Findings could lead to new therapies and clinical laboratory biomarkers for detecting and defeating antibiotic-resistant bacteria
Once again, new research shows that human gut bacteria (microbiota) may be useful in fighting antibiotic-resistant bacterial infections. The study findings could provide new therapeutics and clinical laboratory biomarkers for diagnosing and treating severe gastrointestinal disorders.
Antibiotic-resistant bacterial infections often appear in patients with chronic intestinal conditions and in those with long-term antibiotic use. Enterobacteriaceae is a large family of gram-negative bacteria that includes more than 30 genera and over 100 species.
“Despite two decades of microbiome research, we are just beginning to understand how to define health-promoting features of the gut microbiome,” said Marie-Madlen Pust, PhD, a computational postdoctoral researcher at the Broad Institute and co-first author of the paper, in the news release.
“Part of the challenge is that each person’s microbiome is unique. This collaborative effort allowed us to functionally characterize the different mechanisms of action these bacteria use to reduce pathogen load and gut inflammation,” she added.
The researchers identified a way to treat patients infected by antibiotic-resistant strains of bacteria that does not involve antibiotics. Should further research validate these early findings, this could be a viable approach to treating patients with this condition.
“Microbiome studies can often consist of analyzing collections of genetic sequences, without understanding what each gene does or why certain microbes are beneficial,” said Ramnik Xavier, MD (above), director of Broad Institute’s immunology program, co-director of the infectious disease and microbiome program, and co-senior author on the study, in a news release. “Trying to uncover that function is the next frontier, and this is a nice first step towards figuring out how microbial metabolites influence health and inflammation.” Clinical laboratories that test for intestinal conditions caused by antibiotic resistance will want to follow the Broad Institute’s research. (Photo copyright: Broad Institute.)
Suppressing Growth of Antibiotic-resistant Bacteria
To perform their research, the scientists isolated about 40 strains of bacteria from the stools of five healthy fecal donors. They then used those stool samples in fecal microbiota transplants to treat mice that had been infected with either Escherichia coli (E. coli) or Klebsiella, both forms of Enterobacteriaceae. The scientists tested different combinations of the 40 strains and identified 18 that suppressed the growth of Enterobacteriaceae.
“Antibiotic-resistant Enterobacteriaceae such as E. coli and Klebsiella bacteria are common in hospitals, where they can proliferate in the gut of patients and cause dangerous systemic infections that are difficult to treat. Some research suggests that Enterobacteriaceae also perpetuates inflammation in the intestine and infection by other microbes,” the Broad Institute news release notes.
The researchers discovered that Klebsiella changed the gene expression in carbohydrate uptake and metabolism in the Klebsiella-infected mice that were treated with the 18 beneficial strains. The gene expression included the downregulating of gluconate kinase and transporter genes, which revealed there is increased competition among gut bacteria for nutrients.
When combined, these 18 strains alleviated inflammation in the guts of the treated mice by depriving the harmful gut bacteria of carbohydrates. This non-antibiotic approach also prevented harmful bacteria from colonizing in the gut.
“In partnership with the Broad’s Metabolomics Platform, led by senior director and study co-author Clary Clish, PhD, they analyzed samples from pediatric patients with ulcerative colitis, looking for the presence of alternate gluconate pathway genes of gut microbes and fecal gluconate levels. They found higher levels of gluconate linked to more gluconate-consuming Enterobacteriaceae in samples from pediatric patients with ongoing inflammation, indicated by high levels of the protein calprotectin,” the study authors wrote in Nature.
“Together, the findings suggest that Enterobacteriaceae processes gluconate as a key nutrient and contributes to inflammation in patients. But when a gut microbiome includes the 18 helpful strains, they likely compete with Enterobacteriaceae for gluconate and other nutrient sources, limiting the proliferation of the harmful bacteria,” the scientists concluded.
Promising New Bacterial Therapies
This research could ultimately lead to the development of fecal microbiota transplants for individuals to eradicate antibiotic-resistant bacteria in a more objective and specific manner, with fewer side effects than current treatments.
“Harnessing these activities in the form of live bacterial therapies may represent a promising solution to combat the growing threat of proinflammatory, antimicrobial-resistant Enterobacteriaceae infection,” the scientists wrote in Nature.
