Researchers at the university suggested their findings could lead to new genetic tests that could be offered by medical laboratories
New research conducted at the University of Utah suggests that clinical laboratories may someday be able to deploy genetic tests to indicate whether a couple has a higher-than-average risk of stillbirth.
This is yet another example of how researchers are cracking DNA’s code to understand how certain gene variants may affect the healthcare of offspring. The knowledge produced by this research, as confirmed by additional studies, may lead to genetic markers that medical laboratories can use to diagnose the risk of stillbirth using the parent’s DNA.
“Stillbirth is one of those problems that is so tragic and life-changing,” said study co-author Jessica Page, MD (above). “It is especially frustrating when you don’t have a good answer for why it happens. This knowledge may give us the opportunity to change how we risk stratify people and reduce their risk through prevention.” Should this research be validated, clinical laboratories may soon have new genetics tests to help doctors identify risk for stillbirth. (Photo copyright: Intermountain Healthcare.)
Can Stillbirth be Prevented?
Jessica Page, MD, an assistant professor in the Department of Obstetrics and Gynecology at the University of Utah School of Medical and co-author of the 2022 study, was lead author of a 2018 study that estimated nearly one-fourth of stillbirths are preventable.
“Stillbirth rate reduction has been slow in the US and we think many stillbirths may be potentially preventable,” she said in a university press release. “This is motivating us to look for those genetic factors so we can achieve more dramatic rate reduction.”
According to the press release, the University of Utah researchers found that stillbirth “can be inherited and tends to be passed down through male members of the family. That risk preferentially comes from the mother’s or father’s male relatives—their brothers, fathers, grandfathers, uncles, or male cousins. But the odds of a couple losing a baby to stillbirth are even greater when the condition comes from the father’s side of the family.”
The researchers made this discovery by analyzing data from the Utah Population Database (UPDB), which contains information on eight million people who were born in the state or have other connections there. The database is maintained by the Huntsman Cancer Institute at the University of Utah. It includes genealogical information and health records that allowed the researchers to trace incidence of stillbirths across multiple generations of families.
The researchers examined 9,404 stillbirth cases between 1978 and 2019, along with 18,808 live births that served as controls. They identified 390 multi-generational families with high numbers of stillbirths. Within that group, they looked at incidence of stillbirth among first-, second-, and third-degree relatives of stillborn babies. They then compared those numbers with data from unaffected families.
“We were able to evaluate multigenerational trends in fetal death as well as maternal and paternal lineages to increase our ability to detect a familial aggregation of stillbirth,” said genetic epidemiologist Tsegaselassie Workalemahu, PhD, lead author of the study. “Not many studies have examined inherited genetic risk for stillbirth because of a lack of data. The Utah Population Database allows for a more rigorous evaluation than has been possible in the past.”
Workalemahu described the research as “an important step toward identifying specific genes that increase the risk of stillbirth, which could one day lead to better diagnosis and prevention,” according to the university press release.
One caveat, the press release notes, is that Utah’s population is disproportionately of northern European descent. “Future studies will need to determine whether the trends hold true among people of different races and ethnicities,” it stated.
Call for More Testing
The University of Utah study is part of a larger effort to gain a greater understanding of the causes of stillbirths.
The story notes that “more than 20,000 pregnancies in the US end in stillbirth,” and in one in three of those cases, the cause is not determined.
Drucilla Roberts, MD, an obstetric and perinatal pathologist at Massachusetts General Hospital (MGH), told ProPublica that at a minimum, “the placenta should definitely be evaluated in every stillbirth.” But citing CDC data, the story notes that this is done in only 65% of stillbirths, and autopsies are performed in less than 20%.
“Experts blame the low rates on several factors,” the story states. “Because an autopsy often is performed in the days following a stillbirth, doctors and nurses have to ask families soon after they receive news of the death if they would like one. Many families can’t process the loss, let alone imagine their baby’s body being cut open. What’s more, many doctors aren’t trained in the advantages of an autopsy, or in communicating with parents about the exam.”
