nephrology after having done six months of transplant clinic at Stanford. She says, “We saw transplant patients every one or two weeks; this was pre-COVID. It was such a life-changing experience for everybody. More than half were Latin people, so we had a lot in common because I’m from Ecuador.”

Noting that diabetes and high blood pressure in the U.S. put people at risk of developing kidney disease, she says that there are “certain diseases in the Latin community that also put patients at risk of having end stage renal disease at an early age.”

Beginning in July 2021, Romero will spend a year as a transplant fellow at USC. After that, she says, “it is very likely I’m going back to my home country. I will take all the experiences I had here and bring them back to my native country to practice medicine there.”

Perhaps she heard this advice from the new chief of her division: “This is the thing I tell my fellows: If you approach everything with your best effort and come through when you say you will, opportunities will continue to present themselves to you.”

One Company’s Trash: Nephrology’s Collaboration With Industry in the Fight Against COVID-19

by | Feb 26, 2024 | 2021, all stories 2021

One Company’s Trash: Nephrology’s Collaboration With Industry in the Fight Against COVID-19

It all started with leftovers. Ascend Clinical laboratories was already taking regular (typically monthly) blood samples of its thousands of dialysis patients from centers all around the country when the pandemic hit. And they, like so many others, wanted to help at a time when so many felt helpless.

They were already planning to obtain the capability to test for COVID-19 antibodies but realized they could also potentially test some of the remnant blood they had on hand that they usually throw away. So they reached out to Glenn Chertow, MD, then division chief of nephrology and current Norman S. Coplon Satellite Healthcare professor of nephrology, wondering whether they might be able to help in the fight against COVID-19.

It all started with leftovers. Ascend Clinical laboratories was already taking regular (typically monthly) blood samples of its thousands of dialysis patients from centers all around the country when the pandemic hit. And they, like so many others, wanted to help at a time when so many felt helpless.

They were already planning to obtain the capability to test for COVID-19 antibodies but realized they could also potentially test some of the remnant blood they had on hand that they usually throw away. So they reached out to Glenn Chertow, MD, then division chief of nephrology and current Norman S. Coplon Satellite Healthcare professor of nephrology, wondering whether they might be able to help in the fight against COVID-19.

The Idea

The thought was first broached during a coffee break. Chertow and Ascend CEO Paul Beyer, who’ve known each other for several years, met on a windy afternoon in early spring, when COVID-19 was first starting to surge in New York. “We were basically lamenting how powerless we were and what we could possibly do to contribute to the fight against this virus,” Chertow remembers. Their thoughts first turned to testing, and then to antibody testing, and soon the project was born.

“This is basically a story of two frustrated people, one business person and one doctor, sort of knocking heads together over a cup of coffee,”Chertow explains. Beyer told Chertow about the samples he had access to.

“It clicked in my head, well, this would be an unbiased sample,” Chertow says, “because it’s a population of patients who get their blood drawn on a routine basis because of the nature of their treatment.” If they tested these patients for COVID-19 antibodies, they’d be able to get a fairly clear picture of what the COVID-19 prevalence was in the U.S.

“This is basically a story of two frustrated

people, one businessperson and one doctor,

sort of knocking heads together over a cup of coffee”

“This is basically a story of two frustrated

people, one businessperson and one doctor,

sort of knocking heads together over a cup of coffee”

“It clicked in my head, well, this would be an unbiased sample,” Chertow says, “because it’s a population of patients who get their blood drawn on a routine basis because of the nature of their treatment.” If they tested these patients for COVID-19 antibodies, they’d be able to get a fairly clear picture of what the COVID-19 prevalence was in the U.S.

The idea was promising, but one crucial hurdle remained: how to pay for it. Most dialysis patients are covered by Medicare, which couldn’t cover the costs for a study that didn’t lead to direct patient action. So Beyer volunteered to cover them. “It was an incredibly generous gesture on his part,” Chertow states. He accepted the offer, and they moved forward.

The next step was assembling the team.