According to the news release, they plan to continue research to “uncover the identity and function of unknown metabolites that contribute to gut health and inflammation.” The team hopes to discover how different bacteria compete with each other, and to develop microbial therapeutics that improve gut microbiome and curb bacterial infections.
More studies are needed to prove the efficacy of this type of fecal bacterial treatment. However, this research demonstrates how using nano processes enabled by new technologies to identify the actual work of proteins, RNA, and DNA in the body cheaply, faster, and with greater precision, will open doors to both therapeutic and diagnostic clinical laboratory biomarkers.
Though PCR clinical laboratory testing is widely used, some scientists are concerned its specificity may limit the ability to identify all variants of bird flu in wastewater
Wastewater testing of infectious agents appears to be here to stay. At the same time, there are differences of opinion about which methodologies and clinical laboratory tests are best suited to screen for specific contagions in wastewater. One such contagion is avian influenza, the virus that causes bird flu.
Wastewater testing by public health officials became a valuable tool during the COVID-19 pandemic and has now become a common method for detecting other diseases as well. For example, earlier this year, scientists used wastewater testing to learn how the H5N1 variant of the bird flu virus was advancing among dairy herds across the country.
In late March, the bird flu was first detected in dairy cattle in Texas, prompting scientists to begin examining wastewater samples to track the virus. Some researchers, however, expressed concerns about the ability of sewage test assays to detect all variants of certain diseases.
“Right now we are using these sort of broad tests to test for influenza A viruses,” Denis Nash, PhD, Distinguished Professor of Epidemiology at City University of New York (CUNY) and Executive Director of CUNY’s Institute for Implementation Science in Population Health (SPH), told the Los Angeles Times. “It’s possible there are some locations around the country where the primers being used in these tests might not work for H5N1.” Clinical laboratory PCR genetic testing is most commonly used to screen for viruses in wastewater. (Photo copyright: CUNY SPH.)
Effectiveness of PCR Wastewater Testing
Polymerase chain reaction (PCR) tests are most commonly used to distinguish genetic material related to a specific illness such as the flu virus. For PCR tests to correctly identify a virus, the tests must be designed to look for a specific subtype. The two most prevalent human influenza A viruses are known as H1N1 (swine flu) and H3N2, which was responsible for the 1968 pandemic that killed a million people worldwide. The “H” stands for hemagglutinin and the “N” for neuraminidase.
Hemagglutinin is a glycoprotein that assists the virus to attach to and infect host cells. Neuraminidase is an enzyme found in many pathogenic or symbiotic microorganisms that separates the links between neuraminic acids in various molecules.
Avian flu is also an influenza A virus, but it has the subtype H5N1. Although human and bird flu viruses both contain the N1 signal, they do not share an H. Some scientists fear that—in cases where a PCR test only looks for H1 and H3 in wastewater—that test could miss the bird flu altogether.
“We don’t have any evidence of that. It does seem like we’re at a broad enough level that we don’t have any evidence that we would not pick up H5,” Jonathan Yoder, Deputy Director, Infectious Disease Readiness and Innovation at the US Centers for Disease Control and Prevention (CDC) told the Los Angeles Times.
The CDC asserts current genetic testing methods are standardized and will detect the bird flu. Yoder also affirmed the tests being used at all the testing sites are the same assay, based on information the CDC has published regarding testing for influenza A viruses.
Genetic Sequencing Finds H5N1 in Texas Wastewater
In an article published on the preprint server medRxiv titled, “Virome Sequencing Identifies H5N1 Avian Influenza in Wastewater from Nine Cities,” the authors wrote, “using an agnostic, hybrid-capture sequencing approach, we report the detection of H5N1 in wastewater in nine Texas cities, with a total catchment area population in the millions, over a two-month period from March 4th to April 25th, 2024.”
The authors added, “Although human to human transmission is rare, infection has been fatal in nearly half of patients who have contracted the virus in past outbreaks. The increasing presence of the virus in domesticated animals raises substantial concerns that viral adaptation to immunologically naïve humans may result in the next flu pandemic.”
“So, it’s not just targeting one virus—or one of several viruses—as one does with PCR testing,” Eric Boerwinkle, PhD, Dean of the UTHealth Houston School of Public Health told the LA Times. “We’re actually in a very complex mixture, which is wastewater, pulling down viruses and sequencing them. What’s critical here is it’s very specific to H5N1.”