One consequence, ProPublica notes, is that clinicians are ill-equipped to advise patients on how to reduce risk in future pregnancies. The story describes the case of Karen Gibbins, MD, a maternal-fetal medicine specialist and an assistant professor of obstetrics and gynecology at the Oregon Health and Science University (OHSU) in Portland.
An Opportunity for Pathologists
Gibbins’ son was stillborn in 2018. She asked for an autopsy and learned that her son “had a rare disease caused by her antibodies attacking the cells in his liver,” the story states. When she became pregnant again, her doctor prescribed antibody infusions and she later gave birth to a healthy son. “If we had not had that autopsy, my third child would have died as well,” she told ProPublica.
This parent’s comment about the value of the autopsy done after her son’s stillbirth identifies an opportunity for the pathology profession. For several decades, health plans have become ever more reluctant to pay for autopsies. Yet, pathologists know the value that autopsies can provide.
The immediate value comes from revealing useful insights about all the health conditions of the deceased. The long-term value comes from the ability to gather the findings across a large number of autopsies that can contribute to new knowledge about health conditions that physicians use to improve the diagnoses of different health conditions.
Thus, with the publication of this peer-reviewed study about the connection between genetic variations and stillbirth, there is the opportunity for some of the nation’s pathology societies to advocate for funding a pilot program to fund more autopsies of stillborn babies, specifically to add more knowledge about the role of gene mutations as a causative factor in stillbirths.
As the number of Hospital at Home programs increase, clinical laboratories will want to develop programs for collecting samples from patients where they live
Shortages of nurses and hospital staff, combined with pressure to lower the cost of care, are encouraging more institutions to implement hospital-in-the-home programs. One such project involves Oregon Health and Science University (OHSU), which last November began a Hospital at Home (HaH) program that enables certain patients to receive hospital-level care in the comfort of their own homes. Clinical laboratories servicing these programs will need to develop specimen collection and testing services in support of these patients.
The OHSU program can provide healthcare for eight patients simultaneously, and it has treated more than 100 patients at home since its inception. Although this number is only a small segment of OHSU’s 576 bed capacity, it does affect the overall healthcare provided by the hospital.
Under the program, basic services, such as the monitoring of vital signs—as well as some clinical laboratory work and routine imaging studies—are performed in the patient’s home. Individuals are transported to OHSU for more complex imaging or other procedures.
“Every patient we have in Hospital at Home is one who is not waiting in the emergency room or a hallway for a bed to become available in the hospital,” said Matthias Merkel, MD, PhD (above), Senior Associate Chief Medical Officer, Capacity Management and Patient Flow at OHSU, in a press release. In the same way clinical laboratories support telehealth programs, medical laboratories will need procedures for collecting specimens and testing patients participating in Hospital at Home programs as well. (Photo copyright: Oregon Health and Science University.)
OHSU’s HaH program utilizes advances in technology to connect at-home patients with physicians and nurses around the clock via a smart tablet. In addition, participating patients receive real-time monitoring and at least two daily in-person visits from nurses and paramedics that have been contracted by OHSU.
“It’s a better experience for patients, plus it increases our system’s capacity to provide care for all the people who need it,” said Darren Malinoski, MD, Chief Clinical Transformation Officer and Professor of Surgery at OHSU in the press release. “It allows us to make good on our promise to take care of the state as best we can.”
The current eligibility criteria to participate in OHSU’s Hospital at Home program include:
Patient must be over the age of 18.
Patient’s primary residence must be within a 25-mile radius of the OHSU hospital.
Inpatient hospitalization is initially required.
Patient must have a diagnosis that can be managed remotely, such as COVID-19, pneumonia, cellulitis, congestive heart failure, urinary tract infections, or pyelonephritis.
Malinoski feels that OHSU’s HaH program is ready to expand. In fact, he is so confident in it he enrolled his own 83-year-old mother as one of its first patients. While undergoing treatment for lung cancer, a routine clinical checkup exposed evidence of toxicity in her blood. Typically, she would have been directly admitted to the hospital for monitoring, but instead she was entered into the HaH program.