The Team

The team was composed of Chertow; Shuchi Anand, MD, assistant professor of nephrology; biostatisticians Maria Montez-Rath, PhD, senior research engineer of nephrology, and Jialin Han, MS; and epidemiologist Julie Parsonnet, MD, George DeForest Barnett professor of medicine. They decided to study the remnant blood for the presence of COVID-19 antibodies (also known as “seroprevalence”) and then analyze the anonymized data based on geographical region, ethnicity, and other data points. The process started in June 2020, testing was done throughout the month of July, and initial data were submitted in mid-August, a blisteringly fast pace for this kind of research.

Maria Montez-Rath, PhD

The Team

Nearly all of them worked from home. One of the greatest challenges, Anand explains, came from an overall positive: They had almost too much data coming at them too fast. “We just really had to work hard to interpret it and present it in a rigorous manner,” she says. “And our team was really holding itself to a high standard to do that well.”

As the principal biostatistician of the group, Montez-Rath both planned and designed the data analysis, working “many hours” on the “very intense” project. She adds, “In a pandemic, all data becomes outdated very quickly and new knowledge is created at a very fast pace, which makes it even harder to maintain high-quality work. Given that all my other projects didn’t stop when the pandemic started, it resulted in many more hours of work (including nights and weekends) beyond what I would normally do.”

Still, she remembers the work fondly. “I immediately realized that the project was going to have a really high impact,” she says. Her enthusiasm for her work kept her going. As she explains, “I have my dream job: working closely with people in various projects that ideally have an impact on people. I feel that what I do is useful to patients and to the betterment of the world.”

Han, a biostatistician hired at Stanford in 2018, echoes Montez-Rath’s passion for meaningful work: “It’s always interested me that my work could improve people’s quality of life,” he says. He heard about the project in June 2020, when Montez-Rath realized there was too much statistical work to do all by herself. He describes the hectic pace of the process this way: “We met frequently to summarize the research questions and the analysis plan. It all came really fast, especially since at that time there was no report about national seroprevalence at all. The idea was if we want to do this, we have to do it fast.”

And he means fast—some days he met the team at 7 a.m. to discuss a problem and then again at 5 p.m. that same day to track the progress. He describes the work as “really intense and time sensitive,” but adds, “We understood the importance of this study, so we wanted to do the best we could.” His role included data preparation, data mining, data analysis, and output generation.

Parsonnet was brought on board for her epidemiological expertise, giving opinions on study design and meeting regularly with the team to “discuss what the data showed and go over it and review what it meant and how we interpreted it, given the world around us.” It was her first collaboration with this team and she found it to be “just such a pleasure.”

Shuchi Anand, MD

The Study

Initially, Anand recalls, “it was important to understand in real time what was happening with the epidemic.” Ascend’s data drew from 46 states and a third of all counties in the U.S., spread from coast to coast.

Forty percent of the samples were from patients 65 and older, and since patients on dialysis are often from disproportionately disadvantaged populations, racial and ethnic minorities and people from poorer neighborhoods were actually overrepresented in the population of the study. “That was great,” Anand explains, “because those groups are often the most vulnerable to SARS-CoV-2 but are so hard to reach via a door-to-door survey.”

The researchers were also able to use the results from this population to extrapolate. “Our main goal was not just to provide a sample that was representative of the Ascend dialysis population but also to then analyze the data so it could represent both the overall dialysis population and the general adult population of the U.S.,” Montez-Rath states.

The Results

The results came quickly: Regional and ethnic differences made a significant impact on the prevalence of COVID-19 antibodies (and, therefore, the rates of COVID-19 infection in various communities). The intense outbreak at the time was in New York City, and seroprevalence was up to approximately 25% in New York City at the time of the study, compared with approximately 2% to 5%in the rest of the U.S.

The team also found that people who were living in minority neighborhoods or self-identified as being minorities were at an approximately two-to threefold higher risk at that time for seroprevalence and infection. As Anand concludes, “It wasn’t just that they were getting COVID-19 at the same rate and dying more. It was also that they were getting more COVID-19.”