Epidemiologist Blake Hanson, PhD, Assistant Professor, Department of Epidemiology, Human Genetics, and Environmental Sciences at the UT Health Houston Graduate School of Biomedical Science, agreed with Boerwinkle that though the PCR-based methodology is highly effective at detecting avian flu in wastewater samples, the testing can do more.
“We have the ability to look at the representation of the entire genome, not just a marker component of it. And so that has allowed us to look at H5N1, differentiate it from some of our seasonal fluids like H1N1 and H3N2,” Hanson told the LA Times. “It’s what gave us high confidence that it is entirely H5N1, whereas the other papers are using a part of the H5 gene as a marker for H5.”
Human or Animal Sources
Both Boerwinkle and Hanson are epidemiologists in the team studying wastewater samples for H5N1 in Texas. They are not sure where the virus originated but are fairly certain it did not come from humans.
“Texas is really a confluence of a couple of different flyways for migratory birds, and Texas is also an agricultural state, despite having quite large cities,” Boerwinkle noted. “It’s probably correct that if you had to put your dime and gamble what was happening, it’s probably coming from not just one source but from multiple sources. We have no reason to think that one source is more likely any one of those things.”
“Because we are looking at the entirety of the genome, when we look at the single human H5N1 case, the genomic sequence has a hallmark amino acid change, compared to all of the cattle from that same time point,” Hanson said. “We do not see that hallmark amino acid present in any of our sequencing data. And we’ve looked very carefully for that, which gives us some confidence that we’re not seeing human-human transmission.”
CDC Updates on Bird Flu
In its weekly updates on the bird flu situation, the CDC reported that 48 states have outbreaks in poultry and 14 states have avian flu outbreaks in dairy cows. More than 238 dairy herds have been affected and, as of September 20, over 100 million poultry have been affected by the disease.
In addition, the CDC monitored more than 4,900 people who came into contact with an infected animal. Though about 230 of those individuals have been tested for the disease, there have only been a total of 14 reported human cases in the US.
The CDC posts information specifically for laboratory workers, healthcare providers, and veterinarians on its website.
The CDC also states that the threat from avian flu to the general public is low. Individuals at an increased risk for infection include people who work around infected animals and those who consume products containing raw, unpasteurized cow’s milk.
Symptoms of H5N1 in humans may include fever or chills, cough, headaches, muscle or body aches, runny or stuffy nose, tiredness and shortness of breath. Symptoms typically surface two to eight days after exposure.
Scientists and researchers have been seeking a reliable clinical laboratory test for disease organisms in a fast, accurate, and cost-effective manner. Wastewater testing of infectious agents could fulfill those goals and appears to be a technology that will continue to be used for tracking disease.
Study shows that computer analysis of clinical laboratory test results has improved greatly in recent years
Studies using “big data” continue to show how combining different types of healthcare information can generate insights not available with smaller datasets. In this case, researchers at Washington University School of Medicine (WashU Medicine), St. Louis, Mo., determined that—by using the results from nine different types of clinical laboratory tests—they could correlate those test results to younger people who had “aged faster” and had developed cancer earlier than usual, according to CNN.
“Accumulating evidence suggests that the younger generations may be aging more swiftly than anticipated, likely due to earlier exposure to various risk factors and environmental insults. However, the impact of accelerated aging on early-onset cancer development remains unclear,” said Ruiyi Tian, PhD candidate at WashU Medicine’s Yin Cao Lab in an American Association for Cancer Research (AACR) news release.
The scientists presented their findings, which have not yet been published, at the AACR’s annual meeting held in April. Tian and the other researchers “hypothesized that increased biological age, indicative of accelerated aging, may contribute to the development of early-onset cancers, often defined as cancers diagnosed in adults younger than 55 years. In contrast to chronological age—which measures how long a person has been alive—biological age refers to the condition of a person’s body and physiological processes and is considered modifiable,” AACR noted in a news release.
“We all know cancer is an aging disease. However, it is really coming to a younger population. So, whether we can use the well-developed concept of biological aging to apply that to the younger generation is a really untouched area,” Yin Cao, ScD MPH (above), associate professor of surgery and associate professor of medicine at Washington University School of Medicine in St. Louis, and senior author of the study, told CNN. Analysis of clinical laboratory test results using computer algorithms continues to show value for new research into deadly diseases. (Photo copyright: Washington University.)