“It was unbelievable,” stated Lesley Malinoski in the press release. “I had the feeling of being well taken care of. I was in my own home. I could cook, I could rest—anything I wanted and still have all this care.”
“They didn’t just come in and run out,” she continued. “I felt like a celebrity.”
HaH programs around the country were made possible through a federal waiver granted by the federal Centers for Medicare and Medicaid Services (CMS) in November 2020 in response to the COVID-19 pandemic.
According to the American Hospital Association (AHA), “this care delivery model has been shown to reduce costs, improve outcomes, and enhance the patient experience.”
Prior to the waiver, there were only about two dozen hospitals across the US that had HaH programs. However, as of May 20, 2022, 227 hospitals in 35 states had received a HaH waiver from CMS. This number represents nearly 4% of all hospitals in the country, according to Health Affairs.
In “Two US Studies Show Home-based Hospital Care Lowers Costs while Improving Outcomes and Patient Satisfaction,” we reported on a hospital-based home care program that involved 323 patients at Presbyterian Healthcare Services in Albuquerque, N.M. We surmised that significant growth in the number of patients treated in home-based hospital care programs would directly affect hospital-based clinical laboratories and pathology groups. Among other things, it would reduce the volume of inpatient testing while increasing the number of outpatient/outreach specimens.
And in “Australia’s ‘Hospital in the Home’ Care Model Demonstrates Major Cost Savings and Comparable Patient Outcomes,” Dark Daily saw that wider adoption of that country’s Hospital in the Home (HITH) model of patient care would directly affect pathologists and clinical laboratory managers who worked in Australia’s hospital laboratories. We reported that more HITH patients would increase the need to collect specimens in patient’s homes and transport them to a local clinical laboratory for testing, and that because they are central to the communities they serve, hospital-based medical laboratories would be well-positioned to provide this diagnostic testing.
OHSU’s overall experience with their Hospital at Home program demonstrates that such a model can be a highly successful and cost-effective method of providing patient care. It is probable that in the future, more medical institutions will create similar programs in an effort to effectively serve as many patients as possible while ensuring shorter hospital stays and rendering better healthcare outcomes. As this happens, it will give hospital-based medical laboratories an opportunity to deliver value in home-based patient care.
Findings could lead to new clinical laboratory involvement in diagnostics targeted at overweight patients
Does the SARS-CoV-2 coronavirus make us fat so it can better take over our bodies? It sounds like the plot for a science fiction horror movie! But a team of scientists in the Pacific Northwest say that is exactly what the virus does, and their findings could lead to clinical laboratories playing a role in evaluating how the virus highjacks fat cells to aid in its invasion of humans.
They found that certain types of lipids support replication of the COVID-19 virus. Their study illustrates how lipids may play a more important role in the human body than scientists previously understood.
“This is exciting work, but it’s the start of a very long journey,” said Fikadu Tafesse, PhD (left), Assistant Professor of Molecular Microbiology and Immunology, OHSU School of Medicine and corresponding author of the study in an OHSU press release. “We have an interesting observation, but we have a lot more to learn about the mechanisms of this disease.” Clinical laboratories may eventually be part of a new diagnostic process for overweight COVID-19 patients. (Photo copyright: Oregon Health and Science University.)
Does Obesity Promote COVID-19 Infection?
The OHSU and PNNL scientists performed their research by examining the effect of SARS-CoV-2 on more than 400 lipids in two different cell lines. They observed that individuals with a high body mass index (BMI) appear to be more sensitive to the COVID-19 virus.
The researchers discovered there is a tremendous shift in lipid levels in those cell lines when the virus was present, with some fats increasing by a massive 64 times! Nearly 80% of the fats in one cell line were changed by the virus and more than half of the fats were altered in the other cell line.
The lipids that were most affected by the COVID-19 virus were triglycerides which are critical to human health. Triglycerides are basically tiny bundles of fat that allow the body to store energy and maintain healthy cell membranes. When a body needs energy, these fat parcels are broken up into useful, raw materials to provide the required energy.