And within these results, they were able to extrapolate to larger regions, estimating that seroprevalence in the U.S. at the time would be somewhere near 9% for the U.S. adult population. This estimate, incidentally, ended up being remarkably accurate—at the time the Stanford study was published, the Centers for Disease Control and Prevention was conducting an independent analysis that hadn’t yet been completed, but when it was published in August, their estimates were “very similar.” Initially, Anand recalls, “it was important to understand in real time what was happening with the epidemic.” Ascend’s data drew from 46 states and a third of all counties in the U.S., spread from coast to coast.

Working With Industry

Anand called working with Ascend “mutually inspiring” because the company displayed an incredibly compassionate desire to help in any way. “They understood the true potential of what they had, and we really understood their willingness and capabilities as well,” Anand says.

Montez-Rath agrees: “What surprised me the most about this project was the people involved, especially Ascend’s participation.” She calls this industry/academy collaboration “something to be celebrated.”

Parsonnet was “very happy about how great the renal dialysis units were about wanting to participate.” She adds, “It’s nice to see these dialysis centers really care about doing the right thing for their patients. It makes me feel good about the world.”

Chertow concludes, “Academy and industry partnerships sometimes work!”

“We’re not developing vaccines, we’re not the people doing

the phenomenal earth-shattering stuff, but we have helped to

inform the understanding of where the pandemic was raging, how

it’s been spreading, how it’s been disproportionately affecting

persons of color and other disadvantaged populations. We’re

helping, little by little, in our own way”

“We’re not developing vaccines, we’re not the people doing

the phenomenal earth-shattering stuff, but we have helped to

inform the understanding of where the pandemic was raging, how

it’s been spreading, how it’s been disproportionately affecting

persons of color and other disadvantaged populations. We’re

helping, little by little, in our own way”

Future Studies

The pandemic will eventually end, but studies using this remnant blood are continuing, and projects with this population will continue in the future too. The Stanford team is examining various aspects of dialysis and COVID-19, including studying transmission risks and infection mitigation at dialysis centers and looking to the possibility of future seasonal COVID-19 infections and how they will affect dialysis patients, who often do worse during winter months.

They’re also working on a repeat cross section to try to get a sense of seroprevalence in the U.S. a year into the pandemic, particularly before the vaccine rollout—information that Anand calls “critical.” In addition, they have both vaccine response and vaccine acceptability studies in dialysis patients in the works, including a vaccine acceptability survey among dialysis patients led by nephrology fellow Pablo Garcia, MD.

And their work has even helped inspire other universities and dialysis centers. “I know several dialysis networks are looking at vaccine response in dialysis patients,” Anand says. “They may have chosen to do that independently, but hopefully we gave them sort of a road map for how to do it as well. Which is great, because we want our patients to be protected, and we want our colleagues to study that and improve ways to make that happen.”

Part of the Fight

Chertow concludes, “I think in our own way we’ve contributed to the fight against COVID-19. We’re not developing vaccines, we’re not the people doing the phenomenal earth-shattering stuff, but we have helped to inform the understanding of where the pandemic was raging, how it’s been spreading, how it’s been disproportionately affecting persons of color and other disadvantaged populations. We’re helping, little by little, in our own way.”

   Jialin Han, MS

Working Within and Among Divisions

The team members also enjoyed working among different divisions at Stanford. Han appreciated the learning opportunities the work gave him. “One of the amazing parts about being a biostatistician is that I can work with people from different backgrounds and disciplines, and I really enjoy it,” he says.

Anand loved working with Parsonnet. “She’s one of the world’s experts on epidemiology in general, and just getting her perspective on contextualization for how this work would be important and why it would be important was really great,” she says.

And Parsonnet also loved the team. “Shuchi is amazing, really sharp and hardworking and innovative and really tremendous,” she says. “And Maria is just terrific in thinking about ways to look at the data. I think of it as their work, and it was an honor for me to be able to participate in any way.”

Chertow, too, was filled with enthusiasm for the team, from Ascend and all across Stanford. “It’s been a very meaningful and satisfying collaboration for me,” he states. “The greatest gift to a teacher is when his or her student proves to be 10 times smarter than he is. It’s sort of like planting a seed and watching a grove of fruit-bearing trees grow. And that’s what working with people like Shuchi and Maria and Julie has been like.”