Lab Tests Share Insights about Aging
To acquire the data they needed for their research, the WashU Medicine scientists turned to the UK Biobank, a biomedical and research resource with genetic and health information on half a million UK residents.
The researchers reviewed the medical records of 148,724 biobank participants, age 37 to 54, focusing on nine blood-based biomarkers that “have been shown to correlate with biological age,” CNN reported. Those biomarkers are:
White blood cells: counts in “the high end of the normal range” may relate to “greater age.”
According to CNN, the researchers “plugged” the nine values into an algorithm called PhenoAge. Using the algorithm they compared the biological ages with each person’s actual chronological age to determine “accelerated aging.” They then consulted cancer registries to capture data on those in the study who were diagnosed with cancer before age 55. They found 3,200 cases.
Young Adults Aging Faster than Earlier Generations
According to the AACR news release, the WashU Medicine study found that:
“Individuals born in or after 1965 had a 17% higher likelihood of accelerated aging than those born between 1950 and 1954.
“Each standard deviation increase in accelerated aging was associated with a 42% increased risk of early-onset lung cancer, a 22% increased risk of early-onset gastrointestinal cancer, and a 36% increased risk of early-onset uterine cancer.
“Accelerated aging did not significantly impact the risk of late-onset lung cancer (defined here as cancer diagnosed after age 55), but it was associated with a 16% and 23% increased risk of late-onset gastrointestinal and uterine cancers, respectively.”
“We speculate that common pathways, such as chronic inflammation and cellular senescence, may link accelerated aging to the development of early-onset cancers,” the study’s principal investigator Yin Cao, ScD, MPH, associate professor of surgery and associate professor of medicine at WashU Medicine, told The Hill.
“Historically, both cancer and aging have been viewed primarily as concerns for older populations. The realization that cancer, and now aging, are becoming significant issues for younger demographics over the past decades was unexpected,” Tian told Fox News.
More Screenings, Further Analysis
The study’s results may suggest a change in clinical laboratory screenings for younger people.
In future studies, WashU Medicine scientists may aim to include groups of greater diversity and explore why people are aging faster and have risk of early-onset cancers.
“There is room to improve using better technologies. Looking at the bigger picture, the aging concept can be applied to younger people to include cancers, cardiovascular disease, and diabetes,” Cao told Discover Magazine.
While more research is needed, use of the UK’s Biobank of healthcare data—including clinical laboratory test results—enabled the WashU Medicine researchers to determine that accelerated aging among young adults is happening with some regularity. This shows that capabilities in computer analysis are gaining more refined capabilities and are able to tease out insights impossible to achieve with earlier generations of analytical software.
These findings should inspire clinical laboratory professionals and pathologists to look for opportunities to collaborate in healthcare big data projects involving their patients and the communities they serve.
Declining health of UK’s population also affecting performance of the country’s national health service, report notes
England’s National Health Service (NHS) is “in serious trouble” due to long waiting times, outdated technology, misallocated resources, and numerous other problems, with dire consequences for the country’s populace. That’s according to a new report by NHS surgeon and former Health Minister Lord Ara Darzi, OM KBE FRS FMedSci HonFREng, who was tasked by the United Kingdom’s new Labor government to investigate the ailing healthcare system. His report may contain lessons for US healthcare—including clinical laboratories—as well.
“Although I have worked in the NHS for more than 30 years, I have been shocked by what I have found during this investigation—not just in the health service but in the state of the nation’s health,” Darzi stated in a UK government press release. “We want to deliver high quality care for all but far too many people are waiting for too long and in too many clinical areas, quality of care has gone backwards.”
Many of the problems he identified relate to wait times.
“From access to GPs (general practitioners) and to community and mental health services, on to accident and emergency, and then to waits not just for more routine surgery and treatment but for cancer and cardiac services, waiting time targets are being missed,” he wrote in his report.
For example, “as of June 2024, more than one million people were waiting for community services, including more than 50,000 people who had been waiting for over a year, 80% of whom are children and young people,” he wrote.