“Lipids are an important part of every cell. They literally hold us together by keeping our cells intact, and they’re a major source of energy storage for our bodies,” said Jennifer Kyle, PhD, in the OHSU press release. Kyle is a research scientist at PNNL who specializes in all stages of lipidomic research. “They are an attractive target for a virus,” she noted.
Stopping SARS-CoV-2 Replication
The scientists discovered that SARS-CoV-2 alters our fat-processing system by boosting the number of triglycerides in our cells and changing the body’s ability to utilize stored fat as fuel. The team also analyzed the effects of lipid levels in 24 of the virus’ 29 proteins. They identified several proteins that had a strong influence on triglyceride levels.
The team then searched databases and identified several compounds that interfered with the body’s fat-processing system by cutting off the flow of fatty fuel. They found that several of these compounds were successful at stopping the SARS-CoV-2 virus from replicating.
A synthetic organic compound known as GSK2194069, which selectively and potently inhibits fatty acid synthase (FAS), and a weight-loss medication called Orlistat, were both able to stop viral replication in the lab.
Although the scientists believe their work is an important step in understanding the SARS-CoV-2 coronavirus, they also note that their results occurred in cell culture (in vitro) and not in people (in vivo). Therefore, more research is needed to determine if the compounds will work in the same manner in human trials.
“As the virus replicates, it needs a continuous supply of energy. More triglycerides could provide that energy in the form of fatty acids. But we don’t know exactly how the virus uses these lipids to its advantage,” Tafesse said in the press release.
“Our findings fill an important gap in our understanding of host dependency factors of coronavirus infection. … In light of the evolving nature of SARS-CoV-2, it is critical that we understand the basic biology of its life cycle in order to illuminate additional avenues for protection and therapy against this global pandemic pathogen, which spreads quickly and mutates with ease,” the OHSU/PNNL scientists wrote in Nature Communications.
More research is needed to validate the findings of this study and to better understand the dynamic between lipids and SARS-CoV-2 infection. However, it is reasonable to assume that, in the future, some COVID-19 patients may require a clinical laboratory work-up to determine how the coronavirus may be hijacking their fat cells to exacerbate the illness.
Number of patients eligible for genome-driven oncology therapy is increasing, but the percentage who reportedly benefit from the therapy remains at less than 5%
Advances in precision medicine in oncology (precision oncology) are fueling the need for clinical laboratory companion diagnostic tests that help physicians choose the best treatment protocols. In fact, this is a fast-growing area of clinical diagnostics for the nation’s anatomic pathologists. However, some experts in the field of genome-based cancer treatments disagree over whether such treatments offer more hype than hope.
Prasad and his colleagues evaluated 31 US Food and Drug
Administration (FDA) approved drugs, which were “genome-targeted” or
“genome-informed” for 38 indications between 2006 and 2018. The researchers
sought to answer the question, “How many US patients with cancer are eligible
for and benefit annually from genome-targeted therapies approved by the US Food
and Drug Administration?”
They found that in 2018 only 8.33% of 609,640 patients with
metastatic cancer were eligible for genome-targeted therapy—though this was an
increase from 5.09% in 2006.
Even more telling from Prasad’s view, his research team concluded
that only 4.9% had benefited from such treatments. Prasad’s study found the
percentage of patients estimated to have benefited from genome-informed therapy
rose from 1.3% in 2006 to 6.62% in 2018.
“Although the number of patients eligible for genome-driven treatment has increased over time, these drugs have helped a minority of patients with advanced cancer,” the researchers concluded. “To accelerate progress in precision oncology, novel trial designs of genomic therapies should be developed, and broad portfolios of drug development, including immunotherapeutic and cytotoxic approaches, should be pursued.”
The graph above is based on data from a study published in Science titled, “Estimation of the Percentage of US Patients With Cancer Who Benefit from Genome-Driven Oncology,” co-authored by Vinay Prasad, MD, MPH, et al. (Image copyright: Science.)