Accident and emergency care (A/E) “is in an awful state,” the report noted, “with A/E queues more than doubling from an average of just under 40 people on a typical evening in April 2009 to over 100 in April 2024. One in 10 patients are now waiting for 12 hours or more.”
“In the last 15 years, the NHS was hit by three shocks—austerity and starvation of investment, confusion caused by top-down reorganization, and then the pandemic which came with resilience at an all-time low. Two out of three of those shocks were choices made in Westminster,” said NHS surgeon and former Health Minister Lord Ara Darzi in a government press release. “It took more than a decade for the NHS to fall into disrepair so it’s going to take time to fix it. But we in the NHS have turned things around before, and I’m confident we will do it again.” (Photo copyright: Health Data Research UK.)
Delays in Other Critical Tests
Genetic test results are lagging as well. “In 2024, more than 35,000 genomic tests are being completed each month but only around 60% on time,” Darzi wrote.
He also noted that “only around 5% of eligible patients with brain cancer are able to access whole genome sequencing (WGS), which is important for treatment selection.” Just two-thirds (65.8%) get their first treatment within 62 days, and more than 30% wait more than 31 days for radical radiotherapy, according to the report.
Overall, “the UK has appreciably higher cancer mortality rates than other countries, with no progress whatsoever made in diagnosing cancer at stage one and two between 2013 and 2021,” he wrote.
Patients have also experienced delays in access to cardiovascular treatment. For example, in 2013-2014, high-risk heart attack patients waited an average of 114 minutes for intervention to unblock an artery, Darzi noted in his report. However, in 2022-2023, the average time was 146 minutes, a 28% increase.
“For the most part, once people are in the system, they receive high quality care,” he wrote. “But there are some important areas of concerns, such as maternity care, where there have been a succession of scandals and inquiries.”
Key Factors Leading to Delays
Darzi pointed to four key factors that have led to the problems.
Lack of funding. “The 2010s was the most austere decade since the NHS was founded, with spending growing at around 1% in real terms,” Darzi wrote, compared with a long-term average of 3.4%.
One result was that administrators took funds from the capital budget to cover day-to-day needs, leading to “crumbling buildings that hit productivity,” he noted.
“The backlog maintenance bill now stands at more than £11.6 billion and a lack of capital means that there are too many outdated scanners, too little automation, and parts of the NHS are yet to enter the digital era,” he wrote.
The COVID-19 pandemic. Given the preceding “decade of austerity,” NHS had fewer resources to deal with the crisis than most other high-income health systems, he wrote. As a result, NHS “delayed, cancelled, or postponed far more routine care during the pandemic than any comparable health system.” This led to “a bigger backlog than other health systems.”
Lack of patient and staff engagement. Patient satisfaction “has declined and the number of complaints has increased, while patients are less empowered to make choices about their care,” he wrote. In addition, “too many staff have become disengaged, and there are distressingly high-levels of sickness absence—as much as one working month a year for each nurse and each midwife working in the NHS.”
Management structures and systems. Darzi laid considerable blame on the UK’s Health and Social Care Act of 2012, which led to what he described as “a costly and distracting process of almost constant reorganization of the ‘headquarters’ and ‘regulatory’ functions of the NHS.”
One consequence, he wrote, is that too many clinicians have been deployed in hospitals instead of community-based care, despite years of promises by successive governments to put more emphasis on the latter.
National Health in Decline
Along with issues within the NHS, “the health of the nation has deteriorated and that impacts its performance,” Darzi wrote. “There has been a surge in multiple long-term conditions, and, particularly among children and young people, in mental health needs. Fewer children are getting the immunizations they need to protect their health, and fewer adults are participating in some of the key screening programs, such as for breast cancer.”
Darzi’s investigation included frontline visits to NHS facilities as well as focus groups with NHS staff and patients, the press release states. He also consulted an expert reference group consisting of more than 70 organizations and examined analyses from NHS England, the UK’s Department of Health and Social Care, and external groups.
It is interesting that there is no mention of anatomic pathology and medical laboratory testing services in Lord Darzi’s report. As reported in recent years by new outlets in the United Kingdom, delays in cancer diagnoses—often as long as six months—were severe enough that, in 2018, the NHS announced funding for a program to create a national digital pathology network to improve productivity of pathologists and shorten wait times for the results of cancer tests.
The NIH’s Researching COVID to Enhance Recovery (RECOVER) Initiative used a cohort study of more than 10,000 individuals with and without previous COVID-19 diagnoses and compared samples using 25 common laboratory tests in hopes a useful biomarker could be identified. They were unsuccessful.
Long COVID—or PASC—is an umbrella term for those with persistent post-COVID infection symptoms that negatively impact quality of life. Though it affects millions worldwide and has been called a major public health burden, the NIH/Langone study scientists noted one glaring problem: PASC is defined differently in the major tests they studied. This makes consistent diagnoses difficult.
The study brought to light possible roadblocks that prevented biomarker identification.
“This study is an important step toward defining long COVID beyond any one individual symptom,” said study author Leora Horwitz, MD (above), director of the Center for Healthcare Innovation and Delivery Science and co-principal investigator for the RECOVER CSC at NYU Langone, in a Langone Health news release. “This definition—which may evolve over time—will serve as a critical foundation for scientific discovery and treatment design.” In the future, clinical laboratories may be tasked with finding combinations of routine and reference tests that, together, enable a more precise and earlier diagnosis of long COVID. (Photo copyright: Yale School of Medicine.)
NIH/Langone Study Details
“The study … examined 25 routinely used and standardized laboratory tests chosen based on availability across institutions, prior literature, and clinical experience. These tests were conducted prospectively in laboratories that are certified by the Clinical Laboratory Improvement Amendments (CLIA). The samples were collected from 10,094 RECOVER-Adult participants, representing a diverse cohort from all over the US,” Inside Precision Medicine reported.
However, the scientists found no clinical laboratory “value” among the 25 tests examined that “reliably indicate previous infection, PASC, or the particular cluster type of PASC,” Inside Precision Medicine noted, adding that “Although some minor differences in the results of specific laboratory tests attempted to differentiate between individuals with and without a history of infection, these findings were generally clinically meaningless.”
“In a cohort study of more than 10,000 participants with and without prior SARS-CoV-2 infection, we found no evidence that any of 25 routine clinical laboratory values provide a reliable biomarker of prior infection, PASC, or the specific type of PASC cluster. … Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC,” the study authors wrote in Annals of Internal Medicine.
In addition to a vague definition of PASC, the NIH/Langone researchers noted a few other potential problems identifying a biomarker from the research.
“Use of only selected biomarkers, choice of comparison groups, if any (people who have recovered from PASC or healthy control participants); duration of symptoms; types of symptoms or phenotypes; and patient population features, such as sex, age, race, vaccination status, comorbidities, and severity of initial infection,” could be a cause for ambiguous results, the scientists wrote.
Future Research
“Understanding the basic biological underpinnings of persistent symptoms after SARS-CoV-2 infection will likely require a rigorous focus on investigations beyond routine clinical laboratory studies (for example, transcriptomics, proteomics, metabolomics) to identify novel biomarkers,” the study authors wrote in Annals of Internal Medicine.
“Our challenge is to discover biomarkers that can help us quickly and accurately diagnose long COVID to ensure people struggling with this disease receive the most appropriate care as soon as possible,” said David Goff, MD, PhD, director of the division of cardiovascular sciences at the NIH’s National Heart, Lung, and Blood Institute, in an NHLBI news release. “Long COVID symptoms can prevent someone from returning to work or school, and may even make everyday tasks a burden, so the ability for rapid diagnosis is key.”
“Approximately one in 20 US adults reported persisting symptoms after COVID-19 in June 2024, with 1.4% reporting significant limitations,” the NIH/Langone scientists wrote in their published study.
Astute clinical laboratory scientists will recognize this as possible future diagnostic testing. There is no shortage of need.
Though not biomarkers per se, these scores for certain genetic traits may someday be used by clinical laboratories to identify individuals’ risk for specific diseases
Can polygenic risk scores (a number that denotes a person’s genetic predisposition for certain traits) do a better job at predicting the likelihood of developing specific diseases, perhaps even before the onset of symptoms? Researchers at the Broad Institute of MIT and Harvard (Broad Institute) believe so, and their study could have implications for clinical laboratories nationwide.
In cooperation with medical centers across the US, the scientists “optimized 10 polygenic scores for use in clinical research as part of a study on how to implement genetic risk prediction for patients,” according to a Broad Institute news release.