A Value versus Volume Argument?
Hyman, who leads a team of oncologists that conduct dozens
of clinical trials and molecularly selected “basket studies” each year,
countered Prasad’s assertions by noting the increase in the number of patients
who qualify for precision oncology treatments.
As reported in Science, Hyman said during his AACR
presentation that Sloan Kettering matched 15% of the 25,000 patients’ tumors it
tested with FDA-approved drugs and 10% with drugs in clinical trials.
“I think this is certainly not hype,” he said during the
conference.
Hyman added that another 10% to 15% of patient tumors have a
DNA change that matches a potential drug tested in animals. He expects “basket”
trials to further increase the patient pool by identifying drugs that can work
for multiple tumor types.
The US National Institute of Health (NIH) describes “basket studies” as “a new sort of clinical studies to identify patients with the same kind of mutations and treat them with the same drug, irrespective of their specific cancer type. In basket studies, depending on the mutation types, patients are classified into ‘baskets.’ Targeted therapies that block that mutation are then identified and assigned to baskets where patients are treated accordingly.”
Are Expectations of Precision Medicine Exaggerated?
A profile in MIT Technology Review, titled, “The Skeptic: What Precision Medicine Revolution?,” describes Prasad’s reputation as a “professional scold” noting the 36-year-old professor’s “sharp critiques of contemporary biomedical research, including personalized medicine.” Nevertheless, Prasad is not alone in arguing that precision oncology’s promise is often exaggerated.
“Like most ‘moonshot’ medical research initiatives,
precision medicine is likely to fall short of expectations,” Joyner wrote.
“Medical problems and their underlying biology are not linear engineering
exercises and solving them is more than a matter of vision, money, and will.”
“Although some niche applications have been found for
precision medicine—and gene therapy is now becoming a reality for a few rare
diseases—the effects on public health are miniscule while the costs are astronomical,”
they wrote.
Hope for Precision Medicine Remains High
However, optimism over precision oncology among some industry leaders has not waned. Cindy Perettie, CEO of molecular information company Foundation Medicine of Cambridge, Mass., argues genome-directed treatments have reached an “inflection point.”
“Personalized cancer treatment is a possibility for more patients than ever thanks to the advent of targeted therapies,” she told Genetic Engineering and Biotechnology News. “With a growing number of new treatments—including two pan-tumor approvals—the need for broad molecular diagnostic tools to match patients with these therapies has never been greater. We continue to advance our understanding of cancer as a disease of the genome—one in which treatment decisions can be informed by insight into the genomic changes that contribute to each patient’s unique cancer.”
Prasad acknowledges genome-driven therapies are beneficial for some cancers. However, he told MIT Technology Review the data doesn’t support the “rhetoric that we’re reaching exponential growth, or that is taking off, or there’s an inflection point” signaling rapid new advancements.
“Right now, we are investing heavily in immunotherapy and heavily in genomic therapy, but in other categories of drugs, such as cytotoxic drugs, we have stopped investigating in them,” he told Medscape Medical News. “But it’s foolish to do this—we need to have the vision to look beyond the fads we live by in cancer medicine and do things in a broader way,” he added.
“So, I support broader funding because you have to sustain
efforts even when things are not in vogue if you want to make progress,” Prasad
concluded.
Is precision oncology a fad? Dark Daily has covered the advancements in precision medicine extensively over the past decade, and with the launch of our new Precision Medicine Institute website, we plan to continue reporting on further advancements in personalized medicine.
Time will tell if precision oncology can fulfill its
promise. If it does, anatomic pathologists will play an important role in
pinpointing patients most likely to benefit from genome-driven treatments.
One thing that the debate between proponents of precision
medicine in oncology and their critics makes clear is that more and better
clinical studies are needed to document the true effectiveness of target
therapies for oncology patients. Such evidence will only reinforce the
essential role that anatomic pathologists play in diagnosis, guiding
therapeutic decisions, and monitoring the progress of cancer patients.