The research team “selected, optimized, and validated the tests for 10 common diseases [selected from a total of 23 conditions], including heart disease, breast cancer, and type 2 diabetes. They also calibrated the tests for use in people with non-European ancestries,” the news release notes.
As these markers for genetic risk become better understood they may work their way into clinical practice. This could mean clinical laboratories will have a role in sequencing patients’ DNA to provide physicians with information about the probability of a patient’s elevated genetic risk for certain conditions.
However, the effectiveness of polygenic risk scores has faced challenges among diverse populations, according to the news release, which also noted a need to appropriately guide clinicians in use of the scores.
“With this work, we’ve taken the first steps toward showing the potential strength and power of these scores across a diverse population,” said Niall Lennon, PhD (above), Chief Scientific Officer of Broad Clinical Labs. “We hope in the future this kind of information can be used in preventive medicine to help people take actions that lower their risk of disease.” Clinical laboratories may eventually be tasked with performing DNA sequencing to determine potential genetic risk for certain diseases. (Photo copyright: Broad Institute.)
Polygenic Scores Need to Reflect Diversity
“There have been a lot of ongoing conversations and debates about polygenic risk scores and their utility and applicability in the clinical setting,” said Niall Lennon, PhD, Chair and Chief Scientific Officer of Broad Clinical Labs and first author of the study, in the news release. However, he added, “It was important that we weren’t giving people results that they couldn’t do anything about.”
In the paper, Lennon and colleagues explained polygenic risk scores “aggregate the effects of many genetic risk variants” to identify a person’s genetic predisposition for a certain disease or phenotype.
“But their development and application to clinical care, particularly among ancestrally diverse individuals, present substantial challenges,” they noted. “Clinical use of polygenic risk scores may ultimately prevent disease or enable its detection at earlier, more treatable stages.”
The scientists set a research goal to “optimize polygenic risk scores for a diversity of people.”
While performing the polygenic risk score testing on participants, Broad Clinical Labs focused on 10 conditions—including cardiometabolic diseases and cancer—selected by the research team based on “polygenic risk score performance, medical actionability, and clinical utility,” the Nature Medicine paper explained.
For each condition, the researchers:
Identified “exact spots in the genome that they would analyze to calculate the risk score.”
Used information from the NIH’s All of Us Research Program to “create a model to calibrate a person’s polygenic risk score according to that individual’s genetic ancestry.”
The All of Us program, which aims to collect health information from one million US residents, has three times more people of non-European ancestry than other data sources developing genetic risk scores, HealthDay News reported.
20% of Study Participants Showed High Risk for Disease
To complete their studies, Broad Institute researchers processed a diverse group of eMERGE participants to determine their clinical polygenic risk scores for each of the 10 diseases between July 2022 and August 2023.
Listed below are all conditions studied, as well as the number of participants involved in each study and the number of people with scores indicating high risk of the disease, according to their published paper:
Over 500 people (about 20%) of the 2,500 participants, had high risk for at least one of the 10 targeted diseases, the study found.
Participants in the study self-reported their race/ancestry as follows, according to the paper:
White: 32.8%
Black: 32.8%
Hispanic: 25.4%
Asian: 5%
American Indian: 1.5%
Middle Eastern: 0.9%
No selection: 0.8%
“We can’t fix all biases in the risk scores, but we can make sure that if a person is in a high-risk group for a disease, they’ll get identified as high risk regardless of what their genetic ancestry is,” Lennon said.
Further Studies, Scoring Implications
With 10 tests in hand, Broad Clinical Labs plans to calculate risk scores for all 25,000 people in the eMERGE network. The researchers also aim to conduct follow-up studies to discover what role polygenic risk scores may play in patients’ overall healthcare.
“Ultimately, the network wants to know what it means for a person to receive information that says they’re at high risk for one of these diseases,” Lennon said.
The researchers’ findings about disease risk are likely also relevant to healthcare systems, which want care teams to make earlier, pre-symptomatic diagnosis to keep patients healthy.
Clinical laboratory leaders may want to follow Broad Clinical Labs’ studies as they perform the 10 genetic tests and capture information about what participants may be willing to do—based on risk scores—to lower their risk for deadly diseases